CN102552919B

CN102552919B - A kind of administration composition and its preparation and application

Info

Publication number: CN102552919B
Application number: CN201010590909.9A
Authority: CN
Inventors: 李伟华; 陆峰; 尹�民
Original assignee: Shanghai Bo Biological Medicine Ltd By Share Ltd
Current assignee: SHANGHAI BIOLAXY MEDICAL TECHNOLOGY Co Ltd
Priority date: 2010-12-15
Filing date: 2010-12-15
Publication date: 2018-03-27
Anticipated expiration: 2030-12-15
Also published as: CN102552919A

Abstract

The invention provides a kind of administration composition and its preparation and application.Administration composition includes the solid pharmaceutical preparation for being loaded with effective dose therapeutic component, sorbefacient, pharmaceutic adjuvant and the bio-adhesive layer containing bio-adhesive polymer, also include optional impermeable or semi-permeable coatings, make the therapeutic component in preparation and sorbefacient that there is unidirectional releasability.The unidirectional release channel with unidirectional releasability in preparation is formed by craft or laser ablation process, and therapeutic component and sorbefacient are almost synchronous from the rate of release in solid pharmaceutical preparation.Invention also provides the preparation and application of administration composition.The low dosage solid pharmaceutical preparation prepared using non-solvent granulating process can keep the homogeneity and stability of therapeutic component.Administration composition in the present invention can promote the difficult absorption to absorb the drug, improve bioavailability, adjust Pharmacokinetic Characteristics, improve drug absorption efficiency, and preparation is cheap, relatively easy production.

Description

A kind of administration composition and its preparation and application

Technical field

The invention mainly relates to drug delivery field, and be particularly suitable for use in the low medicine of convenient administration absorption difference, bioavailability Agent component, to improve the absorption of medicine, improve bioavailability.Specifically, the present invention relates to administration composition and its Preparation and application.

Background technology

Oral administration is most generally to be easiest to received administering mode.But for many medicines, the suction of oral administration Rate of producing effects is simultaneously bad.For example the bioactive macromolecule such as albumen, polypeptide, polysaccharide, nucleic acid is due to enzyme degraded, absorption difference or shakiness The factor such as fixed, generally can not be administered orally.Equally, many small-molecule drugs, such as Ciclosporin A, fenofibrate, stanin fat-reducing Mouth be present in antibiotic, the Diphosphonate clodronrate such as medicine, husky smooth hypotensor thing, ceftriaxone or azithromycin etc. The problems such as taking absorption difference, pharmacokinetics shakiness.

In order to solve these problems, people have carried out substantial amounts of exploration and research, to improve the life that these difficulties absorb the drug Thing utilization rate.It is that commonplace method (be shown in by survey article to promote the difficult absorption to absorb the drug using sorbefacient B.J.Aungst, J.Pharm.Sci., 2000,89 (4)：429-442).Numerous examples prove, can be carried using sorbefacient The assimilation effect of high percutaneous dosing or mucosa delivery, such as United States Patent (USP) 4,525,339,4,722,941,5,318,781,5,393, 738,5,424,289,5,597,562,5,714,477,5,817,624,5,827,534,5,854,281,5,912,014,5, 929,027,5,952,000,5,972,911,6,071,538,6,156,731,6,200,602,6,333,046,6,423, 334,6,747,014,7,316,819,7,576,067；Apply patent 2007/0148228,2007/0196464,2007/ in the U.S. 0238707,2008/0275001,2008/0299079,2009/0087484,2009/0111736 and European patent EP 1154761 grades disclose the example of correlation.

But due to the toxicity problem of correlation, use of the sorbefacient in oral formulations has also suffered from a definite limitation. One successful business case is exactly exploitation listing (DoktacillinTM, the Astra that Denmark's ampicillin colon fastens agentAB).Said preparation contains 25mg sodium caprates as sorbefacient, can will most compared with independent Omnipen High blood concentration, serum concentration-time area under the curve and urine recovery ampicillin be respectively increased 2.6,2.3,1.8 times (see T.Lindmark et al., Pharm.Res., 1997,14 (7)：930-935).

The environment of colon wriggling, the medicament holdup time, liquid fluidity, viscosity and intestines it is tolerant etc. with orally Environment has very big difference, and therefore, in oral administration, the requirement of sorbefacient is also relatively more higher.Such as Burcham People have studied sodium caprate and other sorbefacients to peptides imitation medicine DMP728 dog body absorption influence (Pharm.Res., 1995,12 (12)：2065-7200).As a result show, 115~120mg sodium caprates are added in gelatine capsule Certain rush assimilation effect can be produced, bioavailability brings up to 17.7% from 13.0%, and adds equal amount sodium caprate Enteric coated preparations do not show any effect but.

In order to obtain it is lasting, significantly promote assimilation effect, improve bioavailability, need to add the last of the ten Heavenly stems in every tablet preparation The amount of sour sodium is 275~550mg (U.S.Patent Application Pub.No.2008/0275001).But orally making The sorbefacient that such high dose is added in agent can frequently result in toxic reaction, trigger potential safety hazard.

Up to the present, for those absorption is more difficult, bioavailability is relatively low oral drugs, especially macromolecular medicine Thing, also without safely and effectively solution route.Therefore, people can produce obvious there is an urgent need to develop a kind of drug delivery system Drug absorption effect, improve bioavailability, excessive sorbefacient will not be used again.

The content of the invention

An object of the present invention is to provide a kind of absorption that hardly possible can be promoted to absorb the drug, can improve bioavailability Medicament composition without producing toxicity hidden danger.On the other hand it is exactly by adjusting Pharmacokinetic Characteristics, improving medicine Absorption efficiency, and cheap, the relatively easy production of preparation.

On the one hand, the invention provides a kind of medicament composition for being used to be administered, composition to include being loaded with effective dose The solid label of therapeutic component, sorbefacient and pharmaceutic adjuvant and bio-adhesive layer containing bio-adhesive polymer, it is another Aspect, medicament composition can be further coated using enteric material, prevent the leakage of medicine under one's belt, enable preparation in intestines and stomach Specific region such as small enteral release., it is surprising that the presence of bio-adhesive layer, the demand of sorbefacient can be reduced Amount, significantly improve the difficult absorption to absorb the drug and bioavailability.

In some instantiations, the invention provides a kind of medicament composition for being used to be administered, composition includes carrying There is the label of effective dose therapeutic component, sorbefacient and pharmaceutic adjuvant, label uses the life containing bio-adhesive polymer Thing adhesion layer is coated, and using the impermeable or semi-permeable formula coatings coating with hole, make therapeutic component in preparation and Sorbefacient has unidirectional releasability.On the other hand, medicament composition can further use enteric coating, preparation is existed Discharged in the specific region of intestines and stomach.

In some instantiations, therapeutic component and sorbefacient in preparation have almost identical rate of release. So, the therapeutic component in preparation and sorbefacient can realize sectional, slow synchronous release, therefore, with it Other people preceding comparison of results, the present invention can significantly reduce the usage amount to sorbefacient, promote drug absorption, and raising is controlled Therapeutic effect.

On the other hand, the medicament composition in the present invention can adjust the Pharmacokinetic Characteristics of therapeutic component.Pass through tune The component and proportioning of full wafer core, or the component of bio-adhesive layer, with when thickness, or impermeable formula or semi-permeable formula coating coating Component, with when thickness, the release dynamics parameter of drug component and sorbefacient can be adjusted, according to therapeutic effect need Will, using it is prominent release, the delivery mode such as extended release or sustained release.

Invention also provides the preparation method of medicament composition, including prepare and load effective therapeutic component, absorb rush Enter agent, the solid pharmaceutical preparation of excipient substance；Solid pharmaceutical preparation is coated using bio-adhesive polymer；Using optional impermeable formula or Semi-permeable formula coating technology is coated to solid pharmaceutical preparation, makes therapeutic component in preparation and sorbefacient unidirectional from reserved passageway Release.In instantiation, the order that the coating of bio-adhesive layer and impermeable formula or semi-permeable formula are coated can be exchanged mutually； In some instantiations, preparation method is also included to combining further carry out enteric coating.

On the other hand, the present invention passes through oral, nose for needing the patient of drug therapy to provide a kind for the treatment of method The pharmaceutical agent combinations of the present invention are delivered to appointed part by the administering modes such as chamber, oral cavity, sublingual, rectum or vagina.

A kind of administration composition, it is characterised in that combination includes：

A) it is loaded with the solid pharmaceutical preparation of effective therapeutic component, sorbefacient and pharmaceutic adjuvant；

B) the bio-adhesive layer being made up of bio-adhesive polymer.

Bio-adhesive layer content in the present invention account for the 0.5~10% of administration composition gross mass, 1~5%, or 2~ 3%.

In bio-adhesive layer in the present invention content of bio-adhesive polymer account for bio-adhesive layer gross mass 50~ 100%, 70~90%, or 80~90%.

Administration composition in the present invention also includes impermeable or semi-permeable formula coatings, make therapeutic component in preparation and Sorbefacient has unidirectional releasability.

The unidirectional release channel area with unidirectional releasability in the present invention cover the preparation side gross area 20~ 90%, 40~80%, or 50~70%.

Coatings content in the present invention accounts for the 0.5~10% of administration composition gross mass, 1~5%, or 2~4%.

Therapeutic component and sorbefacient in the present invention is almost synchronous from the rate of release in solid pharmaceutical preparation.

Administration composition in the present invention includes enteric layer.

Bio-adhesive polymer in the present invention from carbomer, polycarbophil, hydroxypropyl methyl cellulose and chitosan and Selected in its salt or derivative one or more of.

Also contain enteric polymer in bio-adhesive layer in the present invention.

Impermeable layer or semi-permeable layer in the present invention contain impermeable or semi permeable material.

Impermeable or semi permeable material in the present invention is from ethyl cellulose and cellulose acetate and its salt or derivative Middle selection is one or more of.

Contain plasticizer in impermeable layer or semi-permeable layer in the present invention.

Sorbefacient in the present invention is from aliphatic acid, medium chain triglycerides, surfactant, steroidal cleaning agent, acyl meat Selected in malicious alkali, alkane choline, N- acetylamino acids and esters and its salt or derivative one or more of.

Sorbefacient aliphatic acid in the present invention is made up of the aliphatic chain containing 8~14 carbon atoms.

Sorbefacient in the present invention selects one or more from capric acid and its salt or ester or derivatives thereof.

Sorbefacient in the present invention is sodium caprate or derivatives thereof.

Content of the sodium caprate in the present invention or derivatives thereof in administration composition is 25~300mg, 50~200mg, Or 100~200mg.

Therapeutic component and sorbefacient are delivered to the mucomembranous surface of human or animal by the administration composition in the present invention.

Sufferer is administered by oral way for administration composition in the present invention.

Therapeutic component in the present invention includes bioactive macromolecule.

Bioactive macromolecule in the present invention selects from albumen, polypeptide, polysaccharide, nucleic acid, lipid and carbohydrate It is one or more of.

Bioactive macromolecule in the present invention is from insulin, hematopoietin, interferon, growth hormone, Ai Sai That peptide, GLP-1 agonists, parathyroid hormone, calcitonin, leuprorelin acetate, Sandostatin LAR Depot, low molecular weight heparin and its work( It can change and one kind is selected in analog and mutant and its salt or derivative.

Therapeutic component in the present invention selects one from Exenatide and its salt or the analog or derivative of its functionalization Kind.

