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CN105854022A - Drug carrier capable of slowly releasing drug - Google Patents

Drug carrier capable of slowly releasing drug Download PDF

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Publication number
CN105854022A
CN105854022A CN201610257682.3A CN201610257682A CN105854022A CN 105854022 A CN105854022 A CN 105854022A CN 201610257682 A CN201610257682 A CN 201610257682A CN 105854022 A CN105854022 A CN 105854022A
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CN
China
Prior art keywords
acid
water
gram
pharmaceutical carrier
swellable
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Pending
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CN201610257682.3A
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Chinese (zh)
Inventor
钟术光
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Individual
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Individual
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Publication date
Priority claimed from CN 201110141924 external-priority patent/CN102210871A/en
Application filed by Individual filed Critical Individual
Priority claimed from CN201210171430.0A external-priority patent/CN102698277B/en
Publication of CN105854022A publication Critical patent/CN105854022A/en
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Biophysics (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention discloses a drug carrier capable of slowly releasing drug, and the performance of the drug carrier is improved. The drug carrier comprises (a) an aliphatic additive with an in vivo and vitro melting point higher than 37 DEG C, (b) water-soluble, low-viscosity and non-irritating additive granules, (c) a water-swelling and water-insoluble acidic (or alkaline) polymer, (d) an alkaline (or acidic) material, (e) a water-soluble surface active agent, and (f) a medicine. The drug carrier has a better drug release characteristic, higher 'salt poisoning' resisting effect and better drug release uniformity, and better alleviates or solves the problem of 'releasing at the tail end'; the drug carrier is lower in mucous membrane irritation and better in biocompatibility, and does not easily cause the safety problem of burst drug release, dosage pouring release or the like in drug use.

Description

The pharmaceutical carrier of slow-release
Technical field
The present invention relates to the pharmaceutical carrier of a kind of slow-release.More specifically, the present invention relates to the slow release of a kind of performance improvement and releases The pharmaceutical carrier of medicine, inside and outside this pharmaceutical carrier occlusion body, fusing point is more than the aliphatic additive, water-soluble low of temperature 37 DEG C Viscosity additive granules, water-insoluble acidity (or the alkalescence) polymer of water-swellable, alkalescence (or alkalescence) excipient (material), water soluble surfactant active and medicine.
Technical background
Slow releasing preparation such as slow-release suppository, especially with the preparation that oil material is main slow-release material, often shows so-called " end release " problem, i.e. medicine early stage release is fast, and mid-term is the most slack-off, and the later stage is partially slow, the most usually in regulation (or phase Hope) action time in the most a part of medicine remain in substrate, it is impossible to play intended acting on, show as " release in other words Before speed fast after slow " and problem such as " end release is incomplete ".People are to having made some technological improvements, but usually also have some not Gratifying local, need to carry out technological improvement.
Such as, United States Patent (USP) US4,344,968 disclose a kind of pharmaceutical carrier making suppository, and it is a kind of that this pharmaceutical carrier comprises (a) Fusing point is more than the fatty glyceride of temperature 37 DEG C；(b) a kind of water soluble, low viscosity, non-irritating organic compound, institute The particle diameter of the organic compound stated is less than 28 mesh (about 600 microns, Tyler standard), and the viscosity of its solution of 2% is little In 300cps；C () a kind of particle diameter contacts the organic polymer of swellable less than 28 purposes with water；D () a kind of soluble surface live Property agent.Organic polymer in this pharmaceutical carrier is selected generally from sodium polyacrylate.
The problem of technology before it has been made certain technological improvement by this technology, still has some more serious defects, still has relatively Big room for improvement, such as " release is first quick and back slow " and " end release is incomplete " problem.Additionally, also have other more serious defects, As the pharmaceutical carrier medicine disclosed in this technology is released
It is believed that produce these gap main causes be the pharmaceutical carrier disclosed in this technology typically select contact swellable with water The organic polymer of work " disintegrating agent ", such as sodium polyacrylate etc., the most easily there is " salt poisoning " effect and " gel blockage " effect Should, particularly (can be by the counteracting force of substrate four wall when i.e. expanding), " salt poisoning " effect (lower section herein under artesian condition In implication herewith) refer to contact the organic polymer such as sodium polyacrylate etc. of swellable with water, particularly under artesian condition, Water suction in body fluid in the aqueous solution containing electrolyte such as normal saline, urine, menses, vagina, the body fluid in rectum is molten The phenomenon that swollen ability is substantially reduced relative to deionized water, " gel blockage " effect (implication in lower section is herewith) refers to herein Contact with water that the organic polymer particle of swellable is wetted and particle is swelling, it is suppressed that fluid is to other region of particle such as Interior shifting also inhibits the most swelling phenomenon of particle, just as forming the phenomenon of so-called " not and open dough ", especially It is will be more serious under artesian condition.After the main cause of generation gel blocking phenomenon is swelling, particularly at artesian condition Under, the space between granule is reduced and viscosity increases.There is " salt in the organic polymer of the work " disintegrating agent " contacting swellable with water Poisoning " after effect and " gel blockage " effect, swelling behavior is with the raw bigger change of secondary, and some polymer particles graininesses fail to have Effect expands or fully expands, so that pharmaceutical carrier fails substantially or completely disintegrate, thus produces pharmaceutical carrier " after release is the fastest Slowly " with the problem such as " end release is incomplete ", drug release behavior also becomes unstable, significantly by the shadow of electrolyte solution Ring.
It addition, the pharmaceutical carrier disclosed in this technology also shows certain bio-incompatibility, as zest, patient feel local Discomfort (such as sensation of pricking).It is believed that a major reason is, the organic polymer contacting swellable with water that this technology is typically selected Thing, as sodium polyacrylate has the water absorbing capacity of rapid high intensity, that can make to contact with this pharmaceutical carrier or with this pharmaceutical carrier The quick dehydration of neighbouring mucosa, causes local " being dried ", thus causes zest, patient to feel the discomfort (such as sensation of pricking) of local Deng bio-incompatibility problem.
It needs to be noted the pharmaceutical carrier disclosed in this technology it is also possible that burst drug release dosage in other words inclines releases (dose-dumping) the drug safety problem such as.Such as pharmaceutical carrier comprise more amount in body cavity with during bioresorbable with regard to liquid (this kind of fatty glyceride usually carbon number is the pure of C10～C12 or mixing-in fat to the fatty glyceride changed or melt Acid, such as capric monoglyceride and lauric monoglyceride) or surfactant will make pharmaceutical carrier in body cavity and body Liquefaction or thawing during liquid contact, thus cause burst drug release dosage in other words to incline and release (dose-dumping).
Therefore, reality also needs to it is carried out further technological improvement.
Summary of the invention
The present invention is directed to defect and the other defect of above-mentioned technology, it is carried out technological improvement so that it is Release Performance can obtain more Big improvement.Particularly, it is simply that will reach any one or more or whole following goal of the invention:
One of the main object of the present invention is just to provide the pharmaceutical carrier of the slow-release of a kind of performance improvement, pharmaceutical carrier release Process is affected by electrolyte solution to be further improved, and has more preferable Release Performance, as showed in pharmaceutical carrier drug release process Problems such as " release are first quick and back slow " or " end release is incomplete " that go out is alleviated or is solved.
One of the main object of the present invention is just to provide the pharmaceutical carrier of the slow-release of a kind of performance improvement, the life of pharmaceutical carrier The thing compatibility is enhanced.
One of the main object of the present invention is just to provide the pharmaceutical carrier of the slow-release of a kind of performance improvement, and pharmaceutical carrier is difficult to Occur that burst drug release dosage in other words inclines drug safety problems such as releasing (dose-dumping).
Other purposes see description below.
In order to realize above-mentioned upper purpose, through the research repeatedly of inventor, it is finally completed the present invention.
The present invention relates to the external fusing point of a kind of performance improvement and be above temperature 37 with fusing point during bioresorbable in body cavity DEG C the pharmaceutical carrier of slow-release, this pharmaceutical carrier comprise (a) a kind of pharmaceutically acceptable fusing point more than temperature 37 DEG C and With fusing point during bioresorbable also above the aliphatic additive of temperature 37 DEG C in body cavity；(b) a kind of pharmaceutically acceptable, Additive water-soluble, low viscous, its granule largest cross-sectional sized is less than about 600 microns of (about 28 mesh, Tyler And the viscosity of its solution of 2% is less than 300 centipoises (mPa s) standard),；C () is a kind of pharmaceutically acceptable, water-swellable Property and water-insoluble acidic polymer, its pKa is about 2～about 12；The solid excipient of (d) a kind of pharmaceutically acceptable alkalescence For the basic excipients of liquid, a kind of pharmaceutically acceptable water-swellable at agent and/or the room temperature 25 DEG C that is cured And water-insoluble alkaline polymer；(e) a kind of pharmaceutically acceptable water miscible surfactant；(f) a kind of medicine.
Or, (a) a kind of pharmaceutically acceptable fusing point more than temperature 37 DEG C and in body cavity with fusing point during bioresorbable also Aliphatic additive higher than temperature 37 DEG C；(b) a kind of water soluble, additive low viscous, pharmaceutically acceptable, its Grain largest cross-sectional sized is less than about 600 microns (about 28 mesh, Tyler standard), and the viscosity of its solution of 2% is less than 300 Centipoise (mPa s)；C () a kind of pharmaceutically acceptable, water-swellable and water-insoluble alkaline polymer, its pKb is about 2 ～about 12；For the acid of liquid at the solid excipient of (d) a kind of pharmaceutically acceptable acidity and/or the room temperature 25 DEG C that is cured Property excipient, a kind of pharmaceutically acceptable, water-swellable and water-insoluble acidic polymer；(e) a kind of pharmacy Upper acceptable water miscible surfactant；(f) a kind of medicine.
Terminology used in the present invention " slow-release " refers to that the time of release is a few hours to about 24 hours or longer.
Terminology used in the present invention " active component ", " bioactive ingredients ", " pharmaceutical active components ", " active matter ", " activity Agent " and " bioactive substance ", " medicine " etc. refer to that any material has detectable biological effect bag when it bestows live body Include any physiology, diagnose, preventative or pharmacological effect.This term be intended to include but not limited to any pharmacy, Therapeutic, preventative, the material of threpsology.
Terminology used in the present invention " comprise " and " containing " refer to but be not limited to or except this thing can also comprise other become Grade similar implication.
Terminology used in the present invention " a kind of " refer to including at least one, can be one, two kinds or more kinds of.
Terminology used in the present invention " water soluble " refers to that material dissolubility in the 100ml water of temperature 25 DEG C is not less than 5g, Preferably 10～30g.
Terminology used in the present invention " low viscosity " refers to that the viscosity of the aqueous solution of 2.0% (weight/volume) is not at temperature 25 DEG C Higher than 300 centipoises (mPa s).
Terminology used in the present invention " pharmaceutically acceptable " refers to abiology or the undesirable material of other side, i.e. can be by This material gives individuality, any the most undesirable such as the biological effect of toxicity without causing in individuality, or will not be with bag There is the most harmful interaction in any component in the compositions containing it.
Terminology used in the present invention " additive " refers to that one or more that pharmaceutical carrier comprises can be mixed with each other and without phase interaction With without that there is to reduce pharmaceutical carrier stability and/or effect and be applicable to local or the auxiliary material of oral administration.
Terminology used in the present invention " about " be exponential quantity excursion or can span in ± 30%, preferably ± 20% In, in ± 10%, in most preferably ± 5%, such as from about 10, then it represents that 7～13, preferably 8～12, more preferably 9～11, most preferably 9.5～10.5.
Below the pharmaceutical carrier that the present invention relates to is described in more detail.
The substrate of the pharmaceutical carrier that the present invention relates to and the material of Drug controlled release are that pharmaceutically acceptable fusing point is more than temperature Spend 37 DEG C and in body cavity with fusing point during bioresorbable also above the aliphatic additive of temperature 37 DEG C, preferably fusing point is The aliphatic additive of 40 DEG C～90 DEG C, is more preferably the aliphatic additive of 40 DEG C～80 DEG C, is more preferably 40 DEG C～60 DEG C Aliphatic additive, described aliphatic additive includes but not limited to that fusing point is more than temperature 37 DEG C and connects with body fluid in body cavity Fusing point when touching also above the fatty glyceride of temperature 37 DEG C, higher aliphatic acid propylene glycol ester, higher fatty acids glycol ester, Higher fatty acids binaryglycol ester, higher fatty acids, high fatty alcohol, high-grade aliphatic ester, higher aliphatic hydrocarbon and natural or The mixture being artificially formed such as vegetable and animals oils lipid, semi-synthetic oils and fats, wax class and mixture thereof.
Wherein, above-mentioned fusing point more than temperature 37 DEG C and in body cavity with fusing point during bioresorbable also above the fat of temperature 37 DEG C Fat acid glyceride is most preferably, above-mentioned fatty glyceride can be such as fatty acid glycerine one ester, fatty acid diglyceride, Fatty acid triglycercide and their mixture, fatty acid described herein usually carbon number is the fatty acid of C12～C32, The most above-mentioned positive satisfied fatty acid (as lauric acid (lauric acid/dodecanoic acid), (meat) myristic acid (tetradecylic acid), Palmic acid (hexadecylic acid), Stearic acid (stearic acid), arachidic acid (20 acid), behenic acid (behenic acid), lignoceric acid (acid of tetracosanoic acid, lignin), cerinic acid (hydroxyhexacosanoic acid), montanic acid (octocosoic acid), Cera Flava acid (triacontanoic acid), lacceroic acid (lacceroic acid, lacceroic acid)), Preferably carbon number be the fatty acid of C14～C22, more preferably carbon number be the fatty acid of C16～C18, above-mentioned fatty acid Can be fatty acid mixed (i.e. the unfixed multiple fatty acid of carbon number) can also be the fixing a kind of fat of carbon number Acid, above-mentioned fatty acid glycerine one ester but do not include glyceryl monolaurate, because it has higher surface activity, in water point Dissipate better performances.The fusing point of these fatty glyceride necessarily be greater than temperature 37 DEG C, the most not higher than 80 DEG C, is not less than 40 DEG C, the most not higher than 60 DEG C, it is not less than 40 DEG C, when being especially applicable to suppository.It is preferred for the present invention and can be used for the present invention The example such as GLYCERYL DILAURATE of fatty glyceride, trilaurin (fusing point 45-47 DEG C), single (meat) myristic acid Glyceride (fusing point 68-70 DEG C), glycerol three (meat) myristate (fusing point 56-57 DEG C), two (meat) myristin (fusing point 59 DEG C), hexadecanoic acid direactive glyceride (fusing point 65-68 DEG C), tripalmitin (fusing point 66-68 DEG C), double tripalmitin (molten Point 72-74 DEG C), glyceryl tristearate (fusing point 72-75 DEG C), glyceryl monostearate (fusing point 58-59 DEG C), distearyl acid sweet Grease (72-74 DEG C), glyceryl palmitostearate (fusing point 52～55 DEG C), single arachidic acid glyceride (fusing point 84 DEG C), glycerol Three Arachidates (fusing point 72.2 DEG C), diarachin (fusing point 75 DEG C), behenic acid monoglyceride, behenic acid two glycerol Ester, behenic acid triglyceride (mixing fat fusing point 69-74 DEG C) and their mixture.Can be used for the fatty glyceride of the present invention Commercial examples such as Gattefosse Co., Ltd manufacture Suppocire series in CP (fusing point 37～39 DEG C), C, CM, CS2, CS2X, CT (fusing point 38～40 DEG C), D, DM, ND (fusing point 42～45 DEG C), Dynamic Nobel Chemicals E75, E76 (fusing point 37～39 DEG C) in the Witepsol series that Co.Ltd manufactures, H185 (fusing point 38～39 DEG C), E85 (fusing point 42～44 DEG C).
Wherein, above-mentioned higher aliphatic acid propylene glycol ester preferably carbon number is (positive is saturated) fatty acid third of C18～C32 The single or double ester of glycol or their mixture, described fatty acid example such as stearic acid, arachidic acid, behenic acid, lignoceric acid (20 Tetracid, lignin acid), cerinic acid (hydroxyhexacosanoic acid), montanic acid (octocosoic acid), Cera Flava acid (triacontanoic acid), lacceroic acid (30 Two alkanoic acids, lacceroic acid).Available commercial examples such as the propylene glycol monostearate (fusing point is more than or equal to 45 DEG C) of part, third The double stearate (fusing point 37.0-42.0 DEG C) of glycol list.
Wherein, above-mentioned higher fatty acids glycol ester preferably carbon number is (positive is saturated) fatty acid second of C18～C32 The single or double ester of glycol or their mixture, described fatty acid example such as stearic acid, arachidic acid, behenic acid, lignoceric acid (20 Tetracid, lignin acid), cerinic acid (hydroxyhexacosanoic acid), montanic acid (octocosoic acid), Cera Flava acid (triacontanoic acid), lacceroic acid (30 Two alkanoic acids, lacceroic acid).The available commercial examples such as stearic acid ethylene glycol ester (fusing point 57～63 DEG C) of part, stearic acid second Glycol dibasic acid esters (fusing point 60-65 DEG C), Ethylene Glycol Palmitostearate (fusing point 54～60 DEG C).
Wherein, above-mentioned higher fatty acids binaryglycol ester preferably carbon number is (positive is saturated) fatty acid of C18～C32 The single or double ester of diethylene glycol and stearic acid Palmic acid binaryglycol ester or their mixture, described fatty acid example is as stearic Acid, arachidic acid, behenic acid, lignoceric acid (tetracosanoic acid, lignin acid), cerinic acid (hydroxyhexacosanoic acid), montanic acid (octocosoic acid), Cera Flava acid (triacontanoic acid), lacceroic acid (lacceroic acid, lacceroic acid).The commercial examples such as diethylene glycol list that part can use is hard Fat acid ester (fusing point about 44 DEG C), diethylene glycol distearate, stearic acid Palmic acid binaryglycol ester (fusing point 43～50 DEG C).
Wherein, above-mentioned higher fatty acids preferably carbon number is (positive is saturated) fatty acid of C14～C32, more preferably Carbon number is (positive is saturated) fatty acid of C20～C24, example such as stearic acid, arachidic acid, behenic acid, lignoceric acid (24 Acid, lignin acid, mp 84 DEG C), cerinic acid (hydroxyhexacosanoic acid), montanic acid (octocosoic acid), Cera Flava acid (triacontanoic acid), lacca wax Acid (lacceroic acid, lacceroic acid, mp 95～96 DEG C) or their mixture.The commercial examples such as stearic acid that part is available (Chinese Pharmacopoeia is recorded, and fusing point is not less than 54 DEG C), arachidic acid, behenic acid (fusing point 80 DEG C).
Wherein, above-mentioned high fatty alcohol preferably carbon number is (positive is saturated) fatty alcohol of C16～C32, more preferably Carbon number is (positive is saturated) fatty alcohol of C18～C24, example such as palmityl alcohol, stearyl alcohol, arachidic alcohol, behenyl alcohol, lignoceryl alcohol (tetracosanol, lignin alcohol), ceryl alcohol (hexacosyl alcohol), montanyl alcohol (octacosanol), melissyl alcohol (melissyl alcohol), laccerol (n-Dotriacontanol, lac wax) or their mixture.The commercial examples such as cetyl alcohol (fusing point 45～50 that part is available DEG C), positive octadecanol cetyl alcohol mixture (fusing point 48～56 DEG C), positive octadecanol (fusing point 55～60 DEG C).
Wherein, above-mentioned high-grade aliphatic ester preferably carbon number is (positive is saturated) fatty acid and the carbon atom of C14～C36 The ester of (positive is saturated) fatty alcohol formation that number is C14～C36 or their mixture, wherein said fatty acid or alcohol carbochain On hydrogen can be with single or multiple hydroxylating, wherein, carbon number is that (positive is saturated) fatty acid of C18～C36 is with carbon number The ester that (positive is saturated) fatty alcohol of C18～C36 is formed is more preferably.
Wherein, it is that (preferably carbon chain lengths is 41 to 57 to 31 to 70 carbon that above-mentioned higher aliphatic hydrocarbon preferably comprises carbon chain lengths Individual carbon) straight chain and random side chain saturated alkane, the microwax of cycloalkane.