Administration composition in the present invention can be prepared into capsule, tablet, pill, powder or graininess.

Administration composition in the present invention prepares solid pharmaceutical preparation by direct pressing technique.

Administration composition in the present invention prepares solid pharmaceutical preparation by non-solvent granulating process.

The non-solvent medium in non-solvent granulating process in the present invention includes ethanol, isopropanol, butanol, acetone, acetic acid Ethyl ester.

Solid pharmaceutical preparation prepared by the non-solvent granulating process in the present invention can keep the stability of therapeutic component at room temperature.

The preparation method of administration composition in the present invention includes：

A) solid pharmaceutical preparation containing effective dose therapeutic component, sorbefacient and pharmaceutical excipients is prepared；

B) solid pharmaceutical preparation is coated using the bio-adhesive polymer with bio-adhesive characteristic.

Preparation method in the present invention further comprises：

C) impermeable layer is carried out to solid pharmaceutical preparation or semi-permeable layer is coated, the passage in coating makes the treatment in solid pharmaceutical preparation Component and sorbefacient have unidirectional releasability.

Step b) in preparation method in the present invention and c) interchangeable.

The unidirectional release channel that solid pharmaceutical preparation one in the present invention is surveyed is formed by laser ablation process.

Preparation method in the present invention includes further being coated using enteric layer.

The application method method of administration composition includes taking described administration composition in the present invention.

Detailed description of the invention

B) the bio-adhesive layer being made up of bio-adhesive polymer.

Administration composition in the present invention includes enteric layer.

Also contain enteric polymer in bio-adhesive layer in the present invention.

Sorbefacient in the present invention is sodium caprate or derivatives thereof.

Preparation method in the present invention further comprises：

Step b) in preparation method in the present invention and c) interchangeable.

Term and definition

Unless defined, all technologies and scientific terminology are consistent with the meaning that industry is routinely understood.All patents, public affairs The patent application of cloth and other publications, database, which refer to, to be cited in full text.If other patents of the definition with reference of this section, announce Patent application and other publications, database document it is inconsistent, by this section definition be defined.

Reference to publication or file, which is not meant that, to be recognized these previous publications or file, is not also meant that pair Interior perhaps data recognizes in these publications or file.

In the present invention, "one" refers to " at least one " or " one even more more ".

In the present invention, " pharmaceutical agent combinations " and " reagent combination " refer to the combination that each component can effectively be distributed and formula or in bodies Interior energy reaches the compound of optimum activity.

In the present invention, " effective dose " or " effective dose for the treatment of ", which refers to, will not produce toxicity but to Most patients or individual Body can provide the active component for preferably treating or preventing effect.It is generally believed that the effective dose of active component can with to Medicine approach, the age, body weight, sex change and change.There is experience person to consider such as metabolism, bioavilability in field And factor of other influences blood concentration etc. determines effective dosage ranges, and it is administered using different methods of administration.

In the present invention, " pharmaceutical acceptable " refers to nontoxic, inertia, with the mankind or other physiological mammal phases The component of appearance.

In the present invention, " pharmaceutic adjuvant " refers to adjuvant, carrier, pH regulations buffer, tension regulator, wetting agent, preservative And other similar materials.

In the present invention, " patient ", " individual ", " host ", " patient " are used interchangeably, and refer to what is needed to treat, observe, testing " animal "." animal " includes vertebrate and invertebrate, and such as fish, shellfish, reptile, birds, especially " lactation is moved Thing "." mammal " includes but unlimited and mouse, rat, rabbit, cavy, dog, cat, sheep, goat, ox, horse, primate such as monkey Son, orangutan, apes, the espespecially mankind.

In the present invention, " treatment " refer to all it is any use remedy or the measure of prevention disease or infection or with other Mode is prevented, hindered, delaying or the measure of reverse disease or the progress of infection or other ill symptomses." treatment " or " processing " Refer to the improvement or improvement of disease consequence, not refer in particular to the elimination of disease.The improvement of a certain specific symptoms refers to take the present invention's The mitigation of symptom after pharmaceutical agent combinations, or symptom mitigation with the present invention pharmaceutical agent combinations it is relevant, no matter it is long-term or temporarily.

In the present invention, " taking " or " administration " refers to the medicine group for using any feasible method to provide the present invention for patient Close.It can be administered by modes such as oral, nasal cavity, oral cavity, sublingual, rectum or vaginas.Pharmaceutical agent combinations can be prepared as being adapted to each approach The dosage unit of administration.

In the present invention, " solid pharmaceutical preparation " refer to be in form solid any formulation, including but not limited to tablet, glue Capsule.Capsule includes capsule made of hard or soft material, as gelatin or natural or synthetic gelatine replacement, lozenge, its combination or Analog etc..

In the present invention, " sorbefacient " refers to that the group that active constituents of medicine penetrates mucomembranous surface transmission rate can be improved Point.Generally, sorbefacient can increase permeability of the therapeutic component on mucosal tissue.As sorbefacient can increase treatment Component penetrates the speed that mucous membrane enters blood.After sorbefacient, it is observed that the osmosis of this enhancing.Example Such as, the flux across animal or human body cell film pharmacological component can be measured." effective " amount of sorbefacient refers to energy The amount of the penetrating amount of preferable mucous membrane is enough realized, such as preferable drug absorption or bioavailability can be reached.

In the present invention, what " bio-adhesive " typically referred to contact with biological tissue and/or physiological fluid any sticks.It is " raw Thing adhesion layer " refers to the solid layer for being attached to individual mucosal tissue.The bio-adhesive layer includes at least one " bio-adhesive polymerization Thing ", including but unlimited and carbomer, polycarbophil, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxylic Methylcellulose, polyvinyl alcohol, Sodium Hyaluronate, chitosan, sodium alginate, XANTHAN GUM, acrylate copolymer and its derivative And mixture.

In the present invention, the component that " impermeable or semi-permeable " refers in physiological fluid and drug delivery system is not enough to infiltration The migration amount that material, such liquid and component pass in and out system by impermeable or semipermeable materials is relatively low, will not be to the work(of system It can produce and have a strong impact on.

In the present invention, " unidirectional release " refers to therapeutic component in solid pharmaceutical preparation and sorbefacient can be from impermeable or half In the reserved passageway on penetrable coating layer surface, discharge more than 50%, 60%, 70%, or even 80%, 90%, preferably over 95%.

In the present invention, " identical rate of release " refers to the release of the therapeutic component and sorbefacient in solid pharmaceutical preparation almost It is synchronous.For example, within the specified time, fractional release and release of the sorbefacient within the equal time of therapeutic component The difference of ratio is less than 50%, 40%, 30%, even below 20%, 10%, preferably lower than 5%.

In the present invention, " enteric layer ", " enteric coating ", " enteric material ", " enteric polymer " refer to available for solid pharmaceutical preparation Pharmaceutical excipients mixture, it can prevent release of the active component in oral cavity, esophagus or stomach, but when preparation passes through stomach and intestine During road lower end, medicine therein quickly can thoroughly discharge.Enteric layer can account for 1~15% or 3 in solid pharmaceutical preparation gross weight~ 12%th, best 6~10%.Enteric polymer may be selected but be not limited to cellulose acetate-phthalate (S or L), HPMCP, hydroxypropylmethylcellulose acetate methyl cellulose succinate hydrochlorate, acetic acid -1,2,4- benzene three Acid cellulose, polyvinyl acetate phthalate, shellac and methacrylic acid copolymer.Rate of release selection as needed Coating layer thickness, and rate of release relies on the property and thickness with coating.

In the present invention, " plasticizer " refers to be compounded in drug component, by improving the free body between polymer chain Accumulate and reduce glass transition temperature and the polymeric material of melt viscosity.Plasticizer include but is not limited to citrate (for example, Triethyl citrate, triacetyl glycerine), polyalkylene oxides (such as polyethylene glycol, polypropylene glycol, the poly- second of low molecule amount Alkene/propyleneglycoles), glycerine, pentaerythrite, monoglyceride, acetic acid or triacetate, propane diols, sodium diethyl succinate.Increase It can be the 0.1%~25% of dose weight, best 0.5~15% or 1~20% to mould agent.Other examples of plasticizers are shown in Ash etc. T_HE H_{ANDBOOK OF} P_{HARMACEUTICAL} A_DDITIVES(3^rdEd., Synapse Information Resources, Inc., 2007)。

In disclosure of the invention item, various indexs are stated frequently with data area, and this statement is intended merely to meet Convenient and succinct needs, and do not form the limitation scope to the application jurisdictions mandate.Therefore, this statement is likewise covered by In the range of smaller scope and scope in individual digit.For example, the description to 1~6, cover in the range of such as 1~ 3rd, 1~4,1~5,2~3,2~4,2~5,2~6 etc., while the individual digit in the range of also including, such as 1,2,3,4,5 With 6.This, which is defined in any wide in range data area, is applicable.

Drug delivery system

As described above, the invention provides a kind of medicament composition for being used to be administered, including it is loaded with effective dose treatment group Point, the solid pharmaceutical preparation of the label of sorbefacient and pharmaceutic adjuvant and the bio-adhesive layer containing bio-adhesive polymer, such as press Piece, paster, point, powder etc..In instantiation, drug regimen further can be coated using enteric material, make medicine in stomach and intestine The appointed part release in road.Although using hydroxypropyl methyl cellulose HPMC, PVAC polyvinylalcohol, polyethylene glycol PEG etc. as painting Layer material has been used widely, but inventor has surprisingly found that：The presence of bio-adhesive polymer coating, can substantially it drop The low demand to sorbefacient, significantly improve to the difficult assimilation effect and bioavailability for absorbing medicine.

In some instantiations, it is shown that the effect of disclosed administration combination.The sorbefacient used in example It is sodium caprate, medicine is that the Exenatide containing 39 amino acid (sell by Amylin＆Eli Lilly companiesBy with In treatment stage 2 diabete).In the document of early stage, the addition of sodium caprate needs to reach 275~550mg could be in dog body The absorption (U.S.Patent Application Pub.No.2008/0275001) dramatically increased is realized, in same animal mould In type, lesser amount of sodium caprate (115~120mg) enteric coated preparations be proved to be it is invalid (Burcham et al., Pharm.Res., 1995,12 (12)：2065-2070).

Similar with other people experimental result, inventor has found that the preparation individually containing 100mg sodium caprates is really invalid.But Surprisingly, the formula of same amount sodium caprate (100mg) and bio-adhesive layer is added with being individually added into higher doses sodium caprate Recipe ratio is compared with effect is identical even better.(400mg) the compound bio adhesion layer in the formula containing higher doses sodium caprate, Assimilation effect is more preferable.The presence of one bio-adhesive layer can influence the demand to sorbefacient, and reduce so far forth, This is entirely unexpected phenomenon.

In some instantiations, the invention provides it is a kind of be used for be administered medicament composition, by tabletting, paster, point, The solid pharmaceutical preparations such as powder form, including the label containing effective dose therapeutic component, sorbefacient and pharmaceutic adjuvant and contain The bio-adhesive layer of bio-adhesive polymer, non-containing passage is oozed or pellicle coatings, makes therapeutic component and absorption enhancement Agent can unidirectionally discharge from the passage of solid pharmaceutical preparation.In some instantiations, drug regimen can further use enteric material Coating, medicine is set to be discharged in the appointed part of intestines and stomach.It is surprising that this combination can be reduced further to absorption enhancement The demand of agent, without influenceing the assimilation effect to medicine.

The formulation of many different unidirectional releases has been disclosed at present.Such as United States Patent (USP) No.4,772,470 and No.5, 827,525 disclose a kind of paster or adhesive bandage for oral administration.United States Patent (USP) No.7,097,851 and many non-patents Publication (such as S.Eaimtrakarn et al., Biomaterials, 2002,23 (1)：145-152；S.Eaimtrakarn Et al., Intl.J.Pharm., 2003,250 (1)：111-117；And S.L.Tao＆T.A.Desai, Drug Discov.Today, 2005,10 (13)：909-915) all disclose a kind of oral patch formulation, paster include site selection layer, Drug-loaded layer, adhesion layer, impervious bed etc..There is researcher to have studied impermeability ethyl cellulose bag using rat model in situ The biological insulin of clothing sticks the administering effect of paster, the results showed that sorbefacient can't produce to the transmission effect of system Crucial effect (K.Whitehead et al., J.Control.Release, 2004,98 (1)：37-45).

It is worth noting that, although many patents and some non-patent publications all have been disclosed for mouth paster and unidirectional The formulation of release, but in important pharmaceutical field, but report that this shows that oral patch form is still deposited without follow-up commercialization In great technological challenge.

In a particular embodiment, in the presence of sodium caprate, the unidirectional coatings that discharge are to Exenatide assimilation effect and biology The influence of utilization rate.In formula containing 50mg sodium caprates without unidirectional release coatings, absorption of the dog to Exenatide is Very small, this is consistent with reporting (U.S.Patent No.7,605,123).But after applying unidirectional releasing layer, Chinese mugwort Filling in the absorption of that peptide substantially increases.Impermeability or semipermeable membrane can be used as unidirectional release coatings.

It is well known that sorbefacient, which needs to reach minimum action concentration, can be only achieved effect.Someone estimates sodium caprate Reach 10~13mM concentration can just play promote infiltration effect (see E.K.Anderberg et al., Pharm.Res., 1993,10 (6)：857-864).Meanwhile people it is further recognized that sorbefacient release compared with therapeutic component, it is necessary to Relatively quick synchronous release, to avoid by the liquid rapid dilution in intestines and stomach.United States Patent (USP) No.2008/0275001 is disclosed Using sodium caprate as the low molecular weight heparin quick release of sorbefacient and the formula of sustained release.Add in identical sodium caprate Enter under amount, the positive effect of the formula of sustained release is not so good as the formulation efficacy of quick release.

Therefore, when containing impermeable or semi-permeable coatings and with the recipe ratio simple formulation table of the release characteristic extended When having showed stronger rush assimilation effect, this is unexpected.Inventor is had further been found that in unidirectional delivery formulations, is led to Cross and change non-ooze or semi-transparent film thickness, the content of plasticizer and property, channel size etc. can be dynamic with the medicine generation of adjustment for the treatment of component Mechanics.In some instantiations, therapeutic component and sorbefacient discharge in a synchronous manner.In other instantiations, Drug regimen extends release time, realizes constant absorption.

Therapeutic component

In instantiation, it is necessary to the therapeutic component being passed include be difficult in the gastrointestinal tract it is absorbed, according to biology Biopharmaceutical Classification system (BCS) is classified (see Food and Drug Administration, " Guidance for Industry：Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System ") it is classified as Group III or the medicine of IV classes.

In instantiation, it is difficult to absorbed therapeutic component from can be as selected in the following group：Acetylcysteine, Ah former times Lip river Dimension, albendazole, alcuronium, Ah 's acid, alendronate, Alfuzosin, alprazolam, prostaglandin E1, Ah Meter Ka Xing, aminobisphosphonate, amiodarone, amitriptyline, Amlodipine, Amoxicillin, amphetamine, amphotericin B, Ampicillin, Artemether, artesunate, aspirin, atazanavir, atenolol, atomoxetine, Atorvastatin, atropine, Ah Neat erythromycin, retrovir, Bacitracin, beclomethasone, tardocillin, penicillin, BIPERIDEN, bleomycin, Bosentan, Bupivacaine, buprenorphine, biphenylacetone, Candesartan, candoxatril, capreomycin, captopril, Karma west Flat, carbidopa, Carvedilol, Caspofungin, cephazoline, Cefdinir, Cefixime, CTX, ceftazidime, head Spore ammonia thiophene triazine, celecoxib, Chlorambucil, chloramphenicol, chloroquine, chlorpheniramine, chlorpromazine, cilastatin, Cimetidine, ring Third husky star, Clarith, clofazimine, chlorimipramine, clonidine, clopidogrel, clotrimazole, cloxacillin, ring phosphinylidyne Amine, Ciclosporin A, cytarabine；9- dextrorotation 4- hydrogenation cannabinol, Dacarbazine, dactinomycin D, DANAZOL, to bit amino Double benzene sulfones, daunorubicin, desferrioxamine, desipramine, dexamethasone, Didanosine, diethylcarbamazine, digoxin, dihydroergotamine, That sulphur Zhuo, propyl disulfide, dolargin, domperidone, domperidone, dopamine, Doxazosin, docetaxel, hydroxyl are red Than mycin, Duloxetine；The new element of efavirenz, Eflornithine, enalapril, Enprostil, adrenaline, ergot, angstrom sieve For Buddhist nun, Abboticine, esomeprazole, estradiol, zopiclone, etoposide, ezetimibe；Famotidine, take happy ground Flat, fenofibrate, fentanyl, fexofenadine, Tamsulosin, Flucytosine, fludrocortison, fluorouracil, Prozac, fluorine Perphenazine, fluoroprofen, Fluticasone, Fluvastatin, Formoterol, frusemide；Gabapentin, GCV, gemcitabine, celebrating Big mycin, glibenclamide, Glimepiride, glyceryl trinitrate, griseofulvin, griseofulvin；Haloperole, hydralazine, dihydro Diuril, hydrocortisone, hydroxocobalamine；Ibandronic acid, brufen, Imipenem, imipramine, indinavir, Ipratropium Bromide, Irbesartan, Irinotecan, isoniazid, ISDN, Itraconazole；Kanamycin, ketoconazole, Ketoprofen；Draw belotecan That, Latanoprost, left-handed (four) imidazoles, levodopa, lidocaine, lisinopril, Loperamide, Lopinavir, chlorine are husky Smooth, Lovastatin, lumefantrine；Mebendazole, Medroxyprogesterone, Mefloquine, meglumine antimonic salt, melarsoprol, mercapto (base) purine, mercapto Ethyl sulfonic acid sodium, metformin, methadone, methotrexate (MTX), ethyldopa, ritalin, methylenum careuleum, metoprolol, meter Fei Take charge of ketone, misoprostol, modafinil, Mometasone, montelukast, morphine；Nadolol, naloxone, naproxen, it is new this Bright, NVP, niclosamidum, nifedipine, nifurtimox, nitrofurantoin, norethindrone, nortriptyline, nystatin；Oxygen fluorine Sha Xing, Olmesartan, Omeprazole, ondansetron, oxaliplatin；Taxol, Pamidronate, PAS, Paromomycin, pemetrexed, penicillamine, Pan Ta meter Ding, penicillin Vl phenoxymethylpenicillin, phenylacetic acid mustard, phenytoinum naticum, vitamin K1, Phytosterol, Piroxicam tablets, pilocarpinum, Piperacillin, Pravastatin, praziquantel, prazosin, prednisolone, sprinkle It is Buddhist nun pine, procaine benzylpenicillinate, procarbazine, progesterone, chloroguanide, fenazil, inderal, propyl alcohol, propylthiouracil, preceding Row parathyrine, Pyrantel, pyridostigmine；Quetiapine, quinidine, quinine；Rabeprazole, Raloxifene, Ramipril, thunder Buddhist nun replace Fourth, rapamycin, three (nitrogen) azoles nucleosides, Risedronic Acid, Ritonavir, Ropinirole, rosuvastatin；Albuterol, salicylic acid, Salmeterol, inverase, hyoscine, Sertraline, silaenafil, Simvastatin, sodium nitroprussiate, spectinomycin, stavudine, Steroids, Stibogluconate, stigmasterol, sulfadoxine, sulfamethoxazole, salicylazosulfapyridine, sumatriptan, suramin, Scoline；Tacrolimus, Tadalafei, tamosifen, tegaserod, Telmisartan, Temozolomide, Tenidap, for promise Fu Wei, tenofovir, RMI 9918, testosterone, totokaine, tetracycline, timolol, plug support bromo-amine, Triamcinalone, triclabendazole, trovafloxacin, tubocurarine；Ubiquinone；Valaciclovir, valproic acid, Valsartan, through the ages It is mycin, Vardenafil, Vecuronium Bromide, Venlafaxine, verapamil, vincaleukoblastinum, vincristine, vitamin B12, retrovir, neat Draw western ketone, zoledronic acid, zolpidem, salt, analogs and derivatives.

In instantiation, medicine includes those medicines in the selective absorption of privileged site such as upper part of small intestine, bag Include but be not limited to such as riboflavin, melbine, levodopa and frusemide.

In instantiation, medicine generally also includes some bioactive macromolecule medicines, as protein, polypeptide, carbohydrate, Nucleotides, lipid, carbohydrate and their compound.

In instantiation, protein drug can be：Antifibrin-ferment, albumin, α -1 proteolytic enzymes, anti-blood friend Sick globulin, coagulation factor, antibody, anti-CD 20 antibodies, anti-CD 52 antibody, anti-CD 33 immunotoxin, DNA enzymatic, promoting erythrocyte life Cheng Su, IX factor, the VII factors, the VIII factors, follicle stimulating hormone, granulocyte colony stimulating factor G-CSF, the G- for being grafted PEG CSF, α or beta galactosidase, glucagons, glucocerebrosidase, granulocyte-macrophage colony-stimulating factor, chorion rush property Glandular hormone, hepatitis B antigen, hepatitis B surface antibody, hepatitis B core antigen, hepatitis B envelope antigen, the third type liver Scorching antigen, hirudin, anti-HER-2 antibody, anti-immunoglobulin antibody, anti-IL-2 receptor antibodies, insulin, insulin glargine, Insulin Aspart, insulin lispro, interferon, be grafted PEG interferon, α or α 2a or α 2b interferon, β or β -1a or β -1b interferon, interferon gamma, interleukin 2, interleukin 11, interleukin 12, LH Luteinizing hormone, how west Vertical peptide, Osteogenic Protein-1, osteogenic protein -2, lime vaccine, platelet-derived growth factor, antiplatelet antibody, anti-sarcoma Antiviral antibody (annti-RSV), growth hormone, D2E7, anti-tumor necrosis factor receptor fusion protein, group Textured fiber Plasminogen Activators, TNK-tPA, thyrotropic hormone, fibrinolytic enzyme, thrombus dissolving enzyme, adenosine take off Ammonia enzyme, the adenosine deaminase of PEGylation, anistreplase, asparaginase, Collagenase, streptokinase, sucrose Enzyme, urokinase, aprotinin, botulin toxin, fibroblast growth factor, endothelial growth factor, snake venom etc..It is described Albumen include from genetic recombination, chemical synthesis or biology extraction etc. mode obtain.Albumen includes changing for wild type molecule simultaneously Good analog or derivative etc..The initial source of albumen can be the mankind or other species.