Wherein, (USPNF20 is by Synthetic Spermacet for the above-mentioned natural or mixture preferred embodiment such as Synthetic Spermacet that is artificially formed It is described as mainly by saturated fatty alcohol (C14～C18) and the mixture of the ester of satisfied fatty acid (C14～C18), 43～47 DEG C), (fusing point: 44～52 DEG C is to be esterified the mixture constituted, hexadecanol by a series of fatty acids (C12～C18) with hexadecanol to spermaceti Cetylate (C15H31COOC16H33) is its main component, wherein hexadecanol laurate, hexadecanol myristinate, ten Six alcohol cetylates and hexadecanol stearate at least constitute the 85% of Ester total amount), Brazil wax (cerinic acid, wax Alcohol and ester thereof account for 80～58%, and free ceryl alcohol 10～12%, the chemical formula of ester is CH3 (CH2) n COO (CH2) n+1CH3, n= 22～32, fusing point 80～88 DEG C), bayberry wax, candelilla wax (be mainly composed of cerinic acid ceryl alcohol fat, 30% Arrcostab, 50% hydro carbons Compound and the fusing point such as free alcohol, free acid 66～69 DEG C), yellow beeswax or cera alba (Cera Flava 70～75% composition be to have Even carbon chain, the mixing of the various esters that the monohydroxy straight-chain monohydric alcohol of a length of 24 to 36 carbon is formed with straight-chain acid esterification Thing.Even-numbered carbon atom contained by straight-chain acid is at most up to 36, and some of them are the hydroxy acid of C18 position.The ester formed is main It it is myricyl palmitate.Simultaneous also have free acid (about 14%) and hydrocarbon (about 12%), and about 1% free ceryl alcohol with The stearic alcohol ester of fatty acid.Fusing point: 61～65 DEG C), lignite wax (be mainly composed of alkanol and alkanoic acid that carbon number is 22～32 Fat and free monomer, fusing point: 75～88 DEG C), rice bran wax or decolouring rice bran wax (be by higher fatty acids and high alcohol The ester mixture of composition.It is mainly composed of myricyl cerotate and ceryl cerotate, and containing other esters a small amount of and very small amount alcohols And hydro carbons, 80-82 DEG C), (fusing point should be 81～85 DEG C, the main esters containing macromolecule, therein for Chinese insect wax or Cera Chinensis Alcohols is cerotin, 27 alcohol, Octacosanol, thirty alcohol；Acids therein is cerin, 27 acid, 28 acid, thirty acid, and on a small quantity Palmic acid, stearic acid.The monacid ester mixture of aliphatic account for the 93～95% of total amount containing rate, mainly have carnaubic acid twenty Octaester, melissyl lignocerate, carnaubic acid wax ester, ceryl cerotate, 27 acid 27 ester, ceryl montanate, melissic acid 27 ester, this Outward, still containing free melissyl alcohol, i.e. myricyl alcohol 1%, resin 1～1.5%, heptacosane 2～3%, still containing 27 alcohol, ceryl alcohol etc.), Shellac wax (main component resins acid esters, mp74～98 82), (fusing point 70-84 DEG C is mainly composed of 16 carbocyclic aliphatics to sugarcane wax The ester that acid is constituted with 30 carbon fatty alcohols or stigmasterol), Japan wax or Japan's fine wax (monoacid (palm fibre is put acid and accounts for 75%, other It is made up of stearic acid, oleic acid etc.) glyceride about 90%, binary acid glyceride about 5～6%, free fatty 2～3%；Free wax Alcohol 1～2%.In japanic acid, major part is carbon number 20 to 22 acid.Fusing point: 48～55 DEG C), Chinese haze tallow (16 acid glycerides 68～80%, olein 4～8%, 18 acid glyceride 5～7% fusing points: 48～55 DEG C), castor oil hydrogenated (fusing point 85～ 88 DEG C), hydrogenated vegetable oil (fusing point 57～85 DEG C), and their mixture.
Other available fusing points include but not limited to cholesterol ester stearic acid (fusing point more than the aliphatic additive of temperature 37 DEG C 82.5 DEG C), cholesterol myristinate (fusing point 70～71 DEG C), cholesterol acid ester (fusing point 44～47 DEG C), cholesterol Petiolus Trachycarpi Acid esters (fusing point 90.5 DEG C), terpene resin (fusing point 82～120 DEG C) and their mixture.
When the substrate of pharmaceutical carrier of the present invention and the material of Drug controlled release the most do not include those with bioresorbable Fusing point be not higher than temperature 37 DEG C in other words in body cavity with just can liquefy during bioresorbable, emulsifying or the lipidic matrix of thawing Or the amount that such lipidic matrix is in pharmaceutical carrier be not enough to (such as less than about 5%wt./wt., the most less than about 1%, with Based on the gross weight of pharmaceutical carrier) make pharmaceutical carrier liquefaction, emulsifying or thawing when it is with endoceliac bioresorbable.These Lipidic matrix includes fatty glyceride (the single capryl third as described in WO99/17737 that such as carbon number is C8～C12 Triol and lauric monoglyceride), some self emulsifyings lipophilic surfactant (such as anhydrous sorbitol tristearate) and Containing a certain amount of surfactant can the lipidic matrix of self emulsifying (such as self-emulsifying monostearate, cetomacrogol emulsifying wax, breast Change wax).It is believed that this is because pharmaceutical carrier in body cavity with just can liquefy during bioresorbable, emulsifying or thawing will cause medicine Prominent dosage in other words of releasing inclines and releases (dose-dumping), thus causes drug safety problem.
Fusing point more than temperature 37 DEG C and in body cavity with fusing point during bioresorbable also above the aliphatic additive of temperature 37 DEG C A the content of () is usually 20～90%wt./wt., preferably 30～80%wt./wt., more preferably 40～80%wt./wt.., with Based on the gross weight of pharmaceutical carrier.
Pharmaceutically acceptable and non-irritating additive water-soluble, low viscous present invention is mainly utilized as filler Or diluent, pharmaceutical carrier disintegrate accelerator and drug release rate regulator.
Can be used for water-soluble, the low viscous pharmaceutically acceptable and non-irritating additive of the present invention, including, but It is not limited to this: the neutrality not dissociated in water-soluble aminoacid, oligopeptide (2～9 peptide), monosaccharide and water thereof or nonionic derive The neutrality not dissociated in thing, oligosaccharide (2～9 sugar) and water thereof or nonionic derivant, water-soluble pharmaceutically acceptable The neutrality not dissociated in cyclodextrin and water thereof or nonionic derivant, polysaccharide water-soluble, low viscous (10 and and more than Sugar) and water-soluble low viscous water in do not dissociate neutrality or nonionic derivant and water-soluble low viscous many Carbohydrate gum matter, polypeptide water-soluble, low viscous, in other water water-soluble, low viscous, pharmaceutically acceptable not from The neutrality solved or non-ionic polyalcohol or heteropolymer, and their mixture.
Can be used for water-soluble aminoacid of the present invention or the preferably neutral water-soluble aminoacid of oligopeptide or oligopeptide.Solvable Real such as, but not limited to this in aminoacid or the oligopeptide of water: alanine, glycine, serine, valine, agedoite, bad ammonia Acid, glutamine, methionine, arginine, hydroxyproline, proline, power peptide (L-alanyl-L-glutamine), gluathione Peptide.
The neutrality not dissociated in available water-soluble monosaccharide and water thereof or nonionic derivant, as its methyl-derivatives, Hydroxymethyl derivative, hydroxyethyl derivative, hydroxypropyl derivatives, hydroxyl butyl or its mixed group derivant (i.e. monosaccharide molecule knot Hydrogen (atom) in hydroxyl in structure spreads out after being replaced by methyl, methylol, ethoxy, hydroxypropyl, hydroxyl butyl or its mixed group Biological), include, but are not limited to the left-handed and/or monosaccharide of dextrorotation and sugar alcohol thereof, in fact such as, but not limited to this: triose is (such as D- Glyceraldehyde and dihydroxy acetone), tetrose (such as D-erythrose, D-Erythrulose, erythritol), pentose is (as D-ribose, D-2-take off Oxygen ribose, D-xylose, L-arabinose, pentulose (such as D-ribulose, D-xylulose, xylitol), hexose (glucose, gala Sugar, mannitol, mannose, ketohexose (such as fructose, sorbose)), heptose (such as D-mannoheptulose, D-sedoheptulose), 2- Ethoxy-D-erythrose, 3-methyl-glucose, 3-hydroxypropyl-L-arabinose, hydroxyl butyl galactose.
The neutrality not dissociated in available water-soluble oligosaccharide (2～9 sugar) and water thereof or nonionic derivant, such as its methyl Derivant, hydroxymethyl derivative, hydroxyethyl derivative, hydroxypropyl derivatives, hydroxyl butyl or its mixed group derivant (i.e. oligosaccharide In molecular structure the hydrogen in the hydroxyl on sugar unit (atom) by methyl, methylol, ethoxy, hydroxypropyl, hydroxyl butyl or its mix Close derivant after group replaces), in fact such as, but not limited to this: disaccharidase is (such as maltose, lactose, sucrose, cellobiose, Radix Gentianae Disaccharide, 6-(.alpha.-D-galactosido)-D-glucose., Sargassum disaccharide, hydroxyl isomaltulose, maltose alcohol, lactitol, trehalose), trisaccharide (such as Raffinose), tetrose (such as stachyose), pentasaccharides (such as verbascose, maltopentaose), six to nine sugar (such as Fructus Hordei Germinatus six to nine sugar), methyl-maltose, hydroxyl Butyl-lactose, methylol-sucrose, hydroxypropyl-cellopentaose, ethoxy-honey seven sugar, hydroxypropyl-Fructus Hordei Germinatus nine sugar.
Water-soluble pharmaceutically acceptable and non-irritating cyclodextrin (such as alpha-cyclodextrin, beta-schardinger dextrin-, γ-ring is stuck with paste) and The neutrality not dissociated in its water or nonionic derivant, if its hydroxyl carbon atom number is C1～C4 alkyl derivative, list or widow In sugar glycosyl derivatives, methyl-derivatives, i.e. cyclodextrin molecular structure on sugar unit in hydroxyl hydrogen (atom) by hydroxyl carbon atom Number is the derivant after C1～C4 alkyl, list or oligosaccharide glycosyl, methyl replacement, water-soluble low-molecular-weight (less than 20000) Water in the neutrality that do not dissociates or nonionic cyclodextrin, the most such as molecular weight 3000～19000), β (or γ)- The single or double methyl-derivatives of cyclodextrin), the most such as beta-schardinger dextrin-, gamma-cyclodextrin, one or DM-β-CD (such as 2, 6 DM-β-CD), (2-) hydroxypropyl-cyclodextrin, (2-) hydroxyl butyl-cyclodextrin, (2-) hydroxyethyl-cyclodextrin, hydroxyl Cyclobutenyl ether ring dextrin, glucosyl group cyclodextrin, didextrose cyclodextrin, three glucityl cyclodextrin, malt-base cyclodextrin, two Malt-base cyclodextrin, three malt-base cyclodextrin, side chain-(β-) cyclodextrin and mixture thereof.One preferred example is sulphur Butyl (ether) cyclodextrin and salt thereof such as sodium salt, potassium salt, as described in US-5134127-A.
Polysaccharide water-soluble, low viscous (10 is sugared and sugared above) and water thereof do not dissociate neutrality or nonionic derivant, As its methyl-derivatives, hydroxymethyl derivative, hydroxyethyl derivative, hydroxypropyl derivatives, hydroxyl butyl or its mixed group replace Derivant (i.e. in polysaccharide molecule structure the hydrogen (atom) in the hydroxyl on sugar unit by methyl, methylol, ethoxy, hydroxypropyl Derivant after base, hydroxyl butyl or the replacement of its mixed group) and neutral or nonionic polysaccharide colloid, acidic polysaccharose colloid and salt thereof (such as sulfated polysaccharide colloid, carboxylic esters Quito carbohydrate gum matter), generally selects the mentioned component of (averagely) molecular weight low 20000, Preferably (averagely) molecular weight mentioned component less than 10000, available real such as, but not limited to this: water-soluble low viscous Pharmaceutically acceptable and nonirritant following excipients (material): dextrates (Dextrates), oligosaccharide are (as poly- Right 10～100) (such as oligofructose (such as the degree of polymerization 10～100), oligomeric isomaltose (such as the degree of polymerization 10～100)), dextrin, (sulfuric ester, such as λ-carrageenin, carrageenin sodium for glucosan (glucosan if molecular weight is 1800～20000), carrageenin Salt), Radix Acaciae senegalis (mixture of arabogalactan oligosaccharide, polysaccharide and protein sugar), pulullan polysaccharide is (as molecular weight is Or less than 100000), pectate, pectic acid (galacturonic acid polysaccharide), Calcium Pectate or magnesium or sodium or potassium salt, tamarind Polysaccharide gum, guar gum, xanthan gum (acidic polysaccharose), xylan, mannan, soluble starch, galactan, inulin, sea Propylene glycol alginate, sesbania gum, locust bean gum, tragacanth (acidic polysaccharose), Semen Lini glue (acidic polysaccharose is main), hydroxyl second methyl Cellulose, hydroxyethyl cellulose (product as following in trade name: WP 02, WP and QP 09, WP and QP 3, WP and QP 40, WP and QP 300), hydroxypropyl cellulose (product as following in trade name: Klucel JF, Klucel LF, Klucel EF), hydroxypropyl methylcellulose (product as following in trade name: Methocel K100Premium LVEP, Methocel F50Premium、Methocel E3 Premium LV、Methocel E5Premium LV、Methocel E6 Premium LV, Methocel E15 Premium LV, MethocelE50Premium LV, low viscosity level Metolose 60SH, low viscosity level Metolose 65SH, low viscosity level Metolose90SH), methylcellulose (product as following in trade name Product: A15-LV).
Polypeptide water-soluble, low viscous, including neutral soluble in polypeptide water, low viscous, acid-soluble in water, low The polypeptide of viscosity, alkali soluble in polypeptide water, low viscous, generally select water-soluble many less than 20000 of molecular weight Peptide, the preferably molecular weight water-soluble polypeptide less than 10000, such as 10～100 peptides, available example the most water miscible Semen Tritici aestivi water Solve albumen (peptide), soybean polypeptide, collagen polypeptide, polypeptide from Chlamys farreri.
The neutrality not dissociated in other water water-soluble, low viscous, pharmaceutically acceptable or non-ionic polyalcohol or Heteropolymer, generally select (averagely) molecular weight be less than 20000 water-soluble, low viscous, pharmaceutically acceptable in Property or non-ionic polyalcohol or heteropolymer, preferably (averagely) molecular weight less than 10000 water-soluble, low viscous, Pharmaceutically acceptable neutrality or non-ionic polyalcohol or heteropolymer, the most low viscous polyvinyl alcohol of example, Polyethylene Glycol (such as PEG 1000～20000), low viscous polyvidone (product as following in trade name: K-11/14, K-16/18, K-24/ 27、K-28/32、K-85/95)。
Above-mentioned water soluble, low viscous, the pharmaceutically acceptable and granule largest cross-sectional sized of non-irritating additive Less than about 600 microns (about 28 mesh, Tyler standard), preferably less than about 75 microns (about 200 mesh, Tyler Standard), more preferably less than about 25 microns (about 500 mesh, Tyler standard).With the gross weight of pharmaceutical carrier as base Plinth, water soluble, low viscous, pharmaceutically acceptable and non-irritating additive content is usually 5～70%wt./ Wt., preferably 10～50%wt./wt. preferably 10～40%wt./wt..
Such a kind of medicine is referred at " pharmaceutically acceptable water-swellable and the water-insoluble polymer " used by the present invention Acceptable material (polymer) on, when it is exposed in the water of excess, it is expanded to its equilibrium volume, but is not dissolved in In solution.For definition used herein, if a kind of material is considered as water miscible, it is substantially soluble in the water of excess Middle formation solution, thus loses its initial, the most granular shape, and is substantially scattered in aqueous solution with molecularity In.Common criterion is, water dissolvable material cross-links without substantial extent, because crosslinking will make material have water-insoluble.
Water-swellable and the molecular weight ranges of insoluble polymer in pharmaceutical carrier of the present invention are the widest.Relatively high molecule The water-swellable of amount and insoluble polymer, be typically favourable for using in the present invention.But it is applicable to the present invention's Molecular weight ranges is typically the widest.The weight average molecular weight being applicable to the water-swellable of the present invention and insoluble polymer is usual Greater than about 20000, it is preferred with greater than about 100000, preferably greater than about 200000, more preferably greater than about 500000, is more than 1000000 is preferably, and up to about 10000000.The method measuring polymer molecular weight is generally well known in the art.
The mode expressing polymer molecular weight the most more easily is at 25 DEG C, the viscosity of the aqueous solutions of polymers of 1.0 weight %. It is applicable to the polymer of the present invention, is about 200～about 80000 centipoises with the viscosity of its 1.0 weight % aqueous solution at 25 DEG C (mPa s) is advisable, and about 500～about 80000 centipoises preferably, optimum is about 1000～about 80000 centipoises.
Water-swellable and water-insoluble polymer in pharmaceutical carrier of the present invention are typically crosslinking.The amount of crosslinking is usual Should keep on water-insoluble minimum being enough to make polymer, but also should make polymer keep in water the most swelling Under great Liang, so that polymer can absorb the desired amount of liquid and and swelling.
Generally crosslinking the making for realizing by one of two distinct types of cross-linking agent of polymer.The crosslinking of the first type Agent is polymerisable cross-linking agent.Suitable polymerizable cross-linking agent generally to being reactive for preparing the monomer of polymer, And therefore usually containing at least two can be with the functional group of monomer reaction.The example of suitable polymerizable cross-linking agent, for certainly Include vinyl-based unsaturated monomer for being polymerized by base, such as N, N '-methylene-bisacrylamide, include many for polycondensation Amine or polyol.
The cross-linking agent of Second Type is rear cross-linking agent.Rear cross-linking agent is generally not involved in whole polymerization process, but the time after relatively When being supplied to suitable cross linking conditions, it can be with polymer reaction.Suitable post-treatment condition includes using heat treated, Such as temperature greater than about 60 DEG C, being exposed to ultraviolet, be exposed to microwave, steam or high humility process, HIGH PRESSURE TREATMENT or with organic molten Agent processes.
The rear cross-linking agent being applicable to the present invention is the most water miscible.Suitable rear cross-linking agent be at least have two can be polymerized The functional group of any carboxyl, carboxylic acid, amino or hydroxyl reaction on thing or a kind of organic compound of degree of functionality.Suitable rear friendship The example of connection agent includes, but is not limited to diamine, polyamines, dihydroxylic alcohols, polyol, polycarboxylic acid and polyoxide.Another kind of suitable Rear cross-linking agent contains the metal ion of band more than two positive charge, such as Al3+, Fe2+, Ce3+, Ce4+, Ti4+, Zr4+ and Cr3+.
When polymer is cationic polymer, suitable cross-linking agent is the material of polymer anion, such as sodium polyacrylate, carboxylic Methylcellulose, or polyphosphate.
Pharmaceutically acceptable water-swellable and insoluble polymer in pharmaceutical carrier of the present invention are usually acidity And alkalescence.Refer to can be used as the material of electron acceptor used herein of " acid " material.It is commonly used for pharmaceutical carrier of the present invention In acid water swellability and insoluble polymer be weakly acidic.Thus be accordingly used in the acidity in pharmaceutical carrier of the present invention water-soluble The pKa of swollen property and water-insoluble polymer is advisable with about 2～about 12, the most about 2～about 10, conveniently about 3～ About 6.Sometimes the pH value of monomer for preparing polymer can be measured more easily.Although the pH value of monomer with by these monomer systems The pH value of the polymer obtained is incomplete same, but the two pH value should be the most close.Therefore, in pharmaceutical carrier of the present invention Acid water swellability and water-insoluble polymer, preferably prepared by such monomer, the pKa of these monomers is about 2～about 12, the most about 2～about 10, conveniently about 3～about 6.If polymer is prepared by two or more monomer, each used The pKa of monomer should be about 2～about 12, the most about 2～about 10, conveniently about 3～about 6, it is of course possible to uses few Amount pKa is less than about 2 or the monomer of greater than about 12, as long as these monomers are not to described water-swellable and the institute of insoluble polymer Performance is needed to have a negative impact.
It has been found that use pKa to be less than about 2, highly acid expansiveness, insoluble polymer, generally will cause the present invention Pharmaceutical carrier does not possess required performance, such as low absorption liquid rate, low Release Performance, and there may also be bigger thorn Swash property etc..Generally also find, use pKa be greater than about 12, the most weak acid expansiveness, insoluble polymer, generally To cause pharmaceutical carrier of the present invention does not possess required performance, such as low liquid absorption capacity, low Release Performance.The pKa of acid Value represents the degree of its dissociation, and in other words, the namely intensity of acid, the most described pKa value should measure under given conditions, example As measured under the specified temp that water-swellable and insoluble polymer use.
PKa value is measured more suitable at 25 DEG C.Generally, acid is the most weak, and its pKa value is the highest.Many acid pKa value at different temperatures is Known, it is possible to obtain in any available many lists of references.
Suitable slightly acidic water swellability and insoluble polymer comprise the functional group that can be used as weak acid.These functional groups include But it is not limited to carboxyl, sulfate groups, inferior sulfate radical group, and phosphate groups.Suitable functional group is carboxyl.Generally, this A little functional groups are connected on the base polymer of crosslinking.Suitable base polymer includes polyacrylamide, polyvinyl alcohol, ethylene Copolymer-maleic anhydride, polyvingl ether, polyacrylic acid, poly-carbon number is C1～C4 alkyl acrylic, poly-hydroxyl carbon atom Number is C1～C4 alkyl acrylic, polyvinyl pyrrolidone, polyvinyl beautiful jade, and their copolymer.Can also use Natural polysaccharide polymer, including carboxymethyl cellulose, carboxymethyl starch, hydroxypropyl or ethyl cellulose, alginic acid, alginic acid Salt, humic acids, carrageenin, acrylic acid-grafted starch, acrylic acid-grafted cellulose, and their copolymer.Can also Use the polypeptide of synthesis, if poly-aspartate, polyglutamic acid, poly-mixed acid acidic amino acid are (such as poly-mixing aspartic acid, the example Such as poly-aspartate-aspartic acid-lysine acid (4: 2: 1)；Poly-mixing glutamic acid, the most such as polyglutamic acid-lysine acid (4∶1).Term " poly-mixed acid acidic amino acid " refers to containing the several amino acids including acidic amino acid in chain herein, and The molal quantity of acidic amino acid (such as aspartic acid, glutamic acid) is more than the molal quantity of basic amino acid (such as lysine, arginine) And present acidity poly-several amino acids (poly-several amino acids sees document: US5247068A).