In instantiation, selectable peptides include：Corticotropin (ACTH), anti-angiogenesis polypeptide, Adamtsostatin, adiponectin, adipokinetic hormone, fat are even plain, fat triglyceride fat (fat) enzyme, adrenomedulin, thorn Mouse GAP-associated protein GAP, alarin vasoactive peptides, allatostatin, amelogenin, calcitonin, dextrin, amyloid, blood Pipe generation element, angiotensin, cause become thin peptide, anti-inflammatory peptide, the antidiuresis factor, antimicrobial peptide, apelin, peptide antibioticses, RGD peptide, atrial natriuretic peptide, atriopeptin, auriculin, autocrine motility factor, Magainin, bombinakinin, bradykinin, Brain natriuretic peptide, BDNF, frog antibacterial peptide, C peptides, caspase anti-factor, pancreas [gland] peptide, cheek Peptide, bursin, c-type natriuretic peptide, calcitonin related peptide, CTR kassinin kinin, calmodulin, CART, Cartilostatin, casomokinin, a hydrolyzed casein, catestatin, cathepsin, attacin, cerebellin, Chemerin, chelocystokinin, chromograin, CNTF, conotoxin peptide, aconopressin, taro Spiral shell toxin and peptide element, promote male corticosteroids, cortico-trophin-releasing factor (CRF), cortex chalone, coupling factor, defence It is element, delta EEG, dermorphin, antidiuretic hormone, desamino- antidiuretic hormones, diuretic hormone, dynorphin, endokinin, interior Morphine peptide, endorphin, endostatin, Endothelin, enkephalins, enterostatin, exendin, Exenatide, RBC acceptor garland rate peptide, on Skin growth factor, fat orientation peptide, galanin, gastrointestinal inhibitory peptide, gastrin, gastrin releasing peptide, growth swash Plain release peptide, glucagons, glucagon like peptide, Agifutol derivative, Wheat Gluten Exorphin, hormone releasing factor Son, granulocyte-macrophage colony-stimulating factor restrain peptide, growth hormone peptide, guanylin peptide, AIDS virus peptide, Helodemine, tachykinin, hepatitis c virus peptide, hepatitis B phallotoxins, HSV peptides, blister sore phallotoxins, hirudin, leech Peptide, IGF, hydrin, melanotropin, kassinin, keratinocyte growth factor, kinetensin, swash Peptide former, kiss peptide, kyotorphin, laminin peptide, Leptin peptide, leucokinin, leucopyrokinin, leupeptin, rush Gonadotropin releasing hormone, lymphokines, melanin-concentrating hormone and its inhibitor, melanocyte-stimulating hormone(MSH) release are restrained Agent, melanotropin intensifier, morphine regulation neuropeptide, MSH, neoendorphin, nesfatin, neurokinin, neuromedin, god Through p277, neurotensin, neurotrophic factor, nociceptin, fat supression element, opiate receptor antagonist, aricine, salmon drop Calcium element, oxytocins, pancreastatin, PYY, physalaemin sample peptide, secretin, Somat, seminal fluid activating peptide, P things The sensitive element of matter, syndyphalin, fibrin ferment, thymopoietin, thymosin extrasin, thyrotropin-releasing hormone (TRH), conversion grow because Son, tuftsin, TNF or related peptide, usrechistachykinin, cortin, urotensin antagonism Agent, valorphin, vasotocin, vasoactive intestinal peptide, peptide antibiotics, xenopsin or related peptide, described peptides It can be obtained from modes such as genetic recombination, chemical synthesis or biology extractions.Peptides include the improvement analog of wild type albumen simultaneously Or derivative etc..Source can be the mankind or other species.

In instantiation, bioactive macromolecule is a kind of antimicrobial vaccine, including from adenovirus, anthrax, knot It is pyrenomycetes element, botulin toxin, cholera, diphtheria toxoid, diphtheria and tetanus toxoid, diph-tet and pertussis, thermophilic Blood bacillus B, hepatitis A, hepatitis type B virus, influenza, encephalitis, measles,mumps,rubella, meningococcus, pest Epidemic disease, pertussis, pneumococcus, polio, rabies viruses, rotavirus, rubella, smallpox, tetanus toxoid, typhoid fever, The vaccine extracted in varicella, yellow fever, bacterial antigen and compound substance.

In instantiation, bioactive macromolecule is included from room dirt mouse, animal scurf, mould, pollen, hogweed, rubber Glue, wasp, insect-derived allergen and compound substance in the allergen that selects.

Bioactive macromolecule includes certain macromolecular and the combination of other molecules with similar biological function.Example Such as, wild type molecule passes through the analog of chemistry or biological modification with it.The example of wild type macromolecular and the like includes But it is not limited to such as glucagon-like peptide 1 (GLP-1) and the like, exendin peptides and the like.

In instantiation, medicine can select Exenatide, and (gift comes public a polypeptide containing 39 amino acid The existing commercialized product of department, for treating diabetes B), and salt or derivatives thereof.

Sorbefacient

As described above, sorbefacient is well known, in instantiation, sorbefacient can be by aliphatic acid, middle chain Glyceride, surfactant, steroidal detergent, fatty acyl carnitine, alkane choline, select in N- acetylamino acids, ester, salt and its derivative Select.

In instantiation, sorbefacient contains aliphatic acid, including but not limited to butyric acid, caproic acid, octanoic acid, n-nonanoic acid, certain herbaceous plants with big flowers Acid, laurate, nutmeg, palm, stearic acid, peanut, oleic acid, linoleic acid, flax resin acid, its salt and its derivative etc..One In a little instantiations, sorbefacient contains the glyceride in aliphatic acid, including but not limited to butyric acid, caproic acid, octanoic acid, certain herbaceous plants with big flowers acid, Laurate, nutmeg, palm, stearic acid, peanut, oleic acid, linoleic acid, flax resin acid, its salt, derivative and combinations thereof.Glycerine Ester can be monoglyceride, glycerine two refers to or triglycerides.Aliphatic acid can be by the combination of identical or different aliphatic acid.Specific In example, sorbefacient contains the aliphatic chain of 8~14 carbon atoms.

In instantiation, sorbefacient contains cholic acid or salt, including the cholic acid for being conjugated or not being conjugated, such as courage Acid, deoxycholic acid, taurocholate, glycocholic acid, taurodeoxycholic acid salt, ursodeoxycholate, tauroursodeoxycholate, goose Deoxycholate, its derivative and compound etc..

In instantiation, sorbefacient includes metal-chelator, such as the double tetrems of ethylenediamine tetra-acetic acid, ethylene glycol Acid, it is surfactant such as lauryl sodium sulfate, glymes or esters, the alkyl ether of polyethylene glycol -12, salicylate, poly- PS80, nonylphenoxypolyoxyethylenes, aerosol OT, saponin, palmitoyl carnitine, lauroyl acetylcarnitine, the moon Osmanthus acyl group maltoside, fatty acyl carnitine, alkanoyl choline.Other penetration enhancers include 3 ' nitrobenzoates, Zoonula occulden toxin, the fatty acid ester of lactate, glycyrrhetate, hydroxyl cyclodextrin, the amino of N- acetylations Acids such as N- [8- (2- hydroxy benzoyls) amino] Sodium Caprylate, chitosan, the derivative of salt and these compounds.

In instantiation, sorbefacient by with selectively targeting and can open it is close-connected (such as chitosan and Its derivative) this kind of compound group into.In instantiation, absorption enhancement is capric acid, salt or derivatives thereof.

Formula and auxiliary material

As described above, pharmaceutical agent combinations provided by the invention especially include pharmaceutical excipients.Pharmaceutical agent combinations can be capsule, piece The forms such as agent, pill or paster.Suitable auxiliary material and formula introduces visible R_EMINGTON：T_HE S_{CIENCE AND} P_{RACTICE OF} P_HARMACY(21^stEd., Lippincott Williams＆Wilkins, 2005).

In instantiation, excipient substance includes helping the material with support dispersion.In instantiation, pharmaceutical excipients bag Include disintegrant.In instantiation, pharmaceutical excipients include polyvinyl pyrrolidone, croscarmellose, PVPP, carboxylic first Base sodium starch and hydroxypropyl cellulose.

Pharmaceutical agent combinations can include other components, such as buffer, preservative, nonionic surface active agent, solubilizer, absorption Accelerator, stabilizer, softening agent, lubricant, tonicity agent etc..The control release of medicine can be achieved after combination.

Pharmaceutical agent combinations exist with suitable oral formulation.Such as tabletting, lozenge, lozenge, hard shell capsules or soft capsule.Oral Drug regimen can be prepared according to known any method.Can contain in combination makes in sweetener, flavor enhancement, colouring agent, protective agent One or more, make drug substance stable, it is easily prepared.

Auxiliary material in tablet includes：Inert diluent or filler, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or phosphoric acid Sodium, microcrystalline cellulose, sucrose, mannitol, D-sorbite；Adhesive such as PVP, polyethylene glycol, hydroxypropyl methyl Cellulose, gelatin, starch or its mixture；Lubricant, example magnesium stearate, superfine silica gel powder, stearic acid or talcum powder.In the present invention In disclosed embodiment formula, forming the auxiliary material of label includes：

Auxiliary material	% contents	Function
			Sodium caprate	40-80	Sorbefacient
Microcrystalline cellulose	15-75	Diluent
			Hydroxypropyl methyl cellulose	0-20	Matrix
Mannitol	0-30	Diluent
			Sodium carboxymethylcellulose	1-8	Disintegrant
PVP	1-5	Adhesive
			Superfine silica gel powder	1-2	Glidant

Magnesium stearate	0.1-2	Lubricant
			Medicine	0.1-20	Therapeutic component

In a particular embodiment, the amount of the especially sodium caprate of the sorbefacient in formula, can be 400mg, 300mg, 200mg, 100mg, 50mg or 25mg.200mg, 100mg or 50mg are best, or even 100mg more preferable.

The presence of hydroxypropyl methyl cellulose (HPMC) can adjust sorbefacient and therapeutic component in label in label Release behavior.The HPMC of different viscosities can be added in label by different proportion, adjust the Adhesion property of label.

The usual potency of macromolecular drug of the present invention is higher, therefore the medicament contg in label is generally relatively low, such as 1%, 0.1%, 0.01%.Significant challenge in terms of the quality that these low dosage formulas face includes stability, content uniformity And analysis method etc..It is generally necessary to design technology condition, the stability of holding therapeutic component while content uniformity is ensured.

Unlike low dose formula facing challenges, heavy dose of formulation of drug ratio is higher, and what is more faced is The problems such as compatibility, mobility.

In instantiation, the medicine in formula can exist in the form of calcium phosphate nano particle, its specific description Referring to U.S. Patent application 2005/0234114, Application U.S. Serial No 12/434,557 and PCT Application No. WO 2005/ Described in 084637 and WO 2009/135190.Above-mentioned entirety is quoted.

The pharmaceutical agent combinations of the present invention can also be suppository form, pass through rectally.By component and nonirritating, normal temperature It is solid down, and is mixed under rectal temperature for the auxiliary material of liquid, after reaching rectum, medicament dissolves, insoluble drug release.These materials Including but not limited to cocoa butter and polyethylene glycol etc..

The pharmaceutical agent combinations of the present invention can also be to be administered by vagina administration mode.Mode suitable for vagina administration include but It is not limited to vagina and fastens agent, tablet or tampon agent.