Preferably it is suitable for the acid water swellability of the present invention and water-insoluble polymer including but not limited to weight average molecular weight Be generally greater than about the acrylate copolymer of 100000, poly-carbon number is C1～C4 alkyl acrylic, poly-hydroxyl carbon atom number is C1～C4 alkyl acrylic, acrylic acid-acrylic ester polymer, polyvinyl alcohol-acrylic block copolymers, starch-grafted propylene Acid polymer, cellulose graft acrylate copolymer, humic acids, polycarbophil (Polycarbophil polymers), Sargassum Acid, poly-aspartate, polyglutamic acid, poly-mixing aspartic acid and poly-mixing glutamic acid, and their mixture.
Generally, acid water swellability and insoluble polymer are required to be its free acid form.Preferably part free acid by The form of sum, because it can play bigger function at pharmaceutical carrier at the release initial stage, can overcome it in release initial stage function relatively Little.The acidic functionality about 10～about 95 of the free form that it is generally desirable to acid water swellability and insoluble polymer rubs You are %, the most about 30～about 95 moles of %, conveniently about 50～about 90 moles of %, the most about 65～about 85 Mole %.In other words, when in pharmaceutical carrier of the present invention, acid water swellability and insoluble polymer are preferably by portion Divide and neutralize.The degree of neutralization about 5～about 90 of the acidic functionality that it is generally desirable to acid water swellability and insoluble polymer rubs You are %, the most about 5～about 70 moles of %, the most about 10～about 50 moles of %, the most about 15～about 35 moles of %.
Refer to can be used as the material of electron donor used herein of " alkaline " material.It is commonly used in pharmaceutical carrier of the present invention Alkaline water swellability and insoluble polymer are weakly alkaline.Thus be accordingly used in the alkaline water swellability in pharmaceutical carrier of the present invention And the pKb of water-insoluble polymer is about 2～about 12, the most about 2～about 10, conveniently about 3～about 6.Sometimes The pH value of monomer for preparing polymer can be measured more easily.Although the pH value of monomer and being polymerized of being prepared by these monomers The pH value of thing is incomplete same, but the two pH value should be the most close.Therefore, the alkaline water in pharmaceutical carrier of the present invention Swellability and water-insoluble polymer, can be about 2～about 12 by pKb, the most about 2～about 10, conveniently about 3～ Prepared by the monomer of about 6.If polymer is prepared by two or more monomer, the pKb of the most each monomer used should be about 2～about 12, More advantageously it is about 2～about 10, conveniently about 3～about 6, it is of course possible to use minimal amount of, pKb to be less than about 2 or greater than about The monomer of 12, as long as the desired properties of described water-swellable and insoluble polymer is not had a negative impact i.e. by these monomers Can.
It is existing that oneself finds, use pKb be less than about 2, alkaline water-swellable and insoluble polymer, generally will cause this Bright pharmaceutical carrier does not possess required performance, such as low absorption liquid rate, low Release Performance, and there may also be bigger Zest etc..Generally also find, use pKb be greater than about 12, alkalescence the most weak water-swellable and insoluble polymer, generally To cause pharmaceutical carrier of the present invention does not possess required performance, such as low liquid absorption capacity, low Release Performance.Alkalescence PKb value represents the degree of its dissociation, in other words, the namely intensity of alkalescence, and pKb value should measure under given conditions here, Such as measure under the specified temp that water-swellable and insoluble polymer use.
Suitable mensuration pKb value at 25 DEG C.Generally, alkali is the most weak, and its pKb value is the highest.Many alkali pKb values at different temperatures are Known, it is possible to obtain in any available many lists of references.
Suitable alkalescent water swellability and insoluble polymer comprise the functional group that can be used as weak base.These functional groups include (but not limited to) primary, secondary and tertiary amino, imino group, and acylamino-.Suitable functional group is amino.Generally, these functional groups are even It is connected on the matrix polymer of crosslinking.Suitable matrix polymer includes polyamine or polyimides, polymine, and polyethylene gathers Amine, polyacrylamide, polypropylene amine, polypropylene carbon number is C1～C4 alkylamine, and poly-carbon number is C1～C4 alkyl third Enamine, poly-carbon number be C1～C4 alkyl carbon number be C1～C4 alkylamine, poly-hydroxyl carbon atom number is C1～C4 Alkyl amine, poly-hydroxyl carbon atom number be C1～C4 alkyl carbon number be C1～C4 alkylamine, and polyquaternary ammonium salt, and Their copolymer.Natural polysaccharide polymer can also be used, many including chitin and chitosan and other amino Sugar.The polypeptide of synthesis can also be used, such as poly-asparagine, polyglutamine, polylysine, poly arginine, poly-mixed-alkali Aminoacid is (such as poly-mixing lysine, the most such as polyglutamic acid-lysine (1: 3)；Poly-mixing arginine, the most such as, gather sky Winter propylhomoserin-arginine (1: 4).Term " poly-mixed-alkali aminoacid " refers in chain containing including basic amino acid herein Several amino acids, and the molal quantity of basic amino acid (such as lysine, arginine) more than acidic amino acid (such as aspartic acid, paddy Propylhomoserin) molal quantity and present alkalescence poly-several amino acids (poly-several amino acids sees document: US5247068A).
Preferably it is suitable for the alkaline water swellability of the present invention and water-insoluble polymer including but not limited to weight average molecular weight It is generally greater than about polyamine or polyimides, polymine, polypropylene amine, polyethylenepolyamine, the polypropylene carbon number of 100000 For C1～C4 alkylamine, poly-carbon number be C1～C4 alkyl amine, poly-carbon number be C1～C4 alkyl carbon atom Number is C1～C4 alkylamine, poly-hydroxyl carbon atom number is C1～C4 alkyl amine, poly-hydroxyl carbon atom number is C1～C4 alkyl Propylene atomic number is C1～C4 alkylamine, chitin, chitosan, other aminopolysaccharides, poly-asparagine, polyglutamic acyl Amine, polylysine, poly arginine, poly-mixing lysine and poly-mixing arginine, and their mixture.
Generally, alkaline water swellability and insoluble polymer are required to be its free alkali form.Preferably part free alkali by The form of sum, because it can play bigger function at pharmaceutical carrier at the release initial stage, can overcome it in release initial stage function relatively Little.The basic functionality about 10～about 95 of the free form that it is generally desirable to alkaline water swellability and insoluble polymer rubs You are %, the most about 30～about 95 moles of %, conveniently about 50～about 90 moles of %, the most about 65～about 85 Mole %.In other words, when in pharmaceutical carrier of the present invention, alkaline water swellability and insoluble polymer are preferably by portion Divide and neutralize.The degree of neutralization about 5～about 90 of the basic functionality that it is generally desirable to alkaline water swellability and insoluble polymer rubs You are %, the most about 5～about 70 moles of %, the most about 10～about 50 moles of %, the most about 15～about 35 moles of %.
In order to preferably make medicine by stripping curve dissolution that is preferable or that preset, in pharmaceutical carrier of the present invention, apply two kinds or Acidity (or alkalescence) water-swellable of more kinds of different degree of neutralization and insoluble polymer, so can make pharmaceutical carrier in difference Disintegrate on time, drug release presents " stage " or " pulsed ", thus drug release release in different time sections, totally On present release before and after speed consistent.In an embodiment, acidity (or alkalescence) water-swellable of a part and water-insoluble gather The degree of neutralization of acidity (or alkalescence) functional group of compound is about 5～about 40 moles of %, acidity (or alkalescence) official of another part The degree of neutralization that can roll into a ball is about 50～about 90 moles of %；In another embodiment, acidity (or the alkalescence) water-swellable of a part and The degree of neutralization of acidity (or alkalescence) functional group of insoluble polymer is about 5～about 30 moles of %, and a part is consumption Acid (or alkalescence) functional group about 40～about 60 moles of %, acidity (or alkalescence) functional group of another part is about 70～about 90 Mole %.Acid (or alkalescence) water-swellable of above-mentioned different degree of neutralization and the consumption in pharmaceutical carrier of insoluble polymer Ratio preferably about 1: 1: 1 ....Acid (or alkalescence) water-swellable of above-mentioned different degree of neutralization and insoluble polymer can positions In same release particulate matter, it is also possible to lay respectively in different release particulate matters, this kind of different release particulate matters dress Enter in same drug release carrier as in capsule, bag agent, or be pressed in a tablet simultaneously.
Can be used for pharmaceutically acceptable acid solid (at the room temperature 25 DEG C) excipient (material) of the present invention and/or be cured It is not less than the acidity of 35 DEG C (being preferably not less than 60 DEG C, be more preferably not less than 100 DEG C) for liquid and its boiling point at room temperature 25 DEG C Excipient includes mineral acid solid (at room temperature 25 DEG C) excipient (material) and organic acidity solid (at room temperature 25 DEG C) figuration Agent (material), particularly in molecular structure, alkane chain high carbon atom number is not higher than C7 (preferably C6, more preferably straight chain are dominant) Organic acidity solid (at room temperature 25 DEG C) excipient (material) and by the high carbon atom number of alkane chain in molecular structure not higher than Acid solid (at the room temperature 25 DEG C) polymer that the monomer of C7 (preferably C6, more preferably straight chain are dominant) is polymerized, and mixed Compound, the example such as (but not limited to):
A), acidic polymer excipient (material) and acid salt thereof or ackd salt, such as (solid or liquid (at room temperature 25 DEG C) poly- Acrylic acid, polyacrylic acid salt or ackd salt, poly and acid salt thereof or ackd salt, carboxymethyl cellulose and acid thereof Formula salt or ackd salt, alginic acid and acid salt thereof or ackd salt, humic acids and acid salt thereof or ackd salt, poly-aspartate and acid thereof Formula salt or ackd salt and polyglutamic acid and acid salt thereof or ackd salt；
B), organic acidity solid or liquid (at room temperature 25 DEG C) excipient (material), as aliphatic and fragrant in solid (at room temperature 25 DEG C) Race's acid and the acid salt of polyprotic acid or ackd salt, it can be used for the example of the present invention such as:
1), ketone group or not ketone group containing or ester group or without ester group monohydroxy or polyhydroxy or hydroxyl is not saturated or unsaturated straight chain Or alkane that branched carbon (preferably straight chain is dominant) atomic number is C2～C7 (preferably C2～C6) or cycloalkane polybasic carboxylic acid:
As along or anti-methylmaleic acid, dihydroxy along or fumaric acid, maleic acid (maleic acid), fumaric acid (anti- Formula butene dioic acid, fumaric acid, Fumaric acid), galactosaccharic acid, glucosaccharic acid, itaconic acid (enedioic acid class), malic acid, oneself two Enedioic acid (muconic acid), oxalic acid, malonic acid, succinic acid (succinic acid), 1,3-propanedicarboxylic acid, adipic acid, mesoxalic acid (ketomalonic acid), grass second Acid (oxaloacetic acid, butanone diacid), ketoglutaric acid, hexanone diacid, diethyl malonic acid, citric acid, tartaric acid, equisetic acid, lemon Herba Marsileae Quadrifoliae acid (2-Hydroxy-2-methylbutanedioic acid), dihydroxytartaric acid,
2), ketone group or not ketone group containing or ester group or without ester group monohydroxy or polyhydroxy or hydroxyl is not saturated or unsaturated straight chain Or alkane that branched carbon (preferably straight chain is dominant) atomic number is C2～C7 (preferably C2～C6) or cycloalkane monocarboxylic acid:
Such as acetic acid (boiling point 117.9 DEG C), propanoic acid (boiling point 141 DEG C), isopropyl acid, butanoic acid (boiling point 164 DEG C), isopropylformic acid. (boiling point 152-155 DEG C), positive valeric acid (boiling point 186 DEG C), isovaleric acid (boiling point 176 DEG C), valproic acid (boiling point 220 DEG C), acid (boiling point 205 DEG C), iso caproic acid (boiling point 200 DEG C), positive enanthic acid (boiling point 223 DEG C), isoamyl acetic acid (boiling point 166 DEG C), lactic acid (boiling point 122 DEG C), Acrylic acid (boiling point 141 DEG C), butenoic acid (boiling point 184 DEG C), methacrylate (boiling point 161 DEG C), pivalic acid (trimethylace tonitric), 2, 2-dihydromethyl propionic acid, gluconic acid, D or L-GuA, glycolic, D-ALPHA-Hydroxypropionic acid (D-Lactic Acid, mp 52.8 DEG C), Pfansteihl (L-Lactic Acid, mp 53 DEG C), hydroxybutyric acid (as α-, β-, γ-type), hydroxyl valeric acid (as α-, β-, γ-type), hydroxyl Caproic acid (as α-, β-, γ-type), dihydroxy valeric acid, two hydroxycaproic acids, three hydroxycaproic acids,
3), benzene compound molecular structure ring hydrogen is C1～C7 (more preferably C1～C6) straight chain by one or many carboxyl carbon atom number Or side chain (preferably straight chain is dominant) alkane or cycloalkyl group, one or many carboxyl one or polyhydroxy carbon number are that C2～C7 is (excellent Select C2～C6) straight or branched alkane (preferably straight chain is dominant) hydrocarbon or cycloalkyl group is substituted and in molecular structure alkane chain the highest Carbon number is not higher than the carboxylic acid of C7 (preferably C6):
Such as anisic acid (methoxybenzoic acid), atrolactic acid, diphenylglycollic acid, benzoic acid, caffeic acid, o/ or p/ or m-methyl Salicylic acid, salicylic acid, aspirin, ferulic acid, high hay-scented acid (4-Hydroxy-3-methoxybenzeneacetic Acid), 4 hydroxyisophthalic acid, phenylpropionic acid, p-hydroxybenzoic acid, M-phthalic acid, mandelic acid (mandelic acid), benzene pregnancy Acid, 4,6-dihydroxy-2-ar-Toluic acid (orsellinic acid), phenylacetic acid, protocatechuic acid (PCA), cumic acid (insoluble), gallic acid, DHB, 2,5-dihydroxyphenyl acetic acid,
4), furan compound, pyrylium compound and pyranone compounds molecular structure ring hydrogen are by one or many carboxyl carbon atom Number is C1～C7 (more preferably C1～C6) straight or branched (preferably straight chain is dominant) alkane or cycloalkyl group, one or many carboxyl one Or polyhydroxy carbon number is C2～C7 (more preferably C1～C6) straight or branched (preferably straight chain is dominant) alkane or cycloalkane The carboxylic acid that base is substituted and in molecular structure, alkane chain high carbon atom number is not higher than C7 (preferably C6):
Such as dihydrochalcone, 2-furylacrylic acid, furancarboxylic acid, D-galacturonic acid, glucuronic acid, a-pyranone-5-carboxylic acid,
5), ascorbic acid, dehydroascorbic acid, (6-) deoxidation-L-AA, glucoascorbic acid, arabo-ascorbic acid,
6), in other molecular structures, alkane chain high carbon atom number is not higher than having of C7 (preferably C6, more preferably straight chain being dominant) Machine acid:
Such as angelic acid ((Z)-2-methyl-2-butenoic acid), dextrocamphoric acid. (diacid), butylmalonic acid, carboxyglutamic acid (carboxyl paddy ammonia Acid, polycarboxylic acid), cinnamic acid, coumaric acid (o/ or p/ or m-hydroxy-cinnamic acid), coumarone-2-carboxylic acid. (2-benzofurancarboxylic acid, benzofuran carboxylic Acid), single ethyl tartaric acid, glucoheptonic acid, glycolic, glycyrrhizic acid, glyoxylic acid hydrate, hydroxyglutamic acid, 1-hydroxyl-2-naphthalene first Acid, 3-hydroxy-2-naphthoic acid, iminodisuccinic acid, heteroauxing .gamma.-pyridinecarboxylic acid, 2-keto-L-gulonic acid, kojic acid, lactose Acid, pivalic (trimethylace tonitric, pivalic acid, PivalicAcid, neopentanoic acid), prephenic acid (1-carboxylic-4-carboxylic-2,5-cyclohexadiene- 1-acetone acid), 2-cyclopenten-2,3-diol-1-one. (1,2-dihydroxy-3-ketone cyclopentenes), quinic acid, crotonic acid (.beta.-methylacrylic acid), sorbic acid, according to ground Acid, pentaacetic acid, 1,5-pentanedicarboxylic acid., clavulanic acid, ribonucleotide, Deoxydization nucleotide, inosinic acid, Alpha-Methyl furan inosinic acid, gland are fast Purine nucleotide (adenylic acid, AMP), guanylic acid (guanyl, GMP), cytidylic acid (cytidylic acid, CMP), uracil Nucleotide (uridylic acid, UMP), thymidylic acid (thymidylic acid, TMP), inosine monophosphate, IMP (inosinic acid, IMP), Huang are fast Purine nucleotide, tyrosine, tryptophan, cystine, phosphorylated amino acid are (such as phosphotyrosine, phosphoserine and phosphoric acid Soviet Union ammonia Acid) and acidic amino acid (such as glutamic acid, aspartic acid), and the acid salt of above-mentioned multicomponent organic acid or ackd salt；
C), mineral acid solid (at room temperature 25 DEG C) excipient (material), such as metal-oxide, such as zinc oxide, aluminium oxide, and Mineral acid salt, such as the ammonium salt of strong acid (such as hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid etc.), mantoquita, zinc salt, iron salt, ferrous salt, calcium Salt, magnesium salt, aluminium salt etc. (example such as iron chloride or ferrous or aluminum, ferric nitrate or ferrous or aluminum, iron sulfate or ferrous or zinc or aluminum or The strong acid ammonium salts such as aluminum potassium or aluminum sodium, ammonium chloride, ammonium nitrate, ammonium sulfate, ammonium phosphate), disulfate, bisulfites, di(2-ethylhexyl)phosphate Hydrogen salt, pyrosulfate, pyrosulfurous acid, such as sodium salt, potassium salt, ammonium salt, and solid (at room temperature 25 DEG C) mineral acid, such as phosphoric acid；
D), in molecular structure alkane chain high carbon atom number be not higher than C7 (preferably C6, more preferably straight chain are dominant) be dissolved in acid And solid (at room temperature 25 DEG C) (both sexes) material of alkali or excipient (material), as creatine, inosine, asparagine, glutamine, Hypoxanthine, aminoacid；
And the mixture of above-mentioned acid e).
At solidification room temperature 25 DEG C, the adjuvant for the acid excipient of liquid includes but not limited to the water-soluble of solid (at room temperature 25 DEG C) The neutrality (or weakly acidic pH) of property or non-ionic polyalcohol are (such as cetomacrogol 1000-20000, polyvinylpyrrolidone, poly-second Enol, hydroxyl second methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), solid (including but not limited to (1) carboxyl alkyl cellulose, (2) have the monoester bond of binary acid to the enteric polymer of (at room temperature 25 DEG C) Cellulose derivative, (3) have the polyvinyl derivative of dibasic acid monoester key, its polymers of (4) maleic acid-ethylene, and (5) third Olefin(e) acid base polymer, (6) other classes and their mixture.(1) special example includes but not limited to carboxymethyl cellulose, carboxylic Methylethylcellulose (CMEC) and their mixture, the special example of (2) includes but not limited to that phthalic acid ester acid is fine Dimension element, succinic acid acetyl cellulose, methyl cellulose ester, phthalic acid hydroxymethyl ethylcellulose ester, Phthalic acid hydroxypropyl methyl cellulose ester, succinic acid hydroxypropyl methyl cellulose ester and the like and their mixture；(3) Special example include but not limited to the dibasic acid monoester of polyvinyl, such as polyvinyl acetate phthallate, adjacent benzene Dioctyl phthalate polyethylene butyl ester, acetyl group acetal phthalic acid polyvinyl ester and the like and their mixture；(4) spy Other example includes but not limited to Vinyl acetate-maleic anhydride copolymer, butyl vinyl ether-copolymer-maleic anhydride, benzene second Alkene-maleic acid monoester copolymer and their mixture；(5) special example includes but not limited to acrylic acid methyl ester .-methyl Acrylic copolymer, Styrene-acrylic copolymer, acrylic acid methyl ester .-methacrylic acid-acrylic acid monooctyl ester copolymer, Eudragit L and S, Eudragit FS (conlon targeting is used) and their mixture；(6) the special example of other classes include but not It is limited to Lac.The most more preferably enteric polymer is carboxymethyl cellulose, carboxymethylethylcellulose, phthalic acid hydroxypropyl Ylmethyl cellulose esters, succinic acid hydroxypropyl methyl acetyl cellulose, Eudragit L, Eudragit S, Eudragit FS Or Lac), solid (at room temperature 25 DEG C) (preferably fusing point is not less than 40 DEG C, and preferably fusing point is not less than 60 DEG C) water solublity neutral or (preferably fusing point is not less than 40 DEG C, excellent for nonionic surfactant (example as listed by the present invention), solid (at room temperature 25 DEG C) Fusing point is selected to be not less than 60 DEG C) organic acid (example as listed by the present invention) and saccharide (example as listed by the present invention), and Mixture.