Pharmaceutical agent combinations in invention can prepare each dosage unit and conveniently take, and can be prepared by known any method.

Bio-adhesive layer

As described above, bio-adhesive layer coating of the pharmaceutical agent combinations of the present invention using bio-adhesive polymer composition.One In a little instantiations, bio-adhesive coating directly contacts with solid pharmaceutical preparation.In other instantiation, bio-adhesive coating There is one or more layers intermediate layer between solid pharmaceutical preparation.It is non-to ooze or pellicle is located at solid pharmaceutical preparation and life in some instantiations Between thing adhesion layer, or, bio-adhesive layer can be located at solid pharmaceutical preparation and it is non-ooze or pellicle between.

In instantiation, bio-adhesive polymer can directly be attached to targeting moiety, such as intestines and stomach in bio-adhesive layer In.Bio-adhesive polymer includes but is not limited to carbomer, polycarbophil, chitosan, sodium alginate, mercaptomerin sodium, gelatin, hydroxyl Propyl methocel, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol, poly- second Alkene pyrrolidone, fumaric acid anhydride copolymer, polyester, acrylate, polysaccharide, modified dextrans, Sodium Hyaluronate, fruit Glue, xanthans, salt and its derivative and mixture.In instantiation, bio-adhesive layer includes hydroxypropyl methyl cellulose Or polycarbophil AA1 (HPMC).

In a particular embodiment, bio-adhesive layer is answered by what such as bio-adhesive polymer, plasticizer or other materials formed Condensation material forms, to adjust rate of release.Tend to the bio-adhesive material using high level.In a particular embodiment, it is raw The ratio that thing sticks polymer is 50%, or higher than 65%, or higher than 75%, or higher than 80%, or higher than 90%.

In instantiation, bio-adhesive layer can contain enteric material, as cellulose acetate phthalate (S orL), HPMCP, hydroxypropyl methyl cellulose acetate, acetic acid -1,2, 4 benzenetricarboxylic acid celluloses, polyvinyl acetate phthalate, methacrylic acid copolymer, shellac, salt, derivative and compound.

The presence of enteric material in bio-adhesive layer, can protect integrality of the preparation in gastric juice, and preparation reaches enteron aisle PH increases, medicine start to discharge and absorbed afterwards.In order to keep stability of the preparation in acid, it is necessary to the enteric material of higher proportion Material, such as 50% even more high.Therefore, when enteric material as little as 10~20%, and it is very when can still keep the stability in acid It is wonderful.

In a particular embodiment, the enteric material content in bio-adhesive layer 5~50%, 10~35%, best 15~ 25%.

In a particular embodiment, plasticizer can be contained in bio-adhesive layer, such as glycerine, glycerol acetate, polyvinyl alcohol, poly- Ethylene glycol, its derivative or mixture.In a particular embodiment, the plasticizer in bio-adhesive layer is 1~35%, 5~25% Preferably, 10~15% is more preferable.

In instantiation, percentage by weight of the bio-adhesive layer in pharmaceutical agent combinations can be 0.1%~10%, 1~ 5%, preferably 2~3%.

In a particular embodiment, the thickness of bio-adhesive layer can be adjusted to obtain preferable release dynamics parameter and suction Produce effects fruit.

Enteric material can quickly dissolve in appropriate pH.Due to the enteric material in bio-adhesive layer and enteric layer in formula The content of material does not have marked difference, therefore the bio-adhesive layer containing enteric material should be consistent with the rate of dissolution of enteric layer 's.

Therefore, with the recipe ratio containing enteric layer compared with when the formula for finding to contain identical enteric material in bio-adhesive layer Absorption and pharmacology accelerate when, this is very unexpected.

This can increase enteric material addition bio-adhesive layer the absorption window in enteron aisle it is surprisingly found that show Mouthful, clinical response is earlier, generally more desirable.

The formula of enteric material addition bio-adhesive layer is reduced into requirement and the technical process to coating, reduces production Time, while reduce production cost.

Impermeable or semi-permeable layer

Ooze or semi-permeable layer can be used for adjusting release dynamics, further reduced to the need of sorbefacient as described above, non- Measure, improve the assimilation effect and bioavailability of the difficult component that absorbs the drug.It is non-to ooze or semi-permeable layer contains out in instantiation Passage is put, the therapeutic component and sorbefacient being easy in solid pharmaceutical preparation unidirectionally discharge.The size and shape of passage depends on solid The property of body preparation and the release dynamics feature needed.The size of passage is generally can determine whether by veteran.In some tools In body example, passage has been fully contemplated by the side of tabletting or capsule.

In a particular embodiment, unidirectionally the release channel of release tabletting covers the 20~90% of the tabletting side gross area, or 30~80%, best 50~70%.

The shape of open channel can be any shape, circle, rectangle, triangle, trapezoidal or square.

It is non-to ooze or semi-permeable layer contains one or more hydrophilic polymers or/and one or more hydrophobic in instantiation Polymer.Hydrophilic polymer includes but is not limited to, polymer (for example, gelatin and casein), pectin, agar based on albumen (agar), chitosan, carragheen, starch, glucan, methylcellulose, calcium carboxymethyl cellulose, sodium carboxymethylcellulose, friendship Join sodium carboxymethylcellulose polymer (such as AC-DI-SOL), microcrystalline cellulose, ethyl cellulose, hydroxy ethyl fiber Element, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalic acid, cellulose ether, acetate fiber Element, cellulose acetate phthalic acid, other cellulose derivatives, polyvinyl alcohol, polyvinylpyrrolidone (PVP), crosslinking are poly- Tie up ketone, other polyvinyls and copolymer, guar gum, poloxamer, polyethylene glycol, polyethylene glycol oxide, polyacrylic acid, Polyethers, alkoxy polymers, sodium alginate, xanthans, other natural hydrogels obtain gel from natural prodcuts, or both Mixture.The example of hydrophobic polymer includes but is not limited to, and (such as polycaprolactone (PCL), polyamides are sub- for ethyl cellulose, polyester Amine (PEA), polyhydroxyalkanoate (PHA), PLA (PLA), PLA alcohol copolymer (PLGA), poly butyric ester- Hydroxyl valerate (PHBV) and polybutadiene acid esters (PBSA), wax, low melt wax, polyethylene and ethylene copolymer, ethene/acetic acid second Alkene, polypropylene, polyurethane, ethylene/vinyl alcohol, polyvinyl alcohol, Corvic, polyolefin or any combinations.

It is non-to ooze or semi-permeable layer also includes solvent or plasticizer in instantiation, so that coatings keep flexible.Solvent bag Include it is any oozed or solvent that semipermeable membrane material is compatible with non-, including such as water and ethanol.Plasticizer includes but unlimited and citric acid Polyalkylene oxides (such as polyethylene glycol, poly- the third two of ester (for example, triethyl citrate, triacetyl glycerine), low molecule amount Alcohol, polyethylene/propyleneglycoles), glycerine, pentaerythrite, monoglyceride, oxalic acid or triacetate, propane diols, butanedioic acid two Ethyl sodium, sugar alcohol and corn syrup and composition.

In instantiation, non-infiltration layer is by ethyl cellulose and glycerine, polyethylene glycol or acetoglyceride as plasticizer Composition.In some instantiations, semi-permeable layer is by cellulose acetate and polyethylene glycol, glycerol acetate or glycerine as plasticizer Composition.

In a particular embodiment, it is non-ooze or pellicle in plasticizer content 5~40%, or 10~30%, 15~ 25% is best.

It is non-to ooze or the weight of semi-permeable layer accounts for 0.1~10% of gross weight or so, or 1~5% or so in instantiation, most Fortunately 2~3% or so.

Can further add other compositions in non-infiltration layer, as preservative, protective agent, other can improve stability of drug products into Grade.Addible plasticizer and component visible M.＆I.Ash, T_HE H_{ANDBOOK OF} P_{HARMACEUTICAL} A_DDITIVES (3^rdEd., Synapse Information Resources, Inc., 2007).

In a particular embodiment, unidirectional release channel can be prepared by laser ablation process, and the technique has been used for permeating Pump produces.But unlike osmotic pumps tabletting, bigger (the unidirectional release channel a diameter of 3 of 10mm tablettings of unidirectional release channel ~9mm, and osmotic pumps are only 0.5mm), coatings are thinner, therefore, it is necessary to using the different lasing light emitters and dress for adapting to the present invention Put.

Enteric layer

In instantiation, the pharmaceutical agent combinations containing label and the coating of bio-adhesive layer and unidirectional releasing layer in the present invention are also Further using site selection material coating, allow medicament to discharge in the position that intestines and stomach are specified.Site selects material by pH Sensitive material forms, and is dissolved within the border in certain pH range ring.Using site selection material coating, sticking for carrier selectivity can be made Attached layer is exposed to the specified location of intestines and stomach.

Enteric coating polymer may be selected, but be not limited to cellulose acetate-phthalate (S or L), hydroxyl Propyl methocel phthalic acid ester, hydroxypropyl methyl cellulose amber acetic acid, acetic acid-TMLA cellulose, Polyvinyl acetate phthalate, methacrylic acid copolymer, shellac, its salt, derivative and compound etc..In instantiation In, enteric-coating material refers toL30D-55。

In instantiation, site selection material includes selectivity and is attached to colon or the material in colon release.It is this Material includes but is not limited to azobenzene polymer, colon degradation of polysaccharide such as pectin, starch, guar gum, xylan, cyclodextrin, Portugal Glycan, its salt and derivative etc..

The rate of release that the thickness of coating is as needed selects, and this relies on the property and thickness with coating.In instantiation In, enteric layer weight accounts for about the 1~15% of solid pharmaceutical preparation gross weight, 3~12%, best 6~10%.

Preparation method

The preparation method of medicament composition provided by the invention comprises the following steps：Prepare the treatment group for including effective dose Point, the solid pharmaceutical preparation of sorbefacient and pharmaceutical excipients；Using bio-adhesive polymer coating bio-adhesive layer, optional non-ooze Or semi-permeable layer coating, there is open channel, therapeutic component and sorbefacient is unidirectionally discharged from preparation.In instantiation In, bio-adhesive layer and it is non-ooze or the coating of semi-permeable layer order be reversible.In instantiation, preparation method includes further It is coated using enteric layer.

In instantiation, can use bio-adhesive material and it is non-ooze or semi-permeable material such as ethyl cellulose orL30D-55 water slurry.In some instantiations, the material can directly be allocated without using solvent to be made With.In some instantiations, use can be directly adjusted after polycaprolactone (PCL) or wax heating.

In a particular embodiment, pharmaceutical agent combinations of the invention are more likely to be prepared as the form of tabletting or capsule.Tabletting piece Core generally use interlocks tabletting and prepared.Tabletting preparation technology, including wet granulation and direct tablet compressing, have been widely used (Developing Solid Oral Dosage Forms：Pharmaceutical Theory and Practice.Ed.by Qiu et al.Academic Press 2009)。

However, the compression forms of macromolecular drug are still there is challenge.Most of macromolecular drugs are polypeptide and albumen, Complicated, stability is very poor.The usual potency of these macromolecular drugs is very high, therefore dosage is relatively low, and this is just needed in technique work Such as homogeneity (the Formulation and Analytical Development of holding content in wet-granulation process in journey for Low Dose Oral Drug Products.Ed.by Zheng.Wiley 2009)。

In process exploitation engineering, Exenatide and insulin all suffer from this problem.When the wet granulation technology system of use During standby tabletting, it is found that the homogeneity of content meets the requirements, but Exenatide and unstable, and Ai Saina under identical condition Peptide material powder can keep stable after directly being mixed with auxiliary material in formula.