Above-mentioned acid excipient (material) is the most highly acid, it is also possible to for weakly acidic.But it has been found that this tax The acid intensity of shape agent (material) will affect the liquid absorption of absorbing particles thing.Generally, compose with containing relatively weak acidity The absorbing particles thing of shape agent (material) is compared, and the absorbing particles thing containing the strongest acid excipient (material) will have relatively Liquid absorption faster.
Alkali (or acid) property excipient (material) that can be used for the present invention also includes above-mentioned alkali (or acid) property water-swellable and water not Soluble polymer, and be preferred.
Solidify and include but not limited to fusion method, solvent method for the acidity of liquid or the method for basic excipients at above-mentioned room temperature 25 DEG C And solvent fusion method, (spraying) coating method, cyclodextrin inclusion compound method etc. (refer to relevant monograph, such as " novel pharmaceutical formulation and new technique ", Lu Bin, People's Health Publisher, April in 1998 the 1st edition, the 1st, 2,5,6 chapters).The most only it is briefly described.
Fusion method: heat acidity or the adjuvant of basic excipients for liquid at above-mentioned solidification room temperature 25 DEG C so that it is fusing, add State at room temperature to be cured 25 DEG C as the acidity of liquid or basic excipients or or add above-mentioned alkali (or acid) property water-swellable And insoluble polymer, mixing, it is cooled to room temperature, pulverizes, sieve on demand.In this method, the fusing point of above-mentioned solidification adjuvant 5 DEG C should be preferably less than less than the boiling point of the above-mentioned excipient that is cured, more preferably less than 10 DEG C, take goodly less than 20 DEG C.
Solvent method or (spraying) coating method: molten for the adjuvant at above-mentioned solidification room temperature 25 DEG C being the acidity of liquid or basic excipients (or dispersion), in appropriate anhydrous organic solvent, adds acidity or basic excipients for liquid at above-mentioned room temperature to be cured 25 DEG C Or add above-mentioned alkali (or acid) property water-swellable and insoluble polymer, mixing, and fling to this organic solvent, pulverize, on-demand Sieve, or carry out being spray-dried coating.In this method, the boiling point of above-mentioned organic solvent should be less than the above-mentioned excipient that is cured Boiling point, is preferably less than 10 DEG C, more preferably less than 20 DEG C, takes goodly less than 30 DEG C.
Solvent fusion method: the most anhydrous have being dissolved in for the acidity of liquid or basic excipients at above-mentioned room temperature to be cured 25 DEG C Machine solvent, for acidity or the adjuvant of basic excipients of liquid at the above-mentioned solidification room temperature 25 DEG C afterwards its addition melted, Or in above-mentioned fused mass, add above-mentioned alkali (or acid) property water-swellable and insoluble polymer, fling to this organic solvent, Pulverize, sieve on demand.In this method, it is desirable to the boiling point of above-mentioned organic solvent should be less than the boiling point of the above-mentioned excipient that is cured, It is preferably less than 10 DEG C, more preferably less than 20 DEG C, takes goodly less than 30 DEG C；The fusing point of above-mentioned solidification adjuvant should be consolidated less than above-mentioned Change the boiling point of excipient, be preferably less than 5 DEG C, more preferably less than 10 DEG C, take goodly less than 20 DEG C.
At above-mentioned solidification room temperature 25 DEG C, the consumption for the acidity of liquid or the adjuvant of basic excipients is 10～500%wt./wt., Preferably 30～300%wt./wt., the acidity as liquid or the consumption of basic excipients at the above-mentioned room temperature 25 DEG C that is cured (individually solidify above-mentioned acidity or basic excipients) or with acidity as liquid at the above-mentioned room temperature 25 DEG C that is cured or alkalescence figuration The total consumption of agent and above-mentioned alkali (or acid) property water-swellable and insoluble polymer (together solidifies above-mentioned acidity or alkalescence is composed Shape agent and above-mentioned acid (or alkali) property water-swellable and insoluble polymer) based on or benchmark.
Above-mentioned acid (or alkali) the property water-swellable generally used in pharmaceutical carrier of the present invention and insoluble polymer are with above-mentioned Alkali (or acid) property excipient (material) exists preferably in granular form.In an embodiment, above-mentioned acid (or alkali) property water-swellable And insoluble polymer can be through granulation (as ground or pulverizing and mix or add with above-mentioned alkali (or acid) property excipient (material) Enter binding agent to pelletize) afterwards (the two coexists in same granule, is called for short " preformed particles thing ") be scattered in above-mentioned aliphatic additive In substrate.In another embodiment, above-mentioned acid (or alkali) property water-swellable and insoluble polymer and above-mentioned alkali (or acid) property Excipient (material) can also directly disperse or each pelletize after (the two is stored in respective granule respectively, and this first mixes redispersion Granule be called for short " premix particulate matter ") be redispersed in above-mentioned aliphatic additive substrate.In actual applications, above-mentioned acid (or alkali) property water-swellable and insoluble polymer can also be simultaneously with above-mentioned with above-mentioned alkali (or acid) property excipient (material) Two kinds of discrete form be scattered in above-mentioned aliphatic additive substrate.When requiring release very fast as little to tens in a few hours Time primarily or entirely with the first dispersing mode, (the two coexists in same granule and is scattered in above-mentioned aliphatic additive substrate In) dispersion, when requiring release slower primarily or entirely with the second dispersing mode (the two when twenties hours in full or longer It is stored in respective granule respectively and is each scattered in above-mentioned aliphatic additive substrate) dispersion.
In other words, above-mentioned water-swellable and water-insoluble acidity (or alkalescence) polymer are composed with above-mentioned alkalescence (or acid) Shape agent (material) is scattered in this pharmaceutical carrier preferably with particulate matter, and the individual particle of this particulate matter contains above-mentioned acidity (or alkali Property) polymer and/or above-mentioned alkalescence (or acid) excipient (material), this particulate matter has the ability relatively slowly expanded, it Make disintegrating agent, regulating drug rate of release in the present invention.The ability that above-mentioned particulate matter expands is come by free wxpansion capacity Express.Combine with embodiment below and give the assay method of free wxpansion capacity.The freedom be given by following algoscopy is swollen Swollen capacity, refers here in 10 hours, under the load of insignificant about 0.01 pound/square inch (psi), and every gram above-mentioned The amount of the grain absorbable aqueous solution containing 0.9 weight % sodium chloride in gram of thing.Generally it is desirable that above-mentioned particulate matter in load is Under about 0.01psi, its initial free wxpansion capacity, typically at least about 3 gram gram, it is preferably about 5 gram gram, the most about 7 grams/ Gram, preferably from about 5～about 100 gram gram, even more preferably about 5～about 100 gram gram, conveniently about 7～about 70 gram gram, suitableeer Preferably it is about 10～about 70 gram gram.Terminology used here " initial free wxpansion capacity " refers to after prepared by above-mentioned particulate matter About 1 day in the free wxpansion capacity that had of particulate matter that measures, described particulate matter is to store at ambient conditions, such as from about 24 At DEG C, relative humidity is about 30～60%.This free wxpansion capacity should be not relatively low, because disintegrating property usual time relatively low is poor, this Free wxpansion capacity discomfort is too high, because too high free wxpansion capacity may cause local " being dried ", then produces zest, allows Patient feels the discomfort (such as sensation of pricking) of local.
Speed or speed that above-mentioned particulate matter expands reach the time used by 60% free wxpansion capacity by it and express.Below with Embodiment combines to give and reaches the assay method of time used by 60% free wxpansion capacity, this refers to above-mentioned particulate matter and inhales Receiving and reach its time used by total absorptive capacity 60%, total absorptive capacity of particulate matter is expressed as the free wxpansion of particulate matter and holds Amount.It is generally desirable to above-mentioned particulate matter reach time of 60% free wxpansion capacity and be at least about 5 minutes, preferably at least about 10 Minute, the most about 10～about 300 minutes, the most about 20～about 200 minutes, conveniently about 20～about 120 points Clock, the most about 20～about 60 minutes.The time reaching 60% free wxpansion capacity the most should be the not shortest, because imbibition is the fastest Local " being dried " may be caused, and then produce zest, allow patient feel the discomfort (such as sensation of pricking) of local；But also uncomfortable mistake Long, not so, drug release is too slow, needs unless there are special sequence, such as time delay release (such as time delay 2～8 hours) or long period release (such as release in 2 days or 7 days or longer time).
Due to above-mentioned particulate matter as absorb disintegrating agent be impregnated in the substrate of pharmaceutical carrier, in bond wherein, thus, it is swollen Time swollen, it not conventional free wxpansion, but by the expansion under the counteracting force (pressure) of substrate four wall, i.e. swollen under pressure-bearing Swollen.The usual resistance to pressure of absorption disintegrating agent used in former inventive technique is poor, the most easily " gel blockage " occurs, swollen Swollen disintegrating property is limited by bigger, and pharmaceutical carrier release may be not exclusively.The present invention use as absorbing disintegrating agent Above-mentioned particulate matter there is preferable pressure effect, be not susceptible to " gel blockage " under artesian condition, there is preferably expansion Disintegrating property.Above-mentioned particulate matter has liquid the ability that expands of absorbing under external pressure or pressure-bearing, is called under pressure-bearing swollen here Swollen capacity.Combine with embodiment below and give the assay method of expansion volume under pressure-bearing.The pressure-bearing be given by following mensuration Lower expansion volume, refers here in 10 hours, under the load of about 0.3 pound/square inch (psi), and every gram of above-mentioned particulate matter The amount of the absorbable aqueous solution containing 0.9 weight % sodium chloride in gram.Generally it is desirable that above-mentioned particulate matter is about in load Under 0.3psi, under its initial pressure-bearing, expansion volume is at least about 2 gram gram, is preferably about 3 gram gram, the most about 5 gram gram, About 7 gram gram goodly, preferably from about 3～about 70 gram gram, more preferably from about 5～about 70 gram gram, conveniently about 5～about 40 grams/ Gram, the most about 7～about 40 gram gram, the most about 5～about 20 gram gram.Terminology used here " initial pressure-bearing Lower expansion volume " refer to about 1 day after prepared by above-mentioned particulate matter in expansion volume under the pressure-bearing that had of particulate matter that measures, Described particulate matter is to store at ambient conditions, and at such as from about 24 DEG C, relative humidity is about 30～60%.Expansion volume under this pressure-bearing Should be not relatively low, because disintegrating property usual time relatively low is poor, under this pressure-bearing, expansion volume is the most uncomfortable too high, expands under too high pressure-bearing Capacity may cause local " being dried ", then produces zest, allows patient feel the discomfort (such as sensation of pricking) of local.
Above-mentioned particulate matter under external pressure or pressure-bearing relative to slowly absorbing liquid the speed expanded or speed with reaching 60% pressure-bearing The time of lower expansion volume expresses.Combine with embodiment below to give and reach expansion volume institute's used time time under 60% pressure-bearing Between assay method.Following measure be given reach the time of expansion volume under 60% pressure-bearing, this refers in minutes, above-mentioned Particulate adsorbent reaches always to absorb the time used by expansion volume under the pressure-bearing of the 60% of this particulate matter, total under the pressure-bearing of particulate matter Absorb expansion volume and be expressed as expansion volume under the pressure-bearing of particulate matter.It is generally desirable to above-mentioned particulate matter reach to expand under 60% pressure-bearing Time during capacity is at least about 5 minutes, preferably at least about 10 minutes, the most about 10～300 minutes, more advantageously About 20～200 minutes, conveniently about 20～120 minutes, the most about 20～60 minutes.Reach swollen under 60% pressure-bearing The time of swollen capacity the most should be the not shortest, may cause local " being dried " because of imbibition the soonest, and then produce zest, allows patient feel Discomfort (such as sensation of pricking) to local；But the most uncomfortable long, not so, drug release is too slow, needs, as time delay is released unless there are special sequence Medicine (such as time delay 2～8 hours) or long period release (such as release in 2 days or 7 days or longer time).
In order to preferably make medicine by stripping curve dissolution that is preferable or that preset, in pharmaceutical carrier of the present invention, apply two kinds or More kinds of different speed expanded or the above-mentioned particulate matter of speed, so can make pharmaceutical carrier disintegrate on different time, medicine Release presents " stage " or " pulsed ", thus drug release release in different time sections, before and after presenting release generally Speed is consistent.In an embodiment, time of expansion volume under 60% pressure-bearing that reaches of above-mentioned particulate matter of a part be about 5～ About 60 minutes (being preferably about 10～about 60 minutes), the above-mentioned particulate matter of another part reach expansion volume under 60% pressure-bearing Time be about 90～about 300 minutes；In another embodiment, a part above-mentioned particulate matter reach under 60% pressure-bearing expand The time of capacity is about 5～about 60 minutes (being preferably about 10～about 60 minutes), reaching of the above-mentioned particulate matter of a part Under 60% pressure-bearing, the time of expansion volume is about 90～about 300 minutes, and the reaching of the above-mentioned particulate matter of another part 60% is held The time of pressure expansion volume is about 180～about 600 minutes.The particulate matter of the above-mentioned different speed expanded or speed at medicine Amount ratio in carrier is preferably about 1: 1: 1 ....The particulate matter of the above-mentioned different speed expanded or speed is dispersed among same In a kind of release particulate matter, it is also possible to be scattered in respectively in different release particulate matters, this kind of different release particulate matter loads As in capsule, bag agent in same drug release carrier, or it is pressed in a tablet simultaneously.
When above-mentioned water-swellable and water-insoluble acidity (or alkalescence) polymer and above-mentioned alkalescence (or acid) excipient When (material) is scattered in this pharmaceutical carrier with particulate matter, the individual particle of this particulate matter contains above-mentioned acidity (or alkalescence) polymerization Thing and/or above-mentioned alkalescence (or acid) excipient (material), it is often desirable that the largest cross-sectional sized of this granule is less than about 600 microns (about 28 mesh, Tyler standard), preferably less than about 75 microns (about 200 mesh, Tylerstandard), more preferably less than About 25 microns (about 500 mesh, Tyler standard).
Generally, take the acidity of substantially its free acid (or free alkali) form or alkaline water swellability respectively and water-insoluble gathers Compound, adds in the pharmaceutical carrier of the present invention with alkalescence (or acid) excipient (material), the acidity of each of which and alkali respectively The mol ratio of property functional group should be enough to be supplied in pharmaceutical carrier of the present invention with required performance.Preferred acidic (or alkalescence) is water-soluble Swollen property and insoluble polymer respectively with acidity and the mol ratio of basic functionality of alkalescence (or acid) excipient (material) It is about 20: 1～about 1: 20, conveniently about, 10: 1～about 1: 10, conveniently about 4: 1～about 1: 4, the most about 2: 1 ～about 1: 2, the most about 1: 1.
Based on the gross weight of pharmaceutical carrier, above-mentioned acid (or alkali) property water-swellable and insoluble polymer and above-mentioned alkali The total content of (or acid) property excipient (material) (content and) typically respectively 0.2～30%wt./wt., preferably 0.5～ 20%wt./wt., more preferably 1～15%wt./wt..Above-mentioned alkali (or acid) property excipient (material) is solid (room temperature 25 DEG C) Time, above-mentioned acid (or alkali) property water-swellable and insoluble polymer contain with the total of above-mentioned alkali (or acid) property excipient (material) The amount (content and) ratio in the granule (above-mentioned preformed particles thing) at its place is 50～100%, preferably 75～ 100%, preferably 90～100%；When above-mentioned alkali (or acid) property excipient (material) is liquid (room temperature 25 DEG C), above-mentioned acid Total content (the content of (or alkali) property water-swellable and insoluble polymer and above-mentioned alkali (or acid) property excipient (material) With) ratio in the granule (above-mentioned preformed particles thing) at its place is 10～70%, preferably 10～60%, it is more preferably 20～50%.Above-mentioned acid (or alkali) property water-swellable and the insoluble polymer granule (above-mentioned premix particulate matter) at its place In ratio be 50～100%, preferably 75～100%, preferably 90～100%.
The preparation method of above-mentioned preformed particles thing or premix particulate matter includes but not limited to:
1), water miscible neutrality (or weakly acidic pH) or non-ionic polyalcohol are (such as polyvinylpyrrolidone, polyvinyl alcohol, hydroxyl second Methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose) anhydrous organic solution Mull technique: take above-mentioned water miscible neutrality or non-ionic polyalcohol molten (or dispersion) must bond use in anhydrous organic solvent Liquid, take appropriate above-mentioned bonding liquid add above-mentioned acidity or basic excipients and/or above-mentioned alkali (or acid) property water-swellable and In insoluble polymer, mixing prepares soft material, then pelletizes, and sieve to obtain required granule.Above-mentioned water solublity as binding agent Neutrality or the consumption of non-ionic polyalcohol be 1～30%wt./wt., preferably 2～15%wt./wt., with above-mentioned alkali (or Acid) property water-swellable and insoluble polymer consumption (when alkali (or acid) polymer is individually pelletized) or with above-mentioned acid Property (or alkalescence) excipient and above-mentioned alkali (or acid) property water-swellable and insoluble polymer total consumption (above-mentioned acidity or When basic excipients and above-mentioned acid (or alkali) property water-swellable and insoluble polymer are together pelletized) based on or benchmark.
2) dry adhesive, using dry adhesives is pelletized: take dry adhesives and above-mentioned acidity or basic excipients and/or above-mentioned alkali (or acid) property water-swellable and insoluble polymer mixing, re-compacted one-tenth block, pulverize, and sieve to obtain required granule. " dry adhesives " used by the present invention, its effect is to make smaller particles be bonded together, it is ensured that particle bigger after granulation can be protected Hold certain form, and can guarantee that reaching certain fragility is beneficial to disintegrate, also ensures that the work of disintegrating agent and sweller simultaneously With more effectively playing, it is to avoid the adverse effect that the disintegrate (expansion) of disintegrating agent (sweller) is acted on by solvent.Useful is dry viscous Mixture includes, but are not limited to: starch, such as Rhizoma Solani tuber osi, Semen Tritici aestivi and corn starch；Polyethylene Glycol, especially molecular weight be 4000～ The Polyethylene Glycol of 6000；Polyvinylpyrrolidone (PVP), crospolyvinylpyrrolidone；Cross-linked carboxymethyl cellulose, carboxymethyl Cellulose, hydroxypropyl methyl cellulose；Pregelatinized Starch, carboxymethyl starch；Microcrystalline Cellulose, crystalline cellulose, cellulose powder End, the microcrystalline Cellulose of silication；Dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, Pulvis Talci, Aerosil 200 (as Aerosil), light anhydrous silicic acid；Mannitol, lactose, maltose alcohol, Sorbitol, xylitol, lactose (anhydrous or work For hydrate, such as monohydrate), D-glucose, maltose, sucrose, glucose, fructose or maltodextrin；And be blended Compound.It is particularly preferred that dry adhesives is microcrystalline Cellulose (MCC).Dry adhesives consumption in granule be 10～50% (weight Amount/weight), preferably 15～40% (w/w), this is with above-mentioned alkali (or acid) property water-swellable and water-insoluble polymerization The consumption (when individually pelletizing) of thing or with above-mentioned acidity (or alkalescence) excipient and above-mentioned alkali (or acid) property water-swellable And the total consumption of insoluble polymer (above-mentioned acidity or basic excipients and above-mentioned acid (or alkali) property water-swellable and water are not When soluble polymer is together pelletized) based on or benchmark.
3), direct pressing granulating method: take above-mentioned acidity or basic excipients and/or above-mentioned alkali (or acid) property water-swellable and water Insoluble polymer mixes, and is pressed into block under bigger pressure (such as 10～50kg/cm2), pulverizes, and sieves required Granule.
Generally, commercially available water-swellable and insoluble polymer are substantially neutralized form or salt form.But it is unfortunate , easily there is " salt poisoning " effect and " gel blockage " effect, especially in water-swellable and the insoluble polymer of salt form Being under artesian condition, its disintegration is easily greatly diminished, thus the release to medicine produces large effect, and, its Height before the side effect such as zest are the most unneutralized, biocompatibility declines.
Thus, the shape of its free acid or free alkali is substantially used for the water-swellable of the present invention and insoluble polymer Formula.But, above-mentioned water-swellable and insoluble polymer and the acidity of polymer or basic functionality are relatively weak respectively Character, when it is individually placed in liquid, as time in water or aqueous sodium chloride solution, these faintly acids or weakly alkaline functional group are not Easily dissociation, is generally difficult to play its performance.
However it is discovered in the present invention that, when above-mentioned acidity (or alkalescence) water being substantially respectively its free acid (or free alkali) form (particularly alkalescence (or acid) water-swellable and water is insoluble with alkali (or acid) excipient (material) for swellability and insoluble polymer Property polymer) when being used in mixed way, the pharmaceutical carrier of gained has better performance.It is mainly manifested in following several aspect.The One, more preferable drug release feature, higher anti-" salt poisoning " effect, can preferably release in high level salt solution；Second, preferably release Medicine homogeneity, preferably alleviates or solves the problem such as " release is first quick and back slow " and/or " end release is incomplete "；3rd, more preferably Biocompatibility.
When being placed in aqueous solution by pharmaceutical carrier, substantially it is respectively acidity (or the alkali of its free acid (or free alkali) form Property) water-swellable and insoluble polymer, will react with contrary alkalescence (or acid) excipient (material) respectively, and this Plant chemical equilibrium and beneficially will be respectively acidity (or alkalescence) compound of its free acid (or free acid) form, be changed into its salt Form.Water-swellable after conversion and insoluble polymer, will have them and can play big with salt form compound generally Cause suitable performance.Convert the water-swellable after (ionizing) and insoluble polymer water absorption and swelling, play disintegrating agent effect, make Drug-carrier matrix decomposition ruptures thus promotes the release of medicine.
Containing dielectric solution, water-swellable and water-insoluble such as acidity above-mentioned in sodium-chloride water solution (or alkalescence) are polymerized Thing converts to its salt form by its free acid (or free alkali) form respectively, and this is substantially to having containing dielectric solution Desalination, has thus relaxed " salt poisoning " effect, thus has been respectively increased its performance.
Additionally, the present inventors have additionally discovered that the water-swellable by the acidity (or alkalescence) of its free acid (or free alkali) form of above-mentioned use Property and insoluble polymer, be used in mixed way with contrary alkalescence (or acid) excipient (material) as absorbing disintegrating agent, should Absorb disintegrating agent and there is preferable pressure effect, be not susceptible to " gel blockage " under artesian condition, thus pharmaceutical carrier disintegrate More fully or more thorough, drug release is more fully or more complete.
It is believed that these factors above-mentioned that are based on, the drug release feature that the pharmaceutical carrier that the present invention relates to has had, higher anti- " salt poisoning " effect, release can show more preferable release homogeneity in high level salt solution, can preferably alleviate or solve " release First quick and back slow " and/or the problem such as " end release is incomplete ".
Due to the water-swellable of acid (or alkalescence) and insoluble polymer respectively by its free acid (or free alkali) form to This conversion of its salt form, is a relatively slow dissociation and the ion process that diffuses into polymer, therefore, acid (or alkali Property) water-swellable and the performance of insoluble polymer can play with slowly continuing so that contact with this pharmaceutical carrier or The mucosa neighbouring with this pharmaceutical carrier is not susceptible to quick dehydration, causes local " being dried ", thus zest lowers, patient feels Discomfort (such as the sensation of pricking) sense of local alleviates.Especially, the water-swellable of above-mentioned acidity and insoluble polymer and alkalescence When water-swellable and insoluble polymer coexist in pharmaceutical carrier, they respectively by its free acid (or free alkali) form to respectively From salt form convert, do not introduce the ion of great quantities of spare, such as sodium ion, potassium ion, chloride ion, sulfate ion, thus While ensureing that they can play the performance roughly the same with salt form compound generally, and it is greatly reduced mucosa etc. Zest.Thus, the biocompatibility of pharmaceutical carrier is preferably enhanced.
One great being particular in that of the present invention and conventional art, by control above-mentioned absorption disintegrating agent swelliong power and Particularly its speed expanded or speed, control pharmaceutical carrier body fluid absorption amount in body cavity, particularly delay medicine to carry Body body fluid absorption speed in vivo, eliminates or delays local " being dried ", lowering zest, alleviates patient and feels local not Suitable sense (such as sensation of pricking).
A kind of pharmaceutically acceptable water-soluble surfactant is also added in the pharmaceutical carrier that the present invention relates to.Institute Porogen mainly made by the surfactant stated, for acid (or alkalescence) water-swellable and insoluble polymer with Alkalescence (or acid) excipient (material) reaction provides more required medium aqueous water, accelerates its reaction, and promotes medicine Thing carrier release.
For water-soluble surfactant of the present invention, with neutral or nonionic surfactant for more preferably.Can make Suitable surfactant example for the present invention includes but not limited to:
A), polyethylene glycol fatty acid such as carbon number is the saturated of C12～C22 or unsaturated straight chain fatty acid or its single or double hydroxyl Base fatty acid monoester class, includes but not limited to PEG6,7,8,9,10,12,15,20,25,30,32,40,45,50,55,100, The lauric acid (lauric acid/dodecanoic acid) of 200,300,400,600 grades, (meat) myristic acid (tetradecylic acid), Palmic acid (hexadecylic acid), stearic acid (ten Eight acid), arachidic acid (20 acid), behenic acid (behenic acid), oleic acid, the esters of ricinoleic acid.Such as, PEG-6 laurate or Stearate, PEG-7 oleate or laurate, PEG-8 laurate or oleate or stearate, PEG-9 oleate or Stearate, PEG-10 laurate or oleate or stearate, PEG-12 laurate or oleate or stearate or Monoricinolein, PEG-15 stearate or oleate, PEG-20 laurate or oleate or stearate, PEG-25 stearic acid Ester, PEG-32 laurate or oleate or stearate, PEG-30 stearate, PEG-40 laurate or oleate or hard Fat acid ester, PEG-45 stearate, PEG-50 stearate, PEG-55 stearate, PEG-100 oleate or stearate, PEG-200 oleate, PEG-400 oleate, PEG-600 oleate；(surfactant belonging to this colony is such as known as Cithrol, Algon, Kessco, Lauridac, Mapeg, Cremophor, Emulgante, Nikkol, Myrj, Crodet, Albunol, Lactomul)；
B), polyethylene glycol fatty acid such as carbon number is the saturated of C12～C22 or unsaturated straight chain fatty acid or its single or double hydroxyl Base fatty acid diesters class, includes but not limited to PEG-8, the lauric acid (lauric acid/dodecanoic acid) of 10,12,20,32,400 grades, (meat) myristic acid (tetradecylic acid), Palmic acid (hexadecylic acid), stearic acid (stearic acid), arachidic acid (20 acid), behenic acid (behenic acid), oleic acid Two esters, such as, PEG-8 dilaurate or distearate, PEG-10 dipalmitate, PEG-12 dilaurate or two Stearate or dioleate, PEG-20 dilaurate or distearate or dioleate, PEG-32 dilaurate or Distearate or oleate, PEG-400 dioleate or distearate；(belong to the surfactant of this colony such as It is known as Mapeg, Polyalso, Kessco, Cithrol)；
C), polyethylene glycol fatty acid such as carbon number is the saturated of C12～C22 or unsaturated straight chain fatty acid or its single or double hydroxyl Base fatty acid list and two ester admixtures, such as PEG4-150 are mono-and dilaurate, PEG4-150 are mono-and distearate etc.； (surfactant belonging to this colony is such as known as Kessco)；
D), Polyethylene Glycol glycerol fatty acid such as carbon number be the saturated of C12～C22 or unsaturated straight chain fatty acid or its singly Or double hydroxy fatty acid esters, such as PEG-20 glyceryl laurate ester or tristerin or olein, PEG-Laurel Acid glyceride, PEG-glyceryl laurate ester etc.；(surfactant belonging to this colony is such as known as Tagat, GlyceroxL, Capmul)；
E), the product of alcohol-oil transesterification comprises alcohols or such as glycerol, propylene glycol, ethylene glycol, Polyethylene Glycol, Pyrusussuriensis The polyalcohols such as sugar alcohol, tetramethylolmethane, with natural and/or its oily or oil-soluble vitamins being hydrogenated such as, Oleum Ricini, The Oleum Ricini that is hydrogenated, vitamin A, vitamin D, vitamin E, vitamin K, edible vegetable oil such as, Semen Maydis oil, Fructus Canarii albi The esters that oil, Oleum Arachidis hypogaeae semen, palmolive core oil, almond oil, Semen Juglandis oil etc. generate, such as PEG-20 Oleum Ricini or the Semen Ricini being hydrogenated Oleum Ricini that oil or corn oil glyceride or Semen Juglandis oil glyceride, PEG-23 Oleum Ricini, PEG-25 are hydrogenated or trioleate, Cremophor ELP, PEG-30 Oleum Ricini or the Oleum Ricini being hydrogenated, PEG-38 Oleum Ricini, PEG-40 Oleum Ricini or be hydrogenated Oleum Ricini or palmolive core oil, PEG-45 be hydrogenated Oleum Ricini, PEG-50 Oleum Ricini or the Oleum Ricini being hydrogenated, PEG-56 Semen Ricini Oil, PEG-60 Oleum Ricini or the Oleum Ricini being hydrogenated or corn oil glyceride or Semen Juglandis oil glyceride, PEG-80 are hydrogenated Oleum Ricini, PEG-100 Oleum Ricini or the Oleum Ricini being hydrogenated, PEG-200 Oleum Ricini, PEG-8 octanoic acid/or glycerol decanoate, PEG-6 octanoic acid/or glycerol decanoate, lauroyl Polyethylene Glycol-32 glyceryl alcohol, stearoyl macrogol glyceride, fertility Base PEG-1000 succinate (TPGS)；(surfactant belonging to this colony is such as known as Emalex, Cremophor, Emulgante, Eumulgin, Nikkol, Thornley, Simulsol, Cerex, Crovol, Labrasol, Softigen, Gelucire, vitamin E TPGS)；
F), by the fatty acid of bound to polyglycerol such as carbon number be the saturated of C12～C22 or unsaturated straight chain fatty acid or its single or Double hydroxy aliphatic acids comprise fatty acid such as carbon number be the saturated of C12～C22 or unsaturated straight chain fatty acid or its single or The polyglycerol esters of double hydroxy fatty acids, such as, polyglyceryl-10 laurate or oleate or stearate, polyglycereol Base-10 list and dioleate, the poly-ricinoleate ester of polyglyceryl etc.；(surfactant belonging to this colony is such as known as Nikkol, Decaglyn, Caprol or Polymuls)；
G), stearyl alcohol derivant comprise the polyethyleneglycol derivative of stearyl alcohol such as, PEG-24 cholesterol ethers, PEG-30 gallbladder alcohol, PEG-25 vegetable stearin alcohol, PEG-30 Semen sojae atricolor stearyl alcohol etc.；(surfactant belonging to this colony is such as known as Solulan or Nikkol BPSH)；
H), Polyethylene Glycol sorbitan fatty acid such as carbon number be the saturated of C12～C22 or unsaturated straight chain fatty acid or its Single or double hydroxy aliphatic acids, such as PEG-10 sorbitol anhydride laurate, PEG-20 sorbitanmonolaureate or Pyrusussuriensis Alcohol acid anhydride tristearate or sorbitan mono-oleic acid ester or SPAN85 or sorbitol anhydride list isostearate or mountain Pears alcohol acid anhydride monopalmitate or sorbitan monostearate, PEG-4 sorbitanmonolaureate, PEG-5 sorbitol anhydride list Oleate, PEG-6 sorbitan mono-oleic acid ester or Span-20 or sorbitan monostearate, PEG-8 Sorbitan monostearate, PEG-30 sorbitol anhydride four oleate, PEG-40 sorbitan mono-oleic acid ester or sorbitol anhydride four Oleate, PEG-60 sorbitol anhydride tetrastearate, PEG-80 sorbitanmonolaureate, PEG sorbitol anhydride six oleate Deng；(belong to the surfactant of this colony be such as known as Liposor, Tween, Dacol MSS, Nikkol, Emalex, Atlas)；
I), polyalkylene glycol alkyl such as carbon number is the saturated of C12～C22 or unsaturated straight chained alkyl or its single or double hydroxyl alkane Base esters, such as PEG-10 oleyl ether or palmityl ether or stearoyl ether, PEG-20 oleyl ether or palmityl ether or or stearoyl Ether, PEG-9 lauryl ether, PEG-23 lauryl ether, PEG-100 stearoyl ether etc.；(belong to the surfactant example of this colony As being known as Volpo, Brij)；
J), sugar esters such as sugar carbons number is the saturated of C12～C22 or unsaturated straight chain fatty acid or its single or double hydroxy aliphatic Esters of gallic acid, the such as acid/of sucrose distearyl or monostearate, sucrose monostearate or monolaurate etc.；(belong to this group The surfactant of body is such as known as Sucro ester, Crodesta, sucrose monolaurate)；
K), polyalkylene glycol alkyl such as carbon number is the saturated of C12～C22 or unsaturated straight chained alkyl or its single or double hydroxyl alkane Base phenol, such as PEG-10～100 nonyl phenols (Triton X series), PEG-15～100 octyl phenol ether (Triton N Series) etc.；
L), polyoxy ethylene-polyoxy propylene-based block copolymer (poloxalkol class (poloxamers), such as poloxalkol 108, poloxamer 188, poloxalkol 237, poloxalkol 288 etc.；(surfactant belonging to this colony is such as known as Synperonic PE, Pluronic, Emkalyx, LutrolTM, Supronic, Monolan, Pluracare, Plurodac)；
M), ionic surfactant includes that cation, anion and amphion interfacial agent, such as fatty acid such as carbon are former Subnumber is the saturated of C12～C22 or unsaturated straight chain fatty acid or its single or double hydroxy aliphatic hydrochlorate, such as enuatrol, lauryl Sodium sulfate, sodium lauryl sarcosinate, dioctyl sodium sulphosuccinate, tetradecanoic acid sodium, sodium palmitate, sodium ricinoleate etc.；Example Such as bile salts such as sodium cholate, sodium taurocholate, sodium glycocholate etc.；Such as phosphide class such as egg/or soybean lecithin, by hydroxylating Lecithin, defat acid phosphatidyl choline, phosphatidylcholine, phosphatidylethanolamine, phosphatidyl glycerol, phosphatidyl silk ammonia Acid etc.；Such as phosphoric acid ester such as diethanol ammonium polyethylene glycol oxide-10 oleyl ether phosphate ester, aliphatic alcohols or fatty alcohol ethoxy hydrochlorate With phosphoric acid or the esterification products of anhydride；Such as carboxylic acid esters is such as, by the monoglyceride class of succinylation, stearoyl butene dioic acid Sodium, stearoyl propylene glycol hydrogen succinate ester, list-and the list/of two glycerolipids or diacetyl be exactly esters of gallic acid, list-and The citric acid ester type of two glyceride, the glyceryl-butterfat class of fatty acid, the lactic acid ester of fatty acid, stearoyl-2-lactic acid Calcium/or sodium, stearic acid calcium lactate/or sodium, diatom salt, propylene glycol silicate, ether carboxylate class etc.；Such as Sulfates and sulphur Barbiturates, as by the alkylsurfuric acid salt of ethoxyquin, alkyl sulfate class, α-olefin sulfonate class, acyl group 2-ethoxy sulphur Esters of gallic acid, N-acyl taurines esters, alkyl glycerol base ether sulfonic acid esters, octyl group disodium sulfosuccinate, endecatylene amide Base-MEA-disodium sulfosuccinate etc.；Such as cationic surfactant class, such as palmityl three ammonium bromide, decyl trimethyl Ammonium bromide, cetyltrimethyl ammonium bromide, dodecyl ammonium chloride, alkyl benzyl dimethyl ammonium salt class, diisobutyl benzene Epoxide ethyoxyl dimethyl benzyl ammonium salt, alkyl pyridine salt, betaines (lauryl betaine), by the amine of ethoxyquin (polyoxy vinyl-15 coconut amine) etc.；
And the mixture of above-mentioned surfactant n).
In suitable surfactant listed above, list different probabilities such as PEG-20 oleyl ether or palmityl Ether or stearoylketene ether this be to represent the meaning that PEG-20 oleyl ether and PEG-20 palmityl ether and PEG-20 stearoyl ether are indication. Thus, such as PEG-20 Oleum Ricini or the Oleum Ricini being hydrogenated or Corn glycerides class or the Semen Juglandis glyceride type palpus being hydrogenated It is read as PEG-20 Oleum Ricini and Oleum Ricini that PEG-20 is hydrogenated and GROVOL M-40 class and PEG-20 be hydrogenated Semen Juglandis oil glyceride type.
Preferred surfactant in the present composition belong to this colony of Polyethylene Glycol sorbitan carboxylic esters class, alcohol- This colony of product of oil transesterification or polyoxy vinyl-this colony of polyoxypropylene block copolymers.Preferably Ground, the surfactant in the present composition belongs to Polyethylene Glycol this colony of sorbitan carboxylic esters class or alcohol-grease This colony of the product of group-transfer effect.Most preferably surfactant is referred to as the surfactant of Tween, is referred to as The surfactant of Cremophor, and vitamin E TPGS (α-fertility base-polyethanediol succinate, is also abbreviated by TGPS), especially Cremophor RH40 and VE TPGS.Some are preferably if castor oil derivatives is (such as commodity Entitled HCO 60, Nikko Chemical Co., Ltd produce polyoxyethylene (60) castor oil hydrogenated), Polysorbate (as Tween61, Tween60, Tween80), polyoxyethylene stearic acid ester (such as Polyethylene Glycol (40) stearate).
As another preferred embodiment of the present composition, surfactant can be by the waxiness of suitable weak surface activity Excipient (material) replaces, and such as Polyethylene Glycol such as PEG 100～20000, is weak table compared with the advantage of other surfactants Face activity, can relatively large use, low toxic and side effects, high security, more preferable pore effect, because its helical structure has bigger dividing Sub-diameter and length.
Water-soluble surfactant amount in pharmaceutical carrier should be not enough so that pharmaceutical carrier is at itself and endoceliac body fluid Liquefaction or emulsifying or thawing during contact, fusing point when pharmaceutical carrier and bioresorbable must be higher than temperature 37 DEG C in other words.This be because of Burst drug release dosage in other words will be caused to incline release with just liquefying during bioresorbable or melt in body cavity for pharmaceutical carrier (dose-dumping), thus cause drug safety problem.Based on the gross weight of pharmaceutical carrier, live in water-soluble surface Property agent consumption is usually 0.01～10%wt./wt., and preferably 005～5%wt./wt., preferably 0.1～2%wt./wt., And the above-mentioned fusing point of amount ratio of above-mentioned water-soluble surfactant more than temperature 37 DEG C and in body cavity with bioresorbable time Fusing point also above the consumption of the aliphatic additive of temperature 37 DEG C less than 18, preferably less than 1 10, do not surpass Cross 1 16 (the most above-mentioned aliphatic additive be single carbon atom number be the fatty glyceride of C14～C22, single carbon atom number It is that the ethylene glycol fatty acid of C18～C22, single carbon atom number are for the fatty acid propylene glycol ester of C18～C22, single carbon atom number When the fatty acid binaryglycol ester of C18～C22 or their mixture, or its consumption accounts for whole above-mentioned aliphatic additive When the ratio of consumption is more than 40%), more more preferably less than 1 25, (the most above-mentioned water-soluble surfactant is ion During type surfactant, because its emulsifying ability is the strongest compared with nonionic surfactant), most preferably less than 1 40 (particularly Above-mentioned aliphatic additive be single carbon atom number be the fatty glyceride of C14～C22, single carbon atom number be the fat of C18～C22 Fat acid propylene glycol ester, single carbon atom number be the ethylene glycol fatty acid of C18～C22, single carbon atom number be the fat of C18～C22 Acid diethylene glycol ester or their mixture, or the ratio of its consumption consumption of accounting for whole above-mentioned aliphatic additive exceedes When 40% and when above-mentioned water-soluble surfactant is ionic surfactant), these restrictions mainly prevent above-mentioned The appearance of deleterious situation, simultaneously again can be relatively low (if single carbon atom number is C14～C22 at above-mentioned aliphatic additive hydrophilic Fatty glyceride, single carbon atom number be the fatty acid propylene glycol ester of C18～C22, single carbon atom number be the fat of C18～C22 Acid glycol ester, single carbon atom number are the fatty acid binaryglycol ester of C18～C22 or the consumption of their mixture accounts on whole State aliphatic additive consumption ratio less than 40% time) and its consumption more such as more than the 60% (gross weight with pharmaceutical carrier Based on amount) time, it is ensured that the consumption of above-mentioned water-soluble surfactant meets release speed in the actual application of pharmaceutical carrier Demand when degree needs very fast, in former technology, when consumption is 80%, aforementioned proportion is 5%/80%=1/16 to the maximum, can Can be difficult to meet demand when drug release rate needs are very fast in the actual application of pharmaceutical carrier, aforementioned proportion is maximum in former technology It is 5%/40%=1/8.
Above-mentioned have fat-soluble there is again the waxiness excipient (material) (PEG) of water miscible weak surfactant because of its emulsibility Can be extremely low, therefore its consumption relatively water soluble surfactant active can be bigger, thus, it is more suitable for the faster medicine of those rate of releasing drug and carries Body.Based on the gross weight of pharmaceutical carrier, above-mentioned have fat-soluble there is again water miscible solid or liquid (room temperature 25 DEG C) Excipient (material) consumption of weak surfactant (PEG100～20000) be usually 0.01～30%wt./wt., preferably 0.1～20%wt./wt., preferably 0.2～10%wt./wt..Owing to PEG1000～20000 can also substitute above-mentioned solvable In additive water, low viscous, double as above-mentioned additive water-soluble, low viscous and water-soluble surface-active the most simultaneously Agent, now, its content is usually 5.0～50%wt./wt., and preferably 10～40%wt./wt., preferably 10～30% Wt./wt., this content is based on the gross weight of pharmaceutical carrier.