Therefore, direct tablet compressing is another the optional technique for preparing the medicine that acceptable dosage is 0.5~2mg.Generally The direct tablet compressing technique of low-dose drugs is relatively easy, because the content of medicine is very low, the performance for not interfering with tabletting is for example compatible Property, the hardness of mobility and tabletting, as long as ensureing the homogeneity of content.Medicine such as insulin powder etc., for the small of crystallization Particle, hygroscopicity is poor, as long as the particle diameter of suitable control drug powder, you can tabletting is prepared using direct tablet compressing technique,

Recipe ingredient in the present invention, due to introducing the sorbefacient such as sodium caprate of larger proportion, its compatibility compared with Difference, while particle agglomeration may be caused, therefore there is other challenge.In a particular embodiment, the direct pressure in the present invention Slice prescription is as shown in the following chart.

Auxiliary material	% contents	Function
			Sodium caprate	40-80	Sorbefacient
Microcrystalline cellulose	15-75	Diluent
			Hydroxypropyl methyl cellulose	0-10	Matrix
Sodium carboxymethylcellulose	1-8	Disintegrant

Superfine silica gel powder	1-2	Glidant
			Magnesium stearate	0.1-2	Lubricant
Medicine	0.1-20	Therapeutic component

The medicine of Exenatide class, it is necessary to unit dose it is even lower, such as/or drug powder there is hygroscopicity, due to It is difficult to reach content uniformity in preparation process, therefore is not proposed with direct tablet compressing technique (ibid. of Zheng 2009).

In the present invention, by using non-solvent granulating process, it can keep between medicine stability and content uniformity Balance.In a particular embodiment, drug powder is suspended in the undissolved fluid media (medium) of medicine, by ultrasound or is homogenized and can be controlled Make and adjust the particle diameter of drug particles.Adhesive can be added in suspension to increase uniformity.What suspension was generally commonly used together Pelletization is similar, adds the mixture of each auxiliary material.

Non-solvent granulating process in the present invention, the stability of medicine can be kept while content uniformity is ensured. The PEG400 of low molecule amount reduces the stability of Exenatide, and content uniformity is fine.

In a particular embodiment, non-solvent usually used in the present invention includes ethanol, isopropanol, acetone and acetic acid second Ester.

Application method

The pharmaceutical agent combinations of the present invention can be effectively by drug delivery to the mucomembranous surface specified.When pharmaceutical agent combinations selectivity When being attached to mucomembranous surface, therapeutic component and sorbefacient in solid pharmaceutical preparation can unidirectionally be discharged into mucomembranous surface simultaneously, together When produce high local concentrations.So, in drug regimen of the invention, the sorbefacient of relatively low amount will be obviously promoted medicine Absorb, be otherwise invalid.

Therefore, on the one hand, the invention provides a kind of method that medicine is transmitted using pharmaceutical agent combinations.On the other hand, this hair The bright patient to need provides the method for drug therapy, including takes pharmaceutical agent combinations disclosed by the invention to patient part, especially It is mucomembranous surface.Pharmaceutical agent combinations can be administered by known any mode, include but is not limited to oral, oral cavity, sublingual administration, Vagina, rectally.Can whole body or local use.

Brief description of the drawings

Fig. 1 show using hydroxypropyl methyl cellulose (HPMC) andAfter L30D-55 enteric coatings, in tabletting Exenatide and sorbefacient sodium caprate be synchronous release.

Fig. 2A and 2B shows using HPMC and enteric coating and cellulose acetate is respectively adopted and ethyl cellulose is unidirectionally released Put the influence discharged after coating to Exenatide in tabletting and sodium caprate.

Fig. 3 A and 3B show bio-adhesive HPMC, polycarbophil AA1 or chitosan coat to Exenatide bioavailability Influence, sodium caprate addition is respectively 100mg and 400mg in tabletting, enteric coating.

After Fig. 4 shows AA1 and enteric coating, influence of the sodium caprate addition to Exenatide bioavailability.

Fig. 5 shows that under the conditions of 50mg sodium caprates, HPMC and enteric coating cellulose acetate and ethyl cellulose are unidirectionally released Put influence of the coatings to Exenatide bioavailability.

Fig. 6 shows under the conditions of 100mg sodium caprates, HPMC, ethyl cellulose one-way membrane and enteric coating, oral Ai Saina The relatively hypodermic bioavailability of peptide.

Fig. 7 shows that under 200mg sodium caprates, HPMC, cellulose acetate one-way membrane coating conditions enteric layer is to Exenatide The influence of bioavailability.

Fig. 8 A show the insulin tabletting containing 200mg sodium caprates, HPMC coatings and unidirectional releasing layer coating in 0.01N Release dynamics in HCl (2h) and pH6.8 simulated intestinal fluids (3~7h)；Fig. 8 B and Fig. 8 C show oral insulin to life respectively The influence of the blood glucose and serum insulin of long chalone infusion dog.

Fig. 9 shows that two kinds of oral insulin formulas are transfused the hypoglycemic effect of dog to growth hormone release inhibiting hormone.The first formula is two layers Tabletting, contain 200mg sodium caprates, HPMC coatings and unidirectional releasing layer coating.Second of formula is three layers of coating, contains 200mg Sodium caprate, HPMC coatings, the coating of unidirectional releasing layer and enteric layer coating.

Figure 10 shows stability of the Exenatide in solid pharmaceutical preparation, different formulations be individually positioned in 60 DEG C (Figure 10 A), 0,5,10 day under the conditions of 92.5% humidity (Figure 10 B), 4500lux illumination (Figure 10 C).

Figure 11 shows influence of the oral insulin to normal dogs blood glucose.Experiment formula used is three layers of coating tabletting, is contained 100mg sodium caprates, HPMC coatings, unidirectional releasing layer and enteric coat layer.

Figure 12 shows what the unidirectional release channel that manual pasting technique and laser ablation process are formed absorbed to Exenatide Influence.It is two-layered coating tabletting used in experiment, the HPMC containing 200mg sodium caprates, containing L30D-55 is coated, using manual or sharp The unidirectional release channel that light technique is formed.

Figure 13 shows that oral insulin dosage (25U, 25U × 2,50U) is transfused the hypoglycemic effect of dog to growth hormone release inhibiting hormone.Experiment Used is two-layered coating tabletting, HPMC coatings and unidirectional releasing layer containing 200mg sodium caprates, containing L30D-55.

Figure 14 shows that bio-adhesive polymer content is in Exenatide release dynamics and normal dogs in bio-adhesive layer The influence of absorption.It is two-layered coating tabletting used in experiment, containing 100mg sodium caprates, containing L30D-55's and 65% or 80%HPMC The unidirectional releasing layer that coatings and laser ablation are formed.

Embodiment

The present invention is expanded on further below by the detailed description of the specific embodiment to the present invention, but embodiment is not Limitation of the present invention.Declare at the same time：On the basis of without departing substantially from the application original meaning and scope, industry professional person also may be used To derive various system under the inspiration of the application, the application covers all equivalent or similar systems.

Embodiment 1

The preparation of tabletting

The preparation of 1.1 tabletting labels

Tabletting label is prepared by the proportioning of table 1, is suppressed after each component is well mixed using monolithic tablet press machine.Except Exenatide and Outside magnesium stearate, remaining component is weighed and is well mixed in advance.Made again with 15% PVP ethanol solutions (25%) for adhesive Grain, 60 DEG C of dry 2hr.Particle crosses 22 mesh sieves and weighs particle, Exenatide and magnesium stearate according to monolithic aequum.Each component It is tabletted after well mixed.Weigh, the label more than average weight ± 5% is cast out.

Table 1：Exenatide and sodium caprate proportioning (unit in label：mg)

1.2 bio-adhesive layers

Label is further coated using bio-adhesive polymer such as hydroxypropyl methyl cellulose or polycarbophil AA1.Using When HPMC is coated, HPMC is formulated as 2% aqueous solution, and (BY300A, Huanghai Sea instrument) is coated in small-sized seed-coating machine afterwards, Coating weight gain amount is 2% or so of label.During AA1 coatings non-using card ripple, the non-AA1 of card ripple is formulated as 4% ethanol solution, together Sample operates in small-sized seed-coating machine, gain in weight 3%.Tabletting after coating is dried 14 hours at 30 DEG C.

1.3 unidirectional releasing layers

Label is then coated using non-or semi-permeable material.During operation, first by the use of sticky paper using the side of label cover as The passage that medicine unidirectionally discharges, then using 4% ethyl cellulose ethanol solution (wherein containing 20% glycerol acetate as increasing Mould agent) or 3% cellulose acetate (using acetone and formic acid as solvent, 9: 1V/V, containing 20% polyethylene glycol 2000 as be plasticized Agent) solution coating.After coating, the dry 30min of 30 DEG C of tabletting, the gain in weight of coating is adjusted to 2~5%.Sticky paper is peeled off afterwards, Expose release channel.

1.4 enteric layer

Tabletting uses enteric polymerL30D-55 is coated.Coating solution includes 200g L30D-55,12g talcums Powder, 6g Macrogol 6000s, adjusted after water mesoscale eddies is uniform to 400ml, it is standby.Coating is carried out in small-sized seed-coating machine, is wrapped Clothing gain in weight is the 10% of tabletting gross weight.Tabletting is dried 14 hours in 30 DEG C.

Embodiment 2

The synchronous release of Exenatide and sodium caprate

The in-vitro evaluation release behavior of Exenatide and sodium caprate in different formulations.

Stability of the preparation in acid is primarily looked at.The tabletting of enteric coating is put into 100ml 0.1N hydrochloric acid, 37 DEG C vibrate 2 hours in dissolution rate instrument, observe the stripping property of medicine.Different time samples, in HPLC (Waters) test solution Exenatide and capric acid na concn.As a result show that tabletting is kept completely in acid, no Exenatide and capric acid sodium leakage.

Tabletting is moved into 100ml simulated intestinal fluids (pH 6.8) afterwards, 37 DEG C of vibrations, different time sampling, investigates tabletting The release behavior of middle Exenatide and sodium caprate.Table 2 lists sodium caprate containing 50mg and is coated HPMC layers and enteric layer successively The release data of Exenatide and sodium caprate in tabletting.Release profiles are shown in Fig. 1.It can be seen that under the conditions of pH6.8, Exenatide and The release of sodium caprate is almost synchronous.

The Exenatide of table 2 and sodium caprate are from the release in the tabletting of HPMC and enteric coating

Time (minute)	Exendin discharges (%)	Certain herbaceous plants with big flowers acid sodium discharges (%)
			0	0	0
15	0	0
			30	0	0
60	21.73	23.54
			90	66.91	60.48
120	90.15	91.55
			180	92.82	92.36
240	92.85	87.72

Table 3 lists sodium caprate containing 50mg and is coated successively in the tabletting of HPMC layers, layer of cellulose acetate and enteric layer and ends Fill in the release data of that peptide and sodium caprate.Release profiles are shown in Fig. 2A.It can be seen that the release of Exenatide and sodium caprate is also almost same Step.But compared with the tabletting of uncoated layer of cellulose acetate, release time is obviously prolonged.