Any medicine or active component may be used to the present invention, are especially suitable for medicine or the active component of sustained-release administration.Close The medicine being applicable to the present invention is to be selected from, but is not limited to this: adrenocortical hormone, local anesthetic, antipyretic/to ease pain/disappear Scorching medicine, antiinflammatory/antipruritic, Wound-healing agent, vitamin, sulfonamides, antibiotic, antifungal, antibacterial, antiviral agents, Vasoconstrictor, antihistaminic, anesthetis, astringent, contraceptive, termination of pregnancy medicine, defecation accelerator, hypnosis tranquilizer, anti- Anxiety medicine, Anti-epileptics, excited inoitantia, antiparkinsonian drug, central nervous system make medication, analgesics, skeletal muscle relaxation Medicine, autonomic drug, spasmolytic, antivertigo drug, antiemetic, cardiac tonic, anti-arrhythmic, diuretic, antihypertensive, hat Shape vasodilation, peripheral vasodilator, hyperlipidemia medicine, breathing accelerator, beta 2 receptor agonist, anti-Meniere's disease Medicine, antitumor agent, antidiarrheal/intestinal function regulator, treatment of ulcerative colitis agent, peptic ulcer therapeutic agent, resistance dysfunction Medicine, Labor-inducing medicine, anthelmintic, bronchodilator, biological product or peptides, anti-allergic drug, cathartic, enema, function of gallbladder promoting Medicine and the multiple hormone in addition to adrenocortical hormone.
The concrete medicine can being compounded in pharmaceutical carrier of the present invention, its illustration can be selected from one or more following medicines Thing, but it is not limited to these: adrenocortical hormone, such as Prednisolone acetate, prednisolone, acetic acid hydrocortisone, hydrogen Change cortisone, acetic acid cortisone, cortisone, DEX A.A, dexamethasone, acetic acid triamcinolone；
Local anesthetic, such as lidocaine hydrochloride, lignocaine, dibucaine hydrochloride, dibucaine, procaine hydrochloride, Procaine, tetracaine hydrochloride, tetracaine, chloroprocaine hydrochloride, chloroprocaine, bupivacaine hydrochloride, bupivacaine, salt Acid the third handkerchief caine (propalacaine), the third handkerchief caine, meprylcaine hydrochloride ((mepurylcaine), meprylcaine, first piperazine card Cause, benzocaine, orthocaine (orsocaine), Mucaine, Ethyl aminobenzoate., hydrochloric acid are to fourth amino Benzoyl diethylaminoethanol, oxidation polyethoxy decane or east flower labor belong to extract；
Antipyretic-analgesia-antibiotic medicine, such as aspirin, acetaminophen, mefenamic acid, acetamido benzene, Phenacetin, Diclofenac sodium, diclofenac potassium, indomethacin, buprenorphin hydrochloride, ibuprofen, mefenamic acid, aminophenazone, benzophenone benzene Propanoic acid, piroxicam, ibuprofen, (S)-ibuprofen, naproxen, sulfasalazine, mesalazine, ketoprofen, meloxicam, salt Acid benzydamine, ethenzamide and piroxicam；
Antiinflammatory-antipruritic, such as enoxolone, lisozima, diformazan isopropyl, ichthyol, Camphora, crotamiton, Lysozyme chloride, tribenoside, aluminium potassium sulfate, Radix Arnebiae (Radix Lithospermi) extract, rosskastanien extract, Hamamelis virginiana (witch hacel) extract, the cana Brava of processing, refined vitelline lecithin, elgen, d-Camphora, dl-Camphora, thin Lotus oil, l-menthol, dl-menthol, Eucalyptus oil；
Vitamin, such as tocopherol acetate, tocopherol, vitamin D2, palmitic retinol, Vitamin A1 acetate, pyridoxine hydrochloride, Hydrochloric acid pyridoxamine, phosphopyridoxamine, pyridoxal hydrochloride, pyridoxal 5-phosphate, riboflavin, Riboflavin butyrate, vitamin A oil, dimension are raw Element C, vitamin B6, vitamin e acetate, senior liver oil or liver oil；
Sulfonamides, such as sulfadiazine, sulfasomidine, sulfasomidine sodium, high sulfonamide, domian, sulphur Amine different diformazan pyrimidine sodium, homosulfamine；
Antibiotic or antifungal, such as cephalosporins such as ceftizoxime sodium, penicillins such as sodium ampicillin, quinolinones Class such as norfloxacin, ofloxacin, ciprofloxacin, ciprofloxacin lactate, pefloxacin mesilate, lactic acid levofloxacin Star, Macrolide such as erythromycin, Tetracyclines such as tetracycline, quadracycline, tetramycin hydrochloride, antimycotic is as gram mould Azoles, miconazole, tinidazole, miconazole nitrate, econazole nitrate, terconazole (triaconazole), ketoconazole, Nitric acid butoconazole, sertaconazole, Oxygen health azoles, Fazol (Schering), hachimycin, nysfungin, natamycin, ciclopirox olamine, nifuratel, econazole, nitre Acid econazole, miconazole, micatin, chlorine trityl imidazole, bifonazole, terbinafine HCl And butenafine hydrochloride, other antibiotic such as streptomycin sulfate, gentamycin sulfate, lincomycin hydrochloride, clindamycin phosphoric acid Ester, polygynax, amphotericin B, kanamycin sulfate, metronidazole, ornidazole, secnidazole, chloromycetin, nitrofurantoin, Fibrauretin, matrine, Sodium Houttuyfonate, pimaricin；
Antibacterial, such as ethacridine, chlorhexidine acetate, poly-aminoethyl glycine Arrcostab, isopropyl cresol, cetyl pyridinium Chlorine, dequalinium chloride, berberine chloride, benzalkonium chloride, Chlorhexidine hydrochloride, cetab, chlorination decahydronaphthalenes, benzene Phenol, resorcin, policresulen, povidone iodine；
Astringent, such as zinc oxide, tannic acid, albumin tannate and aluminum potassium sulfate；
Wound healing promoters, such as allantoin and chlorine hydroxyl aldioxa；
Vasoconstrictor, such as adrenalin hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, hydrochloric acid benzene good fortune Woods, hydrochloric acid dl-methylephedrine and oxymetazoline hydrochloride；
Antihistaminic, such as diphenhydramine, diphhydramine hydrochloride, diphenhydramine tannate, diphenhydramine lauryl sulfate, chlorine Pheniramine maleate or diphenylpyraline hydrochloride；
Anesthetis, such as morphine hydrochloride, ethylmorphine hydrochloride, morphine sulfate, codeine phosphate, dihydrocodeine phosphate, hydrochloric acid Cocaine or pethidine hydrochloride；
Contraceptive, such as mandelic acid, nonoxynolum；
Termination of pregnancy medicine, such as carboprost methylate, dinoprostone；
Defecation accelerator, such as bisacodyl, glycerol；
Peptic ulcer therapeutic agent, such as cuscohygrylis α-acetylbenzoactrium；
Antiemetic, such as domperidone, Ondansetron Hydrochloride；
Progestogens medicine, such as Progesterone；
Resistance dysfunction medicine, such as Alprostadil, phentolamine mesylate；
Anthelmintic, such as Pyrantel Pamoate, levamisole hydrochloride bolt；
Antiviral agents, such as zidovudine；
Progestogens medicine, such as Progesterone；
Alora, such as estriol, estradiol, promestriene；
Labor-inducing medicine, such as PGE2；
Steroid hormone class, such as danazol；
Treatment of ulcerative colitis agent, such as mesalazine；
Analgesics, such as morphine sulfate, tramadol hydrochloride；
Anti-Meniere's disease medicine, such as sodium bicarbonate；
Antitumor agent, such as 5-fluorouracil and ftorafur；
Beta 2 receptor agonist, such as clenbuterol hydrochloride；
Convulsion, epilepsy medicine, such as valpromide；
Bronchodilator, such as aminophylline；
Biological product class, such as recombinant human interferon alpha-2, recombinant human interferon alpha 2 b, peptides such as insulin, recombinant humangranulocyte Macrophage stimulation factor, lactic acid bacteria.
Medicine or the active component content in pharmaceutical carrier is usually 0.0001～50%wt./wt., and preferably 0.1～40% Wt./wt., more preferably 0.1～30%wt./wt., based on the gross weight of pharmaceutical carrier.
The pharmaceutical carrier that the present invention relates to is in addition to above-mentioned matrix components, it is also possible to add other additives, such as fatty acid glycerine (such as anhydrous silicic acid, starch, crystalline cellulose, zinc oxide and alginic acid, wherein, anhydrous silicic acid is excellent to fat insoluble composition Choosing.), antioxidant, preservative, coloring agent etc..These additive amount are usually 0.1～10%wt./wt., with pharmaceutical carrier Based on gross weight, but not limited, depending on being actually needed.
The rate of releasing drug of the pharmaceutical carrier that the present invention relates to can be adjusted by the ratio adjusting above-mentioned Related Component, particularly may be used It is dissolved in water, low viscosity, non-irritating organic compound and water soluble surfactant active's ratio in pharmaceutical carrier, Yi Jihan There are above-mentioned acid (or alkali) property water-swellable and insoluble polymer and/or the granule of above-mentioned alkali (or acid) property excipient (material) The ability of the imbibition of thing regulates rate of releasing drug with speed and the consumption etc. in pharmaceutical carrier thereof.
The fusing point of the pharmaceutical carrier that the present invention relates to must be preferably higher than 40 DEG C higher than temperature 37 DEG C, but is preferably not higher than 80 DEG C, the most not higher than 60 DEG C, the most not higher than 50 DEG C.This ceiling temperature depends on clinical practice, oral interior with also in this way Being tract external, during tract external, normal temperature is the best, such as 40～50 DEG C；Time oral, this temperature is the best, Such as 40～60 DEG C, preferably 50～80 DEG C.Additionally, fusing point when pharmaceutical carrier and bioresorbable must be higher than temperature 37 DEG C, to protect Card pharmaceutical carrier in body cavity with can not liquefy during bioresorbable, emulsifying or thawing, thus avoid burst drug release occurring in other words Dosage inclines drug safety problems such as releasing (dose-dumping).
The formulation application form of the pharmaceutical carrier that the present invention relates to is most preferably dosage form and the suppository of the oral administration of slow-release. It is suitable for the dosage form such as tablet, capsule of oral administration of the present invention, granule, pill (containing drop pill).It is suitably applied this Bright suppository form, as being administered suppository, Qi Zhongyin for rectal administration, vagina administration suppository, urethral administration suppository or auditory meatus Canal drug administration suppository is more preferably.Profile for suppository of the present invention has no particular limits, and is only suitable for clinical practice just, closes It is applicable to example such as the sheet shape, ball shape of the profile of suppository of the present invention, prismatic, pencil shape, spherical, bullet-shaped, top fuller shape, torpedo Shape, ovum shape or duck nozzle shape etc..
The pharmaceutical carrier that the present invention relates to can also comprise the part of a part of medicine rapid release release.
The pharmaceutical carrier that the present invention relates to can produce by the following method, but is not limited to this, is only suitable for producing reality just. Such as, method I: first, above-mentioned aliphatic additive is melted；Then above-mentioned surfactant, above-mentioned water soluble, low viscous Degree, non-irritating organic compound particulate matter (water soluble compound granule), containing above-mentioned acidity (or alkalescence) polymer and/or The preformed particles of the solid excipient of alkalescence (or acid) or premix granule, said medicine and other additives add and stir to Uniformly mixing.Then the mixture generated is loaded into container, shapes, etc., the cooled solidification of molding；After solidification all right Pulverize further, the form of applicable oral administration or cavity/canal drug administration can be made after pulverizing further, such as tablet, capsule, pill.
For another example, method II: take above-mentioned aliphatic additive, surfactant, contain acid (or alkalescence) polymer and/or alkalescence The preformed particles of the solid excipient of (or acid) or premix granule, water soluble compound granule and medicine and other additives, Mixing, is sub-packed in suitable suppository mold or tablet mould or pill mould or capsule etc., and heating makes aliphatic additive melt, and is cooled to Room temperature.
When the fusing point of solid excipient of above-mentioned alkalescence (or acid) is less than 10 DEG C, especially with the difference of the fusing point of aliphatic additive When being 5 DEG C, the solid excipient of the alkalescence (or acid) of the most above-mentioned liquid being cured, more preferably use said method II to make Standby said medicine carrier.
The present invention, relatively with technology, at least has one of a following advantage:
1), more preferable drug release feature, such as higher anti-" salt poisoning " effect, can preferably release in high level salt solution, preferably Release homogeneity, preferably alleviates or solves " release is first quick and back slow " and " end release is incomplete " problem；
2), lower mucous membrane irritation, more preferable biocompatibility；
3), it is difficult to occur that burst drug release dosage in other words inclines drug safety problems such as releasing (dose-dumping)；
4) when, can realize selecting or stage release.
The most describe in detail the present invention, the most also can have each Planting and change, the present invention is not limited by described in description.
Accompanying drawing illustrates:
Fig. 1 embodiment 1 and reference examples 1 drug release test result
Fig. 2 embodiment 2 and reference examples 2 drug release test result
Fig. 3 embodiment 3 and reference examples 3 drug release test result
Fig. 4 embodiment 4 and reference examples 4-1,4-2 drug release test result
Fig. 5 embodiment 5 and reference examples 5-1,5-2 drug release test result
Fig. 6 embodiment 6 and reference examples 6-1,6-2 drug release test result
Fig. 7 measures the device of expansion volume
Embodiment
Following non-limiting examples further describes the preferred embodiment in the scope of the invention.It is to be understood that the present invention It is not limited only to these embodiments.
Embodiment 2:
Note: a2, this granule Specifeca tion speeification is shown in Table 1；
B2, the preparation method of this polylysine citrate granule: acid in the reference examples seen below (or alkalescence) water is insoluble can The preparation method of swelling polymer (granule).
Embodiment 4:
Note: a4, this granule Specifeca tion speeification is shown in Table 1；
B4-1, the preparation method of this sodium polyacrylate granule: acid in the reference examples seen below (or alkalescence) insoluble swellable of water The preparation method of polymer (granule).
B4-2, the preparation method of this chitosan hydrochloride granule: acid in the reference examples seen below (or alkalescence) water is not The preparation method of the polymer (granule) of molten swellable.
Embodiment 5:
Note: a5, this granule Specifeca tion speeification is shown in Table 1；
B5-1, the preparation method of this sodium polyacrylate granule: acid in the reference examples seen below (or alkalescence) insoluble swellable of water The preparation method of polymer (granule).
B5-2, the preparation method of this chitosan hydrochloride granule: acid in the reference examples seen below (or alkalescence) water is not The preparation method of the polymer (granule) of molten swellable.
Embodiment 6:
Note: a6, this granule Specifeca tion speeification is shown in Table 1；
B6-1, the preparation method of this sodium acrylate graft starch granules: acid in the reference examples seen below (or alkalescence) water is insoluble The preparation method of the polymer (granule) of swellable.
B6-2, the preparation method of this polylysine hydrochlorate granule: acid in the reference examples seen below (or alkalescence) water is insoluble can The preparation method of swelling polymer (granule).
Embodiment 8:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 90～150 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 26.2 gram gram, 33 minutes and 18.1 gram gram, 46 minutes.
Embodiment 9:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 90～150 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 7.7 gram gram, 5 minutes and 4.6 Gram gram, 8 minutes.
Embodiment 11:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 50～90 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 26.7 gram gram, 12 minutes and 19.1 gram gram, 19 minutes.
Embodiment 14:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 40～80 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 8.4 gram gram, 17 minutes and 5.2 Gram gram, 23 minutes.
Embodiment 15:
Take above-mentioned acidity and the polymer of the insoluble swellable of alkaline water respectively in the ratio in prescription, make by the method implementing 5 Premix granule uses, and this particle size is 28～48 mesh (Tyler standard)), by enclosed side after two kinds of granule mixings Method measures free wxpansion capacity and reaches under time of 60% free wxpansion capacity and pressure-bearing expansion volume (10 hours) and reach The time of expansion volume under 60% pressure-bearing, result be respectively 35.7 gram gram, 53 minutes and 25.1 gram gram, 82 minutes.
Embodiment 16:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 30～50 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 25.8 gram gram, 13 minutes and 17.7 gram gram, 20 minutes.
Embodiment 18:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 80～160 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 25.7 gram gram, 11 minutes and 17.2 gram gram, 18 minutes.
Embodiment 19:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 70～170 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 27.5 gram gram, 14 minutes and 20.4 gram gram, 22 minutes.
Embodiment 21:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 70～170 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 24.2 gram gram, 13 minutes and 17.3 gram gram, 20 minutes.
Embodiment 22:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 90～160 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 30.2 gram gram, 21 minutes and 21.6 gram gram, 36 minutes.
Embodiment 24:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 28～48 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 18.5 gram gram, 28 minutes and 11.4 gram gram, 43 minutes.
Embodiment 25:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 28～48 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 16.3 gram gram, 33 minutes and 11.2 gram gram, 52 minutes.
Embodiment 26:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 80～160 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 16.2 gram gram, 21 minutes and 10.8 gram gram, 35 minutes.
Embodiment 27:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 28～48 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 20.6 gram gram, 26 minutes and 13.8 gram gram, 46 minutes.
Embodiment 28:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 40～80 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 30.1 gram gram, 18 minutes and 22.2 gram gram, 32 minutes.
Embodiment 29:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 30～60 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 4.1 gram gram, 7 minutes and 2.8 Gram gram, 11 minutes.
Embodiment 31:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 30～60 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 20.5 gram gram, 30 minutes and 17.6 gram gram, 42 minutes.
Embodiment 32:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 30～60 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 21.5 gram gram, 28 minutes and 16.5 gram gram, 40 minutes.
Embodiment 34:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 40～80 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 26.8 gram gram, 17 minutes and 19.2 gram gram, 38 minutes.
Embodiment 36:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 28～48 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 3.8 gram gram, 12 minutes and 2.2 Gram gram, 20 minutes.
Embodiment 37:
Take above-mentioned acidity and the polymer of the insoluble swellable of alkaline water respectively in the ratio in prescription, make by the method implementing 5 Premix granule uses, and this particle size is 90～180 mesh (Tyler standard)), by enclosed after two kinds of granule mixings Method measures free wxpansion capacity and reaches under time of 60% free wxpansion capacity and pressure-bearing expansion volume (10 hours) and reach The time of expansion volume under 60% pressure-bearing, result be respectively 38.5 gram gram, 62 minutes and 26.3 gram gram, 107 minutes.
Embodiment 38:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 40～80 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 23.8 gram gram, 36 minutes and 17.5 gram gram, 65 minutes.
Embodiment 40:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 50～90 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 26.4 gram gram, 32 minutes and 18.4 gram gram, 50 minutes.
Embodiment 41:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 40～80 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 23.3 gram gram, 24 minutes and 16.2 gram gram, 41 minutes.
Embodiment 44:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 40～80 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 22.4 gram gram, 38 minutes and 15.2 gram gram, 69 minutes.
Embodiment 45:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 90～180 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 40.8 gram gram, 66 minutes and 26.2 gram gram, 110 minutes.
Embodiment 46:
Take above-mentioned acidity and the polymer of the insoluble swellable of alkaline water respectively in the ratio in prescription, make by the method implementing 5 Premix granule uses, and this particle size is 28～48 mesh (Tyler standard)), by enclosed side after two kinds of granule mixings Method measures free wxpansion capacity and reaches under time of 60% free wxpansion capacity and pressure-bearing expansion volume (10 hours) and reach The time of expansion volume under 60% pressure-bearing, result be respectively 35.3 gram gram, 58 minutes and 23.1 gram gram, 106 minutes.
Embodiment 47:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 40～80 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 20.2 gram gram, 34 minutes and 14.4 gram gram, 65 minutes.
Embodiment 48:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 40～80 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 25.6 gram gram, 45 minutes and 18.4 gram gram, 85 minutes.
Embodiment 49:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 40～80 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 20.8 gram gram, 35 minutes and 15.3 gram gram, 62 minutes.
Embodiment 50:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 40～80 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 4.4 gram gram, 17 minutes and 2.8 Gram gram, 23 minutes.
Embodiment 51:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 40～80 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 18.6 gram gram, 60 minutes and 12.7 gram gram, 110 minutes.
Embodiment 53:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 40～80 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 14.8 gram gram, 27 minutes and 9.3 gram gram, 50 minutes.
Embodiment 54:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 40～80 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 26.7 gram gram, 65 minutes and 19.2 gram gram, 100 minutes.
★, at representing 25 DEG C, the viscosity of the chitin solution of 1% be dissolved in 1% acetic acid solution.
Embodiment 55:
Take above-mentioned acidity and the polymer of the insoluble swellable of alkaline water respectively in the ratio in prescription, make by the method implementing 5 Premix granule uses, and this particle size is 60～115 mesh (Tyler standard)), by enclosed after two kinds of granule mixings Method measures free wxpansion capacity and reaches under time of 60% free wxpansion capacity and pressure-bearing expansion volume (10 hours) and reach The time of expansion volume under 60% pressure-bearing, result be respectively 42.3 gram gram, 100 minutes and 30.4 gram gram, 182 minutes.
Embodiment 56:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 90～160 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 24.9 gram gram, 55 minutes and 17.8 gram gram, 100 minutes.
Embodiment 57:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 40～80 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 27.8 gram gram, 35 minutes and 19.8 gram gram, 60 minutes.
Embodiment 58:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 70～120 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 30.9 gram gram, 60 minutes and 21.2 gram gram, 105 minutes.
Embodiment 59:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 70～120 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 16.5 gram gram, 24 minutes and 11.4 gram gram, 40 minutes.
★, at representing 25 DEG C, the viscosity of the polylysin solution of 1% be dissolved in 1% acetic acid solution.
Embodiment 60:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 90～180 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 4.9 gram gram, 12 minutes and 3.2 Gram gram, 20 minutes.
★, at representing 25 DEG C, the viscosity of the chitosan solution of 1% be dissolved in 1% acetic acid solution.
Embodiment 61:
Take above-mentioned acidity and the polymer of the insoluble swellable of alkaline water respectively in the ratio in prescription, make by the method implementing 5 Premix granule uses, and this particle size is 100～200 mesh (Tyler standard)), by enclosed after two kinds of granule mixings Method measures free wxpansion capacity and reaches under time of 60% free wxpansion capacity and pressure-bearing expansion volume (10 hours) and reach The time of expansion volume under 60% pressure-bearing, result be respectively 37.3 gram gram, 70 minutes and 26.8 gram gram, 125 minutes.
Embodiment 62:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 60～115 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 32.6 gram gram, 30 minutes and 25.6 gram gram, 50 minutes.
Embodiment 63:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 90～180 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 37.4 gram gram, 70 minutes and 24.2 gram gram, 126 minutes.
Embodiment 64:
Take above-mentioned acidity and the polymer of the insoluble swellable of alkaline water respectively in the ratio in prescription, make by the method implementing 5 Premix granule uses, and this particle size is 30～60 mesh (Tyler standard)), by enclosed side after two kinds of granule mixings Method measures free wxpansion capacity and reaches under time of 60% free wxpansion capacity and pressure-bearing expansion volume (10 hours) and reach The time of expansion volume under 60% pressure-bearing, result be respectively 36.8 gram gram, 60 minutes and 24.7 gram gram, 100 minutes.
Embodiment 65:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 28～48 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 43.7 gram gram, 65 minutes and 28.2 gram gram, 112 minutes.
Embodiment 66:
The polymer taking above-mentioned acidity (or alkalescence) the insoluble swellable of water in the ratio in prescription is solid with above-mentioned alkalescence (or property acid) Body excipient, makes preformed particles by the method implementing 1～4 or 6 and uses, and this particle size is 50～100 mesh (Tyler Standard)), by enclosed method measure free wxpansion capacity and reach 60% free wxpansion capacity time and pressure-bearing under Expansion volume (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 36.8 gram gram, 64 minutes and 24.3 gram gram, 105 minutes.
Embodiment 67:
Take above-mentioned acidity and the polymer of the insoluble swellable of alkaline water respectively in the ratio in prescription, make by the method implementing 5 Premix granule uses, and this particle size is 40～80 mesh (Tyler standard)), by enclosed side after two kinds of granule mixings Method measures free wxpansion capacity and reaches under time of 60% free wxpansion capacity and pressure-bearing expansion volume (10 hours) and reach The time of expansion volume under 60% pressure-bearing, result be respectively 30.2 gram gram, 58 minutes and 21.1 gram gram, 103 minutes.
Embodiment 78:
Change poly arginine (molecular weight 20～the 600000)+MCC (1 0.2) in embodiment 16 prescription into poly arginine (molecular weight 20～600,000)+angelic acid (fusing point 45 DEG C) (1 2), tartaric acid+MCC (1 0.2) changes acrylic acid (boiling point 141 DEG C)+angelic acid into Poly arginine tartrate+MCC in (1 2), and reference examples 16 prescription changes poly arginine acrylates+angelic acid (1 2) into, Other are constant, obtain embodiment 78 and reference examples 78.
Expansion capacity under free wxpansion capacity and the time reaching 60% free wxpansion capacity and pressure-bearing is measured by enclosed method Amount (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 8.2 gram gram, 16 minutes and 5.2 gram gram, 21 minutes.
Embodiment 79:
Change poly arginine (molecular weight 20～the 600000)+MCC (1 0.2) in embodiment 16 prescription into poly arginine (molecular weight 20～600,000)+citric acid (fusing point 153 DEG C) (1 1), tartaric acid+MCC (1 0.2) changes iso caproic acid (boiling point 200 DEG C)+citron into Poly arginine tartrate+MCC in acid (1 1), and reference examples 16 prescription changes poly arginine butenoate+citric acid (1 into 1), other are constant, obtain embodiment 79 and reference examples 79.
Measure under free wxpansion capacity and the time reaching 60% free wxpansion capacity and pressure-bearing swollen by enclosed method Swollen capacity (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 13.8 gram gram, 10 minutes and 8.4 Gram gram, 15 minutes.
Embodiment 80:
Change poly arginine (molecular weight 20～the 600000)+MCC (1 0.2) in embodiment 16 prescription into poly arginine (molecular weight 20～600,000)+PEG 3500 (fusing point 54 DEG C) (1 5), tartaric acid+MCC (1 0.2) change acetic acid (boiling point 117.9 DEG C)+PEG into Poly arginine tartrate+MCC in 3500 (1 5), and reference examples 16 prescription changes poly arginine acetate+PEG 3500 into (1 5), other are constant, obtain embodiment 80 and reference examples 80.
Expansion capacity under free wxpansion capacity and the time reaching 60% free wxpansion capacity and pressure-bearing is measured by enclosed method Amount (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 6.3 gram gram, 9 minutes and 6.5 gram gram, 13 minutes.
Embodiment 81:
Change poly arginine (molecular weight 20～the 600000)+MCC (1 0.2) in embodiment 16 prescription into poly arginine (molecular weight 20～600,000)+poloxamer 338 (fusing point 57 DEG C) (1 2), tartaric acid+MCC (1 0.2) change positive enanthic acid (boiling point 223 DEG C) into Poly arginine tartrate+MCC in+poloxamer 338 (fusing point 57 DEG C) (1 2), and reference examples 16 prescription changes poly-essence into Propylhomoserin positive enanthate+poloxamer 338 (fusing point 57 DEG C) (1 2), other are constant, obtain embodiment 81 and reference examples 81.
Expansion capacity under free wxpansion capacity and the time reaching 60% free wxpansion capacity and pressure-bearing is measured by enclosed method Amount (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 7.5 gram gram, 19 minutes and 4.2 gram gram, 27 minutes.
Embodiment 82:
Change poly arginine (molecular weight 20～the 600000)+MCC (1 0.2) in embodiment 16 prescription into poly arginine (molecular weight 20～600,000)+poloxamer 338 (fusing point 57 DEG C) (1 1), tartaric acid+MCC (1 0.2) changes polyacrylic acid (molecular weight into 3000～6000, boiling point 116 DEG C) poly arginine in+poloxamer 338 (fusing point 57 DEG C) (1 1), and reference examples 16 prescription Tartrate+MCC changes poly arginine hydrochlorate+poloxamer 338 (fusing point 57 DEG C) (1 1) into, and other are constant, obtain embodiment 82 and reference examples 82.
Expansion capacity under free wxpansion capacity and the time reaching 60% free wxpansion capacity and pressure-bearing is measured by enclosed method Amount (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 12.8 gram gram, 13 minutes and 8.7 grams/ Gram, 20 minutes.
Embodiment 95:
2-furylacrylic acid in embodiment 19 prescription is changed into ketoglutaric acid, the polyglutamic acid in reference examples 19 prescription-rely ammonia Acid 2-furylacrylate changes polyglutamic acid-lysine ketoglutarate into, and other are constant, obtain embodiment 95 and reference examples 95.
Expansion capacity under free wxpansion capacity and the time reaching 60% free wxpansion capacity and pressure-bearing is measured by enclosed method Amount (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 29.3 gram gram, 10 minutes and 21.3 grams/ Gram, 16 minutes.
Embodiment 96:
2-furylacrylic acid in embodiment 19 prescription is changed into muconic acid, the polyglutamic acid in reference examples 19 prescription-rely Propylhomoserin 2-furylacrylate changes polyglutamic acid-lysine muconic acid salt into, and other are constant, obtain embodiment 96 and reference examples 96。
Expansion capacity under free wxpansion capacity and the time reaching 60% free wxpansion capacity and pressure-bearing is measured by enclosed method Amount (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 28.6 gram gram, 12 minutes and 20.9 grams/ Gram, 19 minutes.
Embodiment 97:
2-furylacrylic acid in embodiment 19 prescription is changed into alpha, gamma-two hydroxycaproic acid, the polyglutamic acid in reference examples 19 prescription- Lysine 2-furylacrylate changes polyglutamic acid-lysine alpha, gamma-dihydroxy caproate into, and other are constant, obtain embodiment 97 and Reference examples 97.
Expansion capacity under free wxpansion capacity and the time reaching 60% free wxpansion capacity and pressure-bearing is measured by enclosed method Amount (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 25.6 gram gram, 17 minutes and 18.2 grams/ Gram, 26 minutes.
Embodiment 98:
2-furylacrylic acid in embodiment 19 prescription is changed into methoxybenzoic acid, the polyglutamic acid in reference examples 19 prescription- Lysine 2-furylacrylate changes polyglutamic acid-lysine methoxybenzoic acid salt into, and other are constant, obtains embodiment 98 and right As usual 98.
Expansion capacity under free wxpansion capacity and the time reaching 60% free wxpansion capacity and pressure-bearing is measured by enclosed method Amount (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 24.3 gram gram, 19 minutes and 18.2 grams/ Gram, 31 minutes.
Embodiment 99:
2-furylacrylic acid in embodiment 19 prescription changes into 4, and 6-dihydroxy-2-ar-Toluic acid, in reference examples 19 prescription Polyglutamic acid-lysine 2-furylacrylate changes polyglutamic acid-lysine 4 into, 6-dihydroxy-2-ar-Toluic acid salt, other Constant, obtain embodiment 99 and reference examples 99.
Expansion capacity under free wxpansion capacity and the time reaching 60% free wxpansion capacity and pressure-bearing is measured by enclosed method Amount (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 23.8 gram gram, 17 minutes and 17.7 grams/ Gram, 25 minutes.
Embodiment 100:
Butylmalonic acid in embodiment 21 prescription is changed into dihydrochalcone, the polymine butyl in reference examples 21 prescription Malonate changes polyethyleneimine amine hydrochlorate into, and other are constant, obtains embodiment 100 and reference examples 100.
Expansion capacity under free wxpansion capacity and the time reaching 60% free wxpansion capacity and pressure-bearing is measured by enclosed method Amount (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 21.8 gram gram, 43 minutes and 15.8 grams/ Gram, 69 minutes.
Embodiment 101:
Butylmalonic acid in embodiment 21 prescription is changed into a-pyranone-5-carboxylic acid, the polyethyleneimine in reference examples 21 prescription Amine butylmalonic acid salt changes polyethyleneimine amine hydrochlorate into, and other are constant, obtains embodiment 101 and reference examples 101.
Expansion capacity under free wxpansion capacity and the time reaching 60% free wxpansion capacity and pressure-bearing is measured by enclosed method Amount (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 23.4 gram gram, 18 minutes and 16.8 grams/ Gram, 31 minutes.
Embodiment 102:
Butylmalonic acid in embodiment 21 prescription is changed into 2,5-dihydroxyphenyl acetic acid, the polymine in reference examples 21 prescription Butylmalonic acid salt changes polyethyleneimine amine hydrochlorate into, and other are constant, obtains embodiment 102 and reference examples 102.
Expansion capacity under free wxpansion capacity and the time reaching 60% free wxpansion capacity and pressure-bearing is measured by enclosed method Amount (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 21.8 gram gram, 33 minutes and 15.6 grams/ Gram, 50 minutes.
Embodiment 103:
Butylmalonic acid in embodiment 21 prescription is changed into 2-benzofurancarboxylic acid, the polymine butyl third in reference examples 21 prescription Diacid salt changes polyethyleneimine amine hydrochlorate into, and other are constant, obtains embodiment 103 and reference examples 103.
Expansion capacity under free wxpansion capacity and the time reaching 60% free wxpansion capacity and pressure-bearing is measured by enclosed method Amount (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 20.6 gram gram, 36 minutes and 14.7 grams/ Gram, 53 minutes.
Embodiment 104:
Butylmalonic acid in embodiment 21 prescription is changed dextrocamphoric acid. into, the polymine butyl in reference examples 21 prescription the third two Hydrochlorate changes polyethyleneimine amine hydrochlorate into, and other are constant, obtains embodiment 104 and reference examples 104.
Expansion capacity under free wxpansion capacity and the time reaching 60% free wxpansion capacity and pressure-bearing is measured by enclosed method Amount (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 23.4 gram gram, 19 minutes and 18.7 grams/ Gram, 33 minutes.
Embodiment 105:
Butylmalonic acid in embodiment 21 prescription is changed into 1-carboxylic-4-carboxylic-2,5-cyclohexadiene-1-acetone acid, reference examples 21 Polymine butylmalonic acid salt in prescription changes polyethyleneimine amine hydrochlorate into, and other are constant, obtains embodiment 105 and comparison Example 105.
Expansion capacity under free wxpansion capacity and the time reaching 60% free wxpansion capacity and pressure-bearing is measured by enclosed method Amount (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 26.8 gram gram, 10 minutes and 19.9 grams/ Gram, 16 minutes.
Embodiment 106:
Butylmalonic acid in embodiment 21 prescription is changed into 2-cyclopenten-2,3-diol-1-one. (1,2-dihydroxy-3-ketone cyclopentenes), reference examples 21 prescription In polymine butylmalonic acid salt change polyethyleneimine amine hydrochlorate into, other are constant, obtain embodiment 106 and reference examples 106。
Expansion capacity under free wxpansion capacity and the time reaching 60% free wxpansion capacity and pressure-bearing is measured by enclosed method Amount (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 20.7 gram gram, 39 minutes and 14.6 grams/ Gram, 64 minutes.
Embodiment 107:
Changing the angelic acid in embodiment 41 prescription into thymidylic acid, other are constant, obtain embodiment 107 and reference examples 107。
, measure expansion capacity under free wxpansion capacity and the time reaching 60% free wxpansion capacity and pressure-bearing by enclosed method Amount (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 20.4 gram gram, 58 minutes and 16.2 grams/ Gram, 90 minutes.
Embodiment 108:
Changing the angelic acid in embodiment 41 prescription into phosphothreonine, other are constant, obtain embodiment 108 and reference examples 108.
Expansion capacity under free wxpansion capacity and the time reaching 60% free wxpansion capacity and pressure-bearing is measured by enclosed method Amount (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 21.4 gram gram, 45 minutes and 17.4 grams/ Gram, 73 minutes.
Embodiment 109:
Changing the angelic acid in embodiment 41 prescription into tyrosine, other are constant, obtain embodiment 109 and reference examples 109.
Expansion capacity under free wxpansion capacity and the time reaching 60% free wxpansion capacity and pressure-bearing is measured by enclosed method Amount (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 21.8 gram gram, 32 minutes and 15.9 grams/ Gram, 49 minutes.
Embodiment 110:
Changing the angelic acid in embodiment 41 prescription into hypoxanthine, other are constant, obtain embodiment 110 and reference examples 110.
Expansion capacity under free wxpansion capacity and the time reaching 60% free wxpansion capacity and pressure-bearing is measured by enclosed method Amount (10 hours) and reach the time of expansion volume under 60% pressure-bearing, result be respectively 20.1 gram gram, 60 minutes and 14.2 grams/ Gram, 93 minutes.
The preparation method of absorption disintegrating agent granule in embodiment:
Method 1-1 (preformed particles): take the polymer of above-mentioned acidity (or alkalescence) the insoluble swellable of water of shown proportional quantities with upper State alkalescence (or property acid) solid excipient levigate and repeatedly cross 250 mesh sieves, after mix homogeneously, add appropriate PVP anhydrous alcohol (real Execute example and reference examples 1-4,6) or the most shown after appropriate anhydrous alcohol (time in embodiment and reference examples prescription containing PVP) mixing Larger aperture mesh number sieve is pelletized, and obtains the granule of required size after drying after shown relatively big and smaller aperture due mesh number sieve；
Method 1-2 (preformed particles): take the polymer of above-mentioned acidity (or alkalescence) the insoluble swellable of water of shown proportional quantities with upper State alkalescence (or property acid) solid excipient levigate and repeatedly cross 250 mesh sieves, add MCC and (embodiment and reference examples prescription contain During MCC microcrystalline Cellulose) after mix homogeneously, it is pressed into block, pulverize, obtain institute after shown relatively big and smaller aperture due mesh number sieve Need the granule of size；
Method 1-3 (preformed particles): (embodiment 68-71, embodiment, 73-83, and reference examples) takes shown firming agent (mark The person that has fusing point) add heat fusing, add liquid acid or alkali, mixing, the polymerization of the alkalescence added (or acid) the insoluble swellable of water Thing, mixing, it is cooled to room temperature, pulverizes, obtain the granule of required size after shown relatively big and smaller aperture due mesh number sieve；
Method 1-4 (preformed particles): (adhesive-free PVP, MCC and firming agent person) takes above-mentioned acidity (or the alkali of shown proportional quantities Property) polymer and above-mentioned alkalescence (or the property acid) solid excipient of the insoluble swellable of water is levigate and repeatedly crosses 250 mesh sieves, mixing is all After even, under the pressure of 20～50kg/cm2, it be pressed into block (embodiment and reference examples prescription do not contain MCC and PVP Time), pulverize, obtain the granule of required size after shown relatively big and smaller aperture due mesh number sieve；
Method 2-1 (premix granule): the polymer taking the acidity of shown proportional quantities and the insoluble swellable of alkaline water respectively is levigate also Repeatedly cross 250 mesh sieves, add appropriate PVP anhydrous alcohol (embodiment and reference examples 5) or appropriate anhydrous alcohol (embodiment and comparison Time in example prescription containing PVP) cross after mixing shown in larger aperture mesh number sieve pelletize, after drying after shown relatively big and smaller aperture due Mesh number sieve obtains (two kinds) granule of required size.
Method 2-2 (premix granule): the polymer taking the acidity of shown proportional quantities and the insoluble swellable of alkaline water respectively is levigate also Repeatedly cross 250 mesh sieves, after adding MCC (time in embodiment and reference examples prescription containing MCC microcrystalline Cellulose) mix homogeneously, compacting Become block, pulverize, obtain (two kinds) granule of required size after shown relatively big and smaller aperture due mesh number sieve.
Method 2-3 (premix granule): (adhesive-free PVP, MCC person) takes the acidity of shown proportional quantities respectively and alkaline water is insoluble The polymer of swellable is levigate and repeatedly cross 250 mesh sieves, be pressed under the pressure of 20～50kg/cm2 block (embodiment and When reference examples prescription does not contains MCC and PVP), pulverize, obtain required size after shown relatively big and smaller aperture due mesh number sieve (two kinds) granule.
The preparation method of the polymer (granule) of acid (or alkalescence) insoluble swellable of water in reference examples:
The polymer gel of acidity (or alkalescence) the insoluble swellable of water of this embodiment will be used for and little over amount (such as excessive 0.1 weight Amount %) this reference examples in acidity (or alkalescence) the insoluble swellable of water polymer salt shown in alkali (or acid) (such as sodium (salt) uses sodium hydroxide, hydrochlorate hydrochloric acid, salicylate salicylic acid, urethanes salt urethanes etc.) Aqueous solution, after reaction completely, (degree of neutralization is not lower than 95%) separates the polymerization of this acidity (or alkalescence) the insoluble swellable of water Thing salt, cleans to neutrality repeatedly with distilled water, at ambient temperature (23 DEG C, relative humidity 30% time) drying under reduced pressure at least 3 days The most levigate and repeatedly cross 250 mesh sieves, afterwards by embodiment method pelletize.
Embodiment and reference examples preparation method:
Method I: take aliphatic additive heating (to temperature 50～90 DEG C) and make it melt, add surfactant, mix homogeneously； Add containing acid (or alkalescence) polymer and/or the preformed particles of the solid excipient of alkalescence (or acid) or premix granule, Levigate and repeatedly cross the water soluble compound granule of 100 mesh sieves (or 28 mesh or 60 mesh sieves, Tyler standard) and the most levigate And repeatedly cross 200 mesh sieves (Tyler standard) medicine, mixing；Under conditions of molten mixture insulation, pour into suitable bolt Agent mould or tablet mould, after cooling, or when molten mixture is cooled to semisolid paste, by extrude round as a ball mode or its He pelletizes by suitable way, then loads capsule by shown medicine divided dose or is distributed into granule.