The Exenatide of table 3 and sodium caprate from coating HPMC, enteric layer, layer of cellulose acetate tabletting in release

Time (minute)	Exenatide discharges (%)	Sodium caprate discharges (%)
			0	0	0
15	0	0
			30	0	0
60	6.05	7.3
			90	11.41	19.75
120	27.91	44.4
			180	66.99	85.07
240	74.01	91.34

Table 4 list sodium caprate containing 50mg and be coated successively HPMC layers, ethylcellulose, enteric layer tabletting release Data.Release profiles are shown in Fig. 2 B.It can be seen that as with previous experiment, the release of Exenatide and sodium caprate is also almost synchronization. It is worth noting that, using ethylcellulose coat tabletting release than using cellulose acetate coating tabletting release when Between more extend.

The Exenatide of table 4 and sodium caprate are from the release in the tabletting for being coated HPMC, enteric layer, ethylcellulose

Time (minute)	Exenatide discharges (%)	Sodium caprate discharges (%)
			0	0	0
15	0	0
			30	0	0
60	0	0
			90	11.43	7.96
120	25.65	20.78
			180	37.63	40.05
240	49.75	51.29
			300	76.22	87.28
360	79.85	87.58
			540	79.64	91.7

Embodiment 3

Bio-adhesive layer to Exenatide beasle dog body absorption influence

Using the influence that is absorbed to Exenatide of healthy beasle dog evaluation different formulations, capric acid containing 100mg respectively in formula Sodium is as sorbefacient.

Healthy beasle dog 12,8~12kg of body weight is chosen, nursing is responsible for by Shanghai Univ. of Traditional Chinese Medicine's animal center.Will compare Lattice dog is randomly divided into different treatment groups, and animal has the mastery phase of one week or so after experiment.During experiment, beasle dog overnight fasting, 10ml water will be gavaged after the direct feeding of tabletting.Feeding after testing 6 hours.

Beasle dog is tested and packet situation is shown in Table 5.

Animal packet situation in experiment of the bio-adhesive layer of table 5 to Exenatide inhalation effects

Numbering	Group	Administrations
			1	Blank group	Comfort piece
2	Hypodermic injection group	60 μ g/10mM sodium acetate solutions, pH4.0 is subcutaneously injected
			3	Without adhesion layer group	3mg Exenatides, 100mg sodium caprates, enteric coating
4	HPMC coating groups	3mg Exenatides, 100mg sodium caprates, HPMC and enteric coating
			5	AA1 coating groups	3mg Exenatides, 100mg sodium caprates, AA1 and enteric coating
6	Chitosan Coating group	3mg Exenatides, 100mg sodium caprates, chitosan and enteric coating

After administration, different time points using test tube of hepari take blood vessel take blood 1.5ml, 3000rpm take 0.5 after centrifuging 10 minutes~ 0.6ml serum.- 20 DEG C of blood serum sample freezes, and Exenatide concentration is using enzyme linked immunological kit test (Phoenix Pharmaceuticals, Inc.).

Sample includes testing after standard items dilute 5 times.Exenatide concentration in blood serum sample is calculated according to standard curve, According to the relative bioavailability of TG-AUC com-parison and analysis sample, data are shown in Table 6 and Fig. 3 A.

During 6 sodium caprate containing 100mg of table, influence of the bio-adhesive layer to Exenatide bioavailability

Group	Number of animals	Bioavailability (%)
			Blank	3	0
It is subcutaneously injected	3	100
			Without adhesion layer	3	0.19
HPMC is coated	3	2.12
			AA1 is coated	3	2.37
Chitosan Coating	3	1.25

As a result show, bio-adhesive layer can significantly affect the absorption of Exenatide.During sodium caprate containing 100mg, such as inanimate object Adhesion layer, the absorption of Exenatide is very low, and Ai Saina is significantly improved after adding the non-AA1 of card ripple, chitosan or HPMC coatings The absorption of peptide.

Embodiment 4

The influence (sodium caprate containing 400mg) that bio-adhesive layer absorbs to Exenatide in beasle dog body

When evaluating sodium caprate containing 400mg using healthy beasle dog, influence that different formulations absorb to Exenatide.

Beasle dog is tested and packet situation is shown in Table 7.

The bio-adhesive layer of table 7 is to the animal packet situation in the experiment of Exenatide inhalation effects

Numbering	Group	Administrations
			1	Blank group	Comfort piece
2	Hypodermic injection group	60 μ g/10mM sodium acetate solutions, pH 4.0 is subcutaneously injected
			3	Without adhesion layer group	5mg Exenatides, 500mg sodium caprates, enteric coating
4	AA1 coating groups	3mg Exenatides, 400mg sodium caprates, AA1 and enteric coating

Sample includes testing after standard items dilute 5 times.Exenatide concentration in blood serum sample is calculated according to standard curve, According to the relative bioavailability of TG-AUC com-parison and analysis sample, data are shown in Table 8 and Fig. 3 B.

During 8 sodium caprate containing 400mg of table, influence of the bio-adhesive layer to Exenatide bioavailability

Group	Number of animals	Bioavailability (%)
			Blank group	3	0
It is subcutaneously injected	3	100
			Without adhesion layer	3	0.61
AA1 coating groups	3	2.34

It is similar with embodiment 3, the results showed that bio-adhesive layer can significantly affect the absorption of Exenatide.Inanimate object adhesion layer When, even if adding 500mg sodium caprates as sorbefacient, the absorption of Exenatide is still low-down, adds Ka Bofei After AA1 coatings, the absorption of Exenatide has been greatly facilitated.

Embodiment 5

The influence that sodium caprate addition absorbs to Exenatide in beasle dog body

The influence absorbed using being added in healthy beasle dog evaluation formula after not same amount sodium caprate to Exenatide.

Beasle dog is tested and packet situation is shown in Table 9.

Animal packet situation in the experiment of the sodium caprate addition Exenatide inhalation effects of table 9

Numbering	Group	Administrations
			1	Blank group	Comfort piece
2	Hypodermic injection group	60 μ g/10mM sodium acetate solutions, pH 4.0 is subcutaneously injected
			3	50mg groups	3mg Exenatides, 50mg sodium caprates, AA1 and enteric coating
4	100mg groups	3mg Exenatides, 100mg sodium caprates, AA1 and enteric coating
			5	200mg groups	3mg Exenatides, 200mg sodium caprates, AA1 and enteric coating
6	400mg groups	3mg Exenatides, 400mg sodium caprates, AA1 and enteric coating

Sample includes testing after standard items dilute 5 times.Exenatide concentration in blood serum sample is calculated according to standard curve, According to the relative bioavailability of TG-AUC com-parison and analysis sample, data are shown in Table 10 and Fig. 4.

Table 10 contains in HPMC and enteric coating tabletting, influence of the sodium caprate addition to Exenatide bioavailability

Group	Number of animals	Bioavailability (%)
			Blank group	3	0
Hypodermic injection group	3	100
			50mg groups	3	0.08
100mg groups	3	2.37
			200mg groups	3	2.62
400mg groups	3	2.34

As a result show that the absorption of Exenatide is relevant with the addition of sodium caprate, add 50mg sodium caprates as absorption enhancement During agent, the absorption of Exenatide is very weak.When the addition of sodium caprate is higher than 100mg, the absorption of Exenatide significantly improves, and enters One step increases the addition of sodium caprate, and the absorption of Exenatide does not significantly improve.

Embodiment 6

Unidirectional delivery formulations to Exenatide beasle dog body absorption influence

Using the absorption of Exenatide after addition 50mg sodium caprates in healthy beasle dog evaluation formula.

Beasle dog is tested and packet situation is shown in Table 11.

11 unidirectional releasing layer of table influences the animal packet situation in experiment on bioavailability

Sample includes testing after standard items dilute 5 times.Exenatide concentration in blood serum sample is calculated according to standard curve, According to the relative bioavailability of TG-AUC com-parison and analysis sample, data are shown in Table 12 and Fig. 5.

The sodium caprate containing 50mg of table 12, in the tabletting using HPMC coatings, the unidirectional film that discharges is to Exenatide bioavailability Influence

Group	Number of animals	Bioavailability (%)
			Blank group	3	0
Hypodermic injection group	3	100
			Without unidirectional coating group	3	0.08
CA coating groups	3	0.34
			EC coating groups	3	0.78

As a result show that the absorption of Exenatide can be carried further using after unidirectional release coating and bio-adhesive coating It is high.Coatings are not discharged unidirectionally, and the drug absorption and bioavailability of sodium caprate containing 50mg and HPMC coating tablettings are very low. Semi-permeable layer coating is carried out using cellulose acetate or non-infiltration layer coating is carried out using ethyl cellulose, and reserves and releases in wafer surface After putting passage, under same sodium caprate addition and HPMC coating conditions, the absorption of Exenatide is remarkably reinforced.

Embodiment 7

Using the absorption of Exenatide after addition 100mg sodium caprates in healthy beasle dog evaluation formula.

Beasle dog is tested and packet situation is shown in Table 13.

During 13 sodium caprate containing 100mg of table, unidirectional releasing layer influences the animal packet situation in experiment on bioavailability

Sample includes testing after standard items dilute 5 times.Exenatide concentration in blood serum sample is calculated according to standard curve, According to the relative bioavailability of TG-AUC com-parison and analysis sample, data are shown in Table 14 and Fig. 6.

The sodium caprate containing 100mg of table 14, using the biology profit of HPMC, unidirectional release film and enteric coating Exenatide tabletting With rate

Group	Number of animals	Bioavailability (%)
			Blank group	3	0
Hypodermic injection group	3	100
			EC coating groups	3	4.98

As a result show the Exenatide tablet of the sodium caprate containing 100mg using HPMC coatings, ethylcellulose coat and intestines After molten coating, the bioavilability of Exenatide is 4.98%.Tablet is coated using the ethyl cellulose of impermeability, and After release channel is reserved in side, significantly improve absorption and the bioavailability of Exenatide, and use same amount sodium caprate and The bioavailability of the tablet of HMPC art for coating is only 2.37% (see embodiment 5).

Embodiment 8

Enteric layer to Exenatide beasle dog body absorption influence

It is prepared by 8.1 labels

Label is matched by table 15, is suppressed using monolithic tablet press machine.In addition to Exenatide and magnesium stearate, remaining component is advance Weigh and be well mixed.It is granulated, is dried in vacuum overnight for adhesive with 15% PVP ethanol solutions (25%) again.Particle crosses 22 Mesh sieve simultaneously weighs particle, Exenatide and magnesium stearate according to monolithic aequum.It is tabletted after each component is well mixed.Monolithic Weigh, the label more than average weight ± 5% is cast out.

Table 15：Each group distribution ratio (unit in label：mg)

8.2 bio-adhesive layers

Label is coated using HPMC, can be with or without enteric material in HPMCL30D-55.For without L30D-55 HPMC coating, using the aqueous solution containing 6%HPMC and 1.5%PEG6000 in seed-coating machine (BY300A, Huanghai Sea instrument Device) coating, the gain in weight of bio-adhesive layer is 3~4mg.Be coated for the HPMC containing L30D-55, using containing 3%HPMC and 0.6%L30D-55 aqueous solution coating.40 DEG C of dryings 14 hours after compress tablet coating, adhesion layer weightening is 3mg.

8.3 unidirectional releasing layers

Further it is coated after the coating of tabletting bio-adhesive layer using semi-permeable cellulose acetate.During operation, use first Sticky paper covers the side of label in the passage as medicine, then using 3% cellulose acetate and 1.2% polyethylene glycol 2000 (using acetone and formic acid as solvent, 9: 1V/V) solution is coated.40 DEG C of tabletting is dried overnight, and the gain in weight of coating is 2mg.Finally will Sticky paper is peeled off, and exposes release channel.

8.4 enteric layer

Tabletting without L30D-55 coatings in adhesion layer is further coated using enteric material.Coating solution includes 200gL30D-55,12g talcum powder, 6g Macrogol 6000s, adjusted after water mesoscale eddies is uniform to 400ml.Coating is in small package Carry out in clothing machine, dried 14 hours in 40 DEG C of tabletting.Coating weight gain amount is 25mg.

Absorption of 8.5 Exenatides in beasle dog body

Using the influence that is absorbed to Exenatide of healthy beasle dog evaluation enteric layer, sodium caprate containing 200mg respectively in formula.

Healthy beasle dog 12,8~12kg of body weight is chosen, nursing is responsible for by Shanghai Univ. of Traditional Chinese Medicine's animal center.Will compare Lattice dog is randomly divided into different treatment groups, and animal has the mastery phase of one week or so after experiment.Before experiment, beasle dog overnight fasting, Feed is limited during experiment.

Beasle dog is tested and packet situation is shown in Table 16.

During 16 sodium caprate containing 200mg of table, enteric layer influences the animal packet situation in experiment on bioavailability

Sample is diluted to containing test concentrations after 20% serum including standard items.Calculated according to standard curve in blood serum sample Exenatide concentration, according to the relative bioavailability of TG-AUC com-parison and analysis sample, data are shown in Fig. 7.

As a result show, the Exenatide tabletting containing 200mg sodium caprates, be respectively adopted HPMC, cellulose acetate coating or After HPMC, cellulose acetate and enteric coating, there is identical assimilation effect.Compared with the tablet of enteric layer coating, do not have The tablet maximum absorption band time of occurrence for having enteric layer to be coated shifts to an earlier date 1 hour.But either under absorption maximum concentration or curve Area, all do not significantly affected by enteric layer.Therefore, although employing enteric layer coating in some instantiations, It is not the key component of the present invention.

The drug absorption and clinical response occurred in two-layered coating formula shifts to an earlier date, and is preferably in clinical setting.

Embodiment 9

Oral insulin is transfused the effect of dog to growth hormone release inhibiting hormone

9.1 carry the preparation of insulin calcium phosphate nanoparticles

Using calcium phosphate nanoparticles as insulin carrier.Insulin is dissolved in 40ml solution As (5mg/ml, phosphorus containing 20mM Acid dihydride sodium, the HEPES buffer solutions of 20mM pH 6.9,2%PEG6000,0.5% urso UDCA, UDCA are molten before adding In 1.5ml ethanol).The solution B (40ml 0.01N HCl CaCl2 containing 60mM) of same volume forms particle after being mixed with A.Grain Sub- 15000rpm centrifuges 30min, vacuum drying.

Particle is suspended in pH 9.1 50mM phosphate buffers (0.2mg/ml), used after 37 DEG C of vibration 15min RP-HPLC surveys insulin content in particle.Content is calculated according to standard items.Insulin content is 0.56mg/mg in this batch, pancreas The island element rate of recovery is 99%.

It is prepared by 9.2 labels

Matched according to table 16, using monolithic tablet press machine compressed cores.In addition to insulin, superfine silica gel powder and magnesium stearate, its Remaining component is weighed and is well mixed in advance.Use 8% PVP ethanol solutions (25%) to be granulated for adhesive, be dried in vacuum overnight. Particle crosses 22 mesh sieves and adds insulin, superfine silica gel powder and magnesium stearate.It is tabletted after each component is well mixed.More than average The label of weight ± 5% is cast out.The hardness of label, thickness, friability are detected simultaneously.

Table 16：Piece core component (unit：mg)

9.3 bio-adhesive layers

Label uses HPMC E50 and enteric materialL30D-55 is coated.Prepare 3%HPMC and 0.6%L30D- 55 suspension (BY300A, Huanghai Sea instrument) in seed-coating machine is coated.40 DEG C of dryings 14 hours after coating, adhesion layer weightening are 3mg。

9.4 unidirectional releasing layers

Tabletting is further coated using semi-permeable cellulose acetate.First with the sticky papers of circular 7mm diameters by 9mm The side of the tabletting label of diameter covers, then use 3% cellulose acetate and 1.2% polyethylene glycol 2000 (with acetone and Formic acid is solvent, 9: 1V/V) solution coating.40 DEG C of tabletting is dried overnight, and the gain in weight of coating is 2mg.Finally sticky paper is peeled off, As unidirectional release channel.

9.5 insulin releasing

Tabletting is put into dissolution rate instrument first, adds 100ml 0.01N HCl, keeps 37 DEG C and 100rpm release 2h, RP-HPLC is sampled in 1h and 2h respectively and surveys concentration.Tabletting is taken out to the simulated intestinal fluid SIF for being put into 100ml pH 6.8 afterwards In, discharged with the conditions of, different time sampling RP-HPLC surveys concentration.

Insulin releasing curve is shown in Fig. 8 A.Tabletting is stable in acid, and burst size is less than 10% in 2h.Release in SIF Gently, 3~4h releases finish.

Effect of 9.6 tablettings to the dog of infusion growth hormone release inhibiting hormone.

The assimilation effect of oral insulin is evaluated using the beasle dog of venoclysis growth hormone release inhibiting hormone (1 μ g/kg/min).Infusion Growth hormone release inhibiting hormone can suppress endogenic glucagons and insulin secretion (Sakurai et al.J.Clin.Investigati on 54：1395,1974).Quick increase after blood sugar level initial reduction.This model can evaluate oral insulin simultaneously Drug effect and medicine generation.

Healthy beasle dog 12,8~12kg of body weight, is responsible for nursing by animal center.Beasle dog is randomly divided into different control Treatment group, overnight fasting before experiment.Growth hormone release inhibiting hormone (1 μ g/kg/min) is transfused by the ductus venosus of sacculus infusion pump, after being transfused 4h 10ml water feeding tablettings.Feed is limited during experiment, different time points test tube of hepari takes blood vessel to take blood.Beasle dog is tested and packet It is shown in Table 17.

Table 17：The oral insulin experimental animal packet of growth hormone release inhibiting hormone infusion dog

Group	n	Administration
			Blank group	3	Comfort piece
Hypodermic injection group	3	3.5U/ dogs, it is dissolved in 0.01N HCl
			Oral tabletting group	3	50U is oral

Using blood glucose meter and corresponding test paper (Johnson＆Johnson, OneTouch) test blood glucose.Blood sample 3000rpm from The heart 10 minutes, takes 0.5~0.6ml serum.- 20 DEG C of blood serum sample freezes, using ELISA kit (Linco) test sera pancreas Island element concentration.Fig. 8 B and 8C are shown in influence of the oral insulin to blood glucose and serum insulin concentration respectively.

The animal blood glucose initial reduction of blank tabletting group, increases afterwards.Injection group blood glucose significantly quickly reduces.Oral pancreas islet The blood glucose of plain tabletting group is also to significantly reduce.By calculating the AUC of blood glucose, the bioavilability of sample is 5%.

In experimentation, the serum insulin level of blank group is suppressed, and the serum insulin concentration of injection group is then It is significantly increased.The serum islet of oral insulin tabletting group is known as certain increase, and bioavilability is 2% or so.Confirm oral Insulin is similar to the insulin of hepatic portal or natural secretion, has higher bioavilability, and the insulin level of periphery is then It is relatively low, caused hypoglycemia this pressing issues in clinical practice can be significantly reduced.

Embodiment 10

The effect for the dog that the oral insulin tabletting of two-layered coating is transfused to growth hormone release inhibiting hormone

10.1 prepared by label

Matched according to table 18, using monolithic tablet press machine compressed cores.In addition to insulin, superfine silica gel powder and magnesium stearate, its Remaining component is weighed and is well mixed in advance.Use 8% PVP ethanol solutions (25%) to be granulated for adhesive, be dried in vacuum overnight. Particle crosses 22 mesh sieves and adds insulin, superfine silica gel powder and magnesium stearate.It is tabletted after each component is well mixed.Detect label Hardness, thickness, friability.

Table 18：Piece core component (unit：mg)

10.2 bio-adhesive layer

Label is using HPMC E50 or adds addition enteric material simultaneouslyL30D-55 is coated.For not having L30D-55 bio-adhesive layer coating, prepare 6%HPMC and 1.5%PEG6000 solution, coating pan (BY300A, Huanghai Sea instrument Device) in be coated.3~4mg of adhesion layer weightening.Coating for adding L30D-55, prepares 3%HPMC's and 0.6%L30D-55 Suspension is coated in seed-coating machine.40 DEG C of dryings 14 hours after coating, adhesion layer weightening is 3mg.

10.3 unidirectional releasing layer

Tabletting is further coated using semi-permeable cellulose acetate.First will using the sticky paper of circular 7mm diameters The side of the tabletting label of 9mm diameters covers, then use 3% cellulose acetate and 1.2% polyethylene glycol 2000 (with acetone And formic acid is solvent, 9: 1V/V) solution coating.40 DEG C of tabletting is dried overnight, and the weightening of unidirectional releasing layer coating is 2mg.Finally Sticky paper is peeled off, as unidirectional release channel.

10.4 enteric layers

The tabletting for not having L30D-55 in bio-adhesive layer uses enteric coating.Coating suspensions include 200g L30D-55, 12g superfine talcum powders, 6g PEG6000, final volume 400ml in water.Coating is carried out in small-sized coating pan, and 40 DEG C of tabletting is dry Dry 14hr.Enteric layer weightening 25mg.

Effect of 10.5 oral insulins to blood glucose

Using Beagle dogs evaluation two-layered coating (bio-adhesive of the label coating containing L30D-55 of infusion growth hormone release inhibiting hormone Layer, is then coated unidirectional releasing layer) and three layers of coating (bio-adhesive layer of the label coating without L30D-55, then coating is unidirectional Releasing layer, be then coated enteric layer) oral insulin tabletting effect.Experimentation is the same as embodiment 9.

Healthy beasle dog 12,8~12kg of body weight, is responsible for nursing by animal center.Beasle dog is randomly divided into different control Treatment group, overnight fasting before experiment.Growth hormone release inhibiting hormone (1 μ g/kg/min) is transfused by the ductus venosus of sacculus infusion pump, after being transfused 4h 10ml water feeding tablettings.Feed is limited during experiment.Beasle dog experiment packet is shown in Table 19.

Table 19：Oral insulin experiment packet situation

Group	n	Administration
			Blank group	3	Comfort piece

Hypodermic injection group	3	3.5U/ dogs, it is dissolved in 0.01N HCl
			Without enteric coating	3	50U two-layered coating insulin tablettings
Enteric coating	4	Tri- layers of coating insulin tablettings of 50U

Different time takes blood, and blood glucose is tested using blood glucose meter and corresponding test paper.Figure is shown in influence of the oral insulin to blood glucose 9。

As a result show, blood sugar level is significantly reduced after oral insulin tabletting, it is similar to injection group, and blank group is then first Begin quickly to increase after reducing.There is no the tabletting group of enteric layer, 1h starts to reduce blood glucose after the tablet has been ingested, and the pressure