Method II: take aliphatic additive, surfactant, containing acid (or alkalescence) polymer and/or alkalescence (or acid) The preformed particles of solid excipient or premix granule, the most levigate and repeatedly cross 100 mesh sieves (or 28 mesh or 60 mesh sieves, Tyler Standard) water soluble compound granule and the most levigate and mistake 200 mesh sieves (Tylerstandard) repeatedly medicine, mixing, Being sub-packed in suitable suppository mold or tablet mould or capsule by shown medicine divided dose, heating (to temperature 50～90 DEG C) makes aliphatic Additive melts, and is cooled to room temperature.
Embodiment and reference examples 7,17,23,34,41,48,53,68～83 are prepared by method II, in other embodiments and reference examples Suppository or tablet or capsule prepare by method I, it is possible to prepare by method II.
Table 1 absorbs the performance parameter of disintegrating agent
Note: §, by Friedrich Helfferich, Ion Exchange, page 84, MaGraw-Hill BookCompany, 1962 obtain or the value that obtained by inventor's Determination of The Proper Motions.
★, at representing 25 DEG C, the viscosity of the chitosan soln of 1% be dissolved in 1% acetic acid solution.
Attached:
Free wxpansion capacity and reach the method for testing of time of 60% free wxpansion capacity
Free wxpansion solid measure be 1 gram absorb disintegrating agent material in 10 hours, in insignificant load or binding force, example Under the load of such as from about 0.01 pound/square inch, the grams of the absorbable aqueous solution containing 0.9% sodium chloride.
Accompanying drawing 7 describes the method and apparatus measuring free wxpansion capacity.Shown is use during in position should The perspective view of device.Use for laboratory crane 1 has adjustable knob 2, in order to hoistable platform 3.Use for laboratory stand 4 supports Spring 5, this spring 5 is connected to the pachometer probe 6 improved, and this probe 6 is through the survey fixedly secured by use for laboratory stand The chamber 7 of thick meter.There is the liquid permeable end equipped with the to be tested plastic sample cup 8 absorbing disintegrating agent material sample and fall In culture dish 9, culture dish is contained within saline solution to be absorbed.Only under measuring pressure-bearing during absorption value, absorb disintegrating agent sample (not shown) on pad disk on product (not shown) top, has a weight 10 to be put on its top.
Specimen cup is made up of plastic cylinder, and this cylindrical internal diameter is 1 inch, and external diameter is 1.25 inches.To have 75 microns 200 mesh metallic sieves of perforate be adhered to this cylindrical open-ended on, formed specimen cup the end, this bonding is by screen cloth It is heated to more than the fusing point of plastics, and the screen cloth that plastic cylinder presses to heat makes with fusing plastics screen cloth be connected to plastics circle On cylinder.
Thickness measuring for measuring the improvement expanded when sample absorbs saline is calculated as Mitutoyo DigimaticIndicator, IDCSeries 543, Model 543-180, its measurement scope is 0～0.5 inch, and precision is 0.00005 inch of (Mitutoyo Corporation, 31-19, Shiba 5-chome, Minato-ku, Tokyo 108, Japan).By Mitutoyo The thickness measuring that Corporation provides is in respect of being connected to the spring of probe, and this probe is in the chamber of pachometer.Remove spring to carry For free-falling, downward force be about the probe of 27 grams.Additionally, also removes in the probe tip being positioned at pachometer chamber roof Cap so that probe is connected to suspended spring S (by McMaster-CarrSupply Co., Chicago, IIinois Obtain, Item No.9640K41), this spring is in order to offset the downward force of probe or to be decreased to about 1 ± 0.5 gram.Can be by metal Line hook is connected to the top of probe, so that probe is connected with the spring being folded down.The finger of extension is also provided in the bottom of probe Pin (Mitutoyo Corporation, Part No.131279), so that probe can be plugged in specimen cup.
For being measured, 0.160 gram of absorption disintegrating agent sample is placed in specimen cup.Then by this sample weight 4.4 grams, diameter Being about the plastic spacer disk covering of 0.995 inch, the effect of this pad disk is to prevent sample disturbed in test process, And put on sample with making uniform load.Then specimen cup and material sample and pad disk are weighed, do obtaining it Weight.Specimen cup is placed in the culture dish on platform, and use for laboratory crane is raised, until the top of plastic spacer disk Limit and the nib contacts of probe.Pachometer is returned to zero.The saline solution (50～100 milliliters) of q.s is added in culture dish, Start test.Absorb saline solution by probe assay sample and expand the distance that the plastic spacer disk caused raises.Should be away from From being multiplied by the interior sectional area of specimen cup, it is sample by absorbing caused expansion volume.Density and sample in conjunction with saline solution The weight of product, it is easy to calculate the amount of the saline solution of absorption.The saline solution weight absorbed after 10 hours, is every gram of suction Receive the free wxpansion capacity expressed with grams that disintegrating agent absorbs.If desired, can be by continuous for the reading of the pachometer improved Be input in computer (Mitutoyo Digimatic Miniprocessor DP-2DX), to carry out calculating and to coming from By expansion volume.As cross check, it is also possible to by measure specimen cup before testing after weight difference determine free wxpansion Capacity, this weight difference is the amount of solution that sample absorbs.
According to the continuous monitoring to free wxpansion capacity provided by computer, it is easy to determine and reach 60% free wxpansion capacity Time.
Expansion volume and reach the assay method of the time of expansion volume under 60% pressure-bearing under pressure-bearing
Under pressure-bearing, expansion volume test determination is under the load or the binding force that apply about 0.3 pound/square inch, 1 gram of absorption The grams of the aqueous solution containing 0.9% sodium chloride that disintegrating agent material is absorbed after 10 hours.Measure and absorb the suction of disintegrating agent pressure-bearing The method of receipts value is essentially identical with the method measuring free wxpansion capacity, except that place at the top of plastic spacer disk The weight of 100 grams, thus applies the load of about 0.3 pound/square inch on the absorption disintegrating agent absorb saline solution.
According to the continuous monitoring to pressure-bearing absorption value provided by computer, it is easy to determine and reach 60% pressure-bearing absorptive capacity value Time.
According to said method determine some absorb disintegrating agents free wxpansion capacity and reach 60% free wxpansion capacity time Between and pressure-bearing under expansion volume and reach the time of expansion volume under 60% pressure-bearing, be shown in Table 1.
Inspection example 1: the mensuration of drug release rate
Test sample:
The suppository of embodiment and reference examples is used as test sample.
The method of inspection:
Each test sample prepares 6 root lengths 17mm and equipped with 10ml compound sodium chloride injection (ringer's solution) (Chinese Pharmacopoeia Version two in 2005) test tube.Test tube is inserted in the temperature chamber of 37 DEG C and remains static.Test sample gauze wraps up And be dipped in the invisible spectro compound sodium chloride injection being numbered 1, at regular intervals after test sample taken out and depends on In next test tube compound sodium chloride injection of secondary immersion.Discharge into the medicine spectrophotography of solution or HPLC or other are fitted Preferably method measures.
Result: Fig. 1-6 and table 2 show the rate of release of medicine.
Table 2-1 pharmaceutical carrier outer (accumulation) release (spending) test result
Table 2-2 pharmaceutical carrier outer (accumulation) release (spending) test result
Table 2-3 pharmaceutical carrier outer (accumulation) release (spending) test result
Table 2-4 pharmaceutical carrier outer (accumulation) release (spending) test result
Table 2-5 pharmaceutical carrier outer (accumulation) release (spending) test result
Table 2-6 pharmaceutical carrier outer (accumulation) release (spending) test result
Table 2-7 pharmaceutical carrier outer (accumulation) release (spending) test result
Table 2-8 pharmaceutical carrier outer (accumulation) release (spending) test result
Table 2-9 pharmaceutical carrier outer (accumulation) release (spending) test result
Table 2-10 pharmaceutical carrier outer (accumulation) release (spending) test result
Table 2-11 pharmaceutical carrier outer (accumulation) release (spending) test result
Table 2-12 pharmaceutical carrier outer (accumulation) release (spending) test result
Table 2-13 pharmaceutical carrier outer (accumulation) release (spending) test result
Table 2-14 pharmaceutical carrier outer (accumulation) release (spending) test result
Table 2-15 pharmaceutical carrier outer (accumulation) release (spending) test result
Table 2-17 pharmaceutical carrier outer (accumulation) release (spending) test result
Table 2-18 pharmaceutical carrier outer (accumulation) release (spending) test result
The suppository of embodiment demonstrates more preferable drug release characteristics, if higher salt tolerance and effectively alleviation are " after release is the fastest Slowly " with the problem such as " end release is incomplete ".
Inspection example 2 vaginal mucosa irritation is tested
Test sample:
The granule of embodiment and the suppository of reference examples or tablet or capsule or loading capsule is used as test sample.
The method of inspection:
Take rabbit (healthy adult new zealand rabbit, body weight 2.5～2.7kg, female) 12, be randomly divided into administration group, right by body weight According to group, often group 6.Administration group gives embodiment suppository or tablet or capsule or loads the granule of capsule, and matched group gives right Suppository or tablet or capsule or load the granule of capsule as usual, dosage presses the above-mentioned of rabbit vagina maximum dosage-feeding 1.0g The granule of suppository or tablet or capsule or loading capsule/only, give in administration group and matched group rabbit vagina respectively, continue 6h, is administered and continues in rabbit puts fixed bin therebetween, successive administration 10 days.After last administration 24h, put to death animal, dissect Taking out vagina specimen, longitudinally slit, perusal mucosa, with or without phenomenons such as hyperemia, swelling, carries out mucous membrane irritation reaction by table 3 and comments Point.Simultaneously by every rabbit vagina tissue, fix more than 24h with 10% formalin, choose central part through dehydration, embedding, Section and H-E dyeing, carry out histopathological examination under the microscope after film-making, every by table 4 pathological reaction standards of grading record Animal pathological reaction scoring.Result is shown in (being shown in Table 5, table 6 and table 7).
Result shows, the mucous membrane irritation of the bolt/tablet of embodiment is considerably less than relatively reference examples.
Table 3 mucous membrane irritation reaction standards of grading
Table 4 mucosal tissue pathological reaction standards of grading
Table 5 embodiment bolt is to rabbit vagina mucosa perusal irritant reaction result
Table 6 bolt is to rabbit vagina mucous membrane irritation response organization pathology microscopy result
Note: ☆, represents the scoring of epithelial tissue pathology microscopy；★, represents the scoring of leukocyte infiltration histopathology microscopy；※: Represent (epithelial tissue pathology microscopy scoring sum+leukocyte infiltration histopathology microscopy scoring sum) ÷ 6.
Table 7-1 vaginal mucosa irritation is tested
Table 7-2 vaginal mucosa irritation is tested
Table 7-3 vaginal mucosa irritation is tested
Table 7-4 vaginal mucosa irritation is tested
Table 7-5 vaginal mucosa irritation is tested
Table 7-6 vaginal mucosa irritation is tested
Table 7-7 vaginal mucosa irritation is tested
Illustrate: scoring I: mucosa perusal irritant reaction average score (scoring sum ÷ sample number) marks II: epithelial tissue Pathology microscopy average score (scoring sum ÷ sample number) marks III: leukocyte infiltration histopathology microscopy average score (scoring sum ÷ sample number)
Inspection example 3: mucous membrane of rectum irritation test
Test sample:
Prepare blank suppository or tablet or the capsule of not pastille by the prescription of embodiment and reference examples and technique or load capsule Granule.The granule of embodiment and the blank suppository of reference examples or tablet or capsule or loading capsule is used as test sample Product.
The method of inspection:
By 12 rabbit (healthy adult new zealand rabbit, body weight 2.5～2.7kg, male and female half and half), (anus gives reality to be divided into administration group Execute example blank suppository or tablet or capsule or load capsule granule) and matched group (anus give reference examples blank suppository or Tablet or capsule or load the granule of capsule), often group 6, male and female half and half.By embodiment blank suppository or tablet or capsule or The granule of loading capsule, with each 1 of grain (weight 1.0g), continuous 7d, is inserted rabbit internal rectum, is at least contacted 6h every time with it (1d overnight fasting before being administered, next day morning dose), observe to after tested material 24,48h overall health of patients and local excitation reaction.The Within 7 days, put to death rabbit, take out rectum, observe with or without phenomenons such as hyperemia, rednesses, carry out local by the method in inspection example 2 and table 3 glutinous Film irritative response grade scale is marked, and carries out mucosa histopathologic examination and by table 4 according to the method in inspection example 2 Result of determination.The results are shown in Table 8,9,10.
The blank bolt of table 8 is to rabbit mucous membrane of rectum perusal irritant reaction result
The blank bolt of table 9 is to rabbit mucous membrane of rectum irritant reaction histopathology microscopy result
Note: ☆: represent the scoring of epithelial tissue pathology microscopy；★: represent the scoring of leukocyte infiltration histopathology microscopy；※: Represent (epithelial tissue pathology microscopy scoring sum+leukocyte infiltration histopathology microscopy scoring sum) ÷ 6.
Table 10-1 mucous membrane of rectum irritation test
Table 10-2 mucous membrane of rectum irritation test
Table 10-3 mucous membrane of rectum irritation test
Table 10-4 mucous membrane of rectum irritation test
Table 10-5 mucous membrane of rectum irritation test
Table 10-5 mucous membrane of rectum irritation test
Table 10-5 mucous membrane of rectum irritation test
Illustrate: scoring I: mucosa perusal irritant reaction average score (scoring sum ÷ sample number) marks II: epithelial tissue Pathology microscopy average score (scoring sum ÷ sample number) marks III: leukocyte infiltration histopathology microscopy average score (scoring sum ÷ sample number)
Result shows, the mucous membrane irritation of the blank suppository of embodiment is considerably less than the blank suppository of relatively reference examples.
Synthesis result shows, the overall performance of embodiment is better than reference examples.

Claims (10)

1. the external fusing point of a performance improvement and be above the slow release of temperature 37 DEG C in body cavity with fusing point during bioresorbable The pharmaceutical carrier of release, this pharmaceutical carrier comprises (a) a kind of pharmaceutically acceptable fusing point more than temperature 37 DEG C and in body cavity With fusing point during bioresorbable also above the aliphatic additive of temperature 37 DEG C；(b) a kind of water soluble, low viscous, pharmacy Upper acceptable additive, its granule largest cross-sectional sized is less than 600 microns, and the viscosity of its solution of 2% is less than 300 lis Pool；C () a kind of pharmaceutically acceptable, water-swellable and water-insoluble alkaline polymer, its pKb is 2～12；D () is a kind of Solid excipient selected from following pharmaceutically acceptable acidity: tartaric acid, citric acid, maleic acid, fumaric acid, Malic acid, adipic acid, succinic acid, lactic acid, glycolic, ascorbic acid, acidic amino acid, dihydric phosphate, and their mixing Thing, and pharmaceutically acceptable, water-swellable and water-insoluble acidic polymer；E () is a kind of pharmaceutically acceptable water-soluble The surfactant of property；(f) a kind of medicine.
Pharmaceutical carrier the most according to claim 1, wherein said aliphatic additive selected from fusing point more than temperature 37 DEG C and With fusing point during bioresorbable also above the fat that the fatty glyceride of temperature 37 DEG C, carbon number are C18～C32 in body cavity The single or double ester of acid propylene glycol, carbon number be the single or double ester of fatty acid ethylene glycol of C18～C32, carbon number be C18～C32 The single or double ester of fatty acid diethylene glycol, stearic acid Palmic acid binaryglycol ester, carbon number be the fatty acid of C14～C32, carbon Atomic number be the fatty alcohol of C16～C32, carbon number be the fatty acid of C14～C36 and the fat that carbon number is C14～C36 Ester that alcohol is formed, comprise straight chain that carbon chain lengths is 31 to 70 carbon and random side chain saturated alkane, the microwax of cycloalkane, and Its mixture that is natural or that be artificially formed.
Pharmaceutical carrier the most according to claim 1, wherein said pharmaceutically acceptable, water-soluble, low viscous adds Add agent and be selected from water-soluble aminoacid, oligopeptide, monosaccharide, oligosaccharide, water-soluble pharmaceutically acceptable cyclodextrin, dissolve in Polysaccharide water, low viscous, polypeptide water-soluble, low viscous, and their mixture.
Pharmaceutical carrier the most according to claim 1, wherein said pharmaceutically acceptable, water-swellable and water-insoluble alkali Property polymer selected from weight average molecular weight more than 100000 polyamine or polyimides, polymine, polypropylene amine, polyethylene gather Amine, polypropylene carbon number be C1～C4 alkylamine, poly-carbon number be C1～C4 alkyl amine, poly-carbon number be C1～ C4 alkyl carbon number be C1～C4 alkylamine, poly-hydroxyl carbon atom number be that C1～C4 alkyl amine, poly-hydroxyl carbon are former Subnumber is that C1～C4 alkyl atomic number is C1～C4 alkylamine, chitin, chitosan, other aminopolysaccharides, gathers Agedoite, polyglutamine, polylysine, poly arginine, poly-mixing lysine and poly-mixing arginine, and theirs is mixed Compound, or
Described acid excipient is selected from pharmaceutically acceptable, water-swellable and water-insoluble acidic polymer.
Pharmaceutical carrier the most according to claim 1, wherein said water-swellable and water-insoluble alkaline polymer are with described Acid excipient be scattered in this pharmaceutical carrier with particulate matter, the individual particle of this particulate matter contains described alkaline polymer And/or described acid excipient, the largest cross-sectional sized of this granule is less than 600 microns.
Pharmaceutical carrier the most according to claim 1, wherein said water-swellable and water-insoluble alkaline polymer are with described Acid excipient be scattered in this pharmaceutical carrier with particulate matter, the individual particle of this particulate matter contains described alkaline polymer And/or described acid excipient, this particulate matter is under load is 0.01psi, and its initial free wxpansion capacity is at least 3 gram gram,
Or
Wherein said water-swellable and water-insoluble alkaline polymer are scattered in particulate matter with described acid excipient In this pharmaceutical carrier, the individual particle of this particulate matter contains described alkaline polymer and/or described acid excipient, this particulate matter The time reaching 60% free wxpansion capacity is at least 5 minutes.
Pharmaceutical carrier the most according to claim 1, wherein said water-swellable and water-insoluble alkaline polymer are with described Acid excipient be scattered in this pharmaceutical carrier with particulate matter, the individual particle of this particulate matter contains described alkaline polymer And/or described acid excipient, this particulate matter under load is 0.3psi, under its initial pressure-bearing expansion volume be at least 2 grams/ Gram,
Or
Wherein said water-swellable and water-insoluble alkaline polymer are scattered in particulate matter with described acid excipient In this pharmaceutical carrier, the individual particle of this particulate matter contains described alkaline polymer and/or described acid excipient, this particulate matter The time of expansion volume under 60% pressure-bearing that reaches is at least 5 minutes.
Pharmaceutical carrier the most according to claim 1, wherein said water-swellable and water-insoluble alkaline polymer are with described The acidity of acid excipient and the mol ratio of basic functionality be 20: 1～1: 20.
Pharmaceutical carrier the most according to claim 1, wherein said water miscible surfactant is selected from polyethylene glycol fatty acid Or its single or double hydroxy fatty acid monoester class, polyethylene glycol fatty acid or its single or double hydroxy aliphatic acid diesters class, Polyethylene Glycol Glycerol fatty acid or its single or double hydroxy fatty acid esters, glycerol, propylene glycol, ethylene glycol, Sorbitol, tetramethylolmethane with The esters that natural and/or its oily or oil-soluble vitamins being hydrogenated generates, by the fatty acid of bound to polyglycerol or it is single Or double hydroxy aliphatic acids, the polyethyleneglycol derivative of stearyl alcohol, Polyethylene Glycol sorbitan fatty acid or its single or double hydroxyl Fatty acid, sugar esters, PEG-10 oleyl ether or palmityl ether or stearoyl ether, PEG-20 oleyl ether or palmityl ether or tristearin Acyl ether, PEG-9 lauryl ether, PEG-23 lauryl ether, PEG-100 stearoyl ether, polyalkylene glycol alkyl or its single or double hydroxyl Alkylbenzene phenols, polyoxy ethylene-polyoxy propylene-based block copolymer, ionic surfactant, and above-mentioned surfactant Mixture.
Pharmaceutical carrier the most according to claim 1, wherein said medicine is selected from adrenocortical hormone, local anesthetic, solution The medicine of a warm nature, antibiotic medicine, Wound-healing agent, vitamin, antibiotic, vasoconstrictor, antihistaminic, anesthetis, astringent, contraception Agent, termination of pregnancy medicine, defecation accelerator, central nervous system make medication, analgesics, skeletal muscle relaxant, autonomic drug, solution Convulsion agent, antivertigo drug, antiemetic, cardiac tonic, anti-arrhythmic, diuretic, coronary vasodilator, peripheral vasodilation Medicine, hyperlipidemia medicine, breathing accelerator, beta 2 receptor agonist, anti-Meniere's disease medicine, antitumor agent, diarrhea, exedens knot Enteritis treatment agent, peptic ulcer therapeutic agent, resistance dysfunction medicine, Labor-inducing medicine, anthelmintic, bronchodilator, biological system Product, anti-allergic drug, cathartic, enema, choleretic and the hormone in addition to adrenocortical hormone.
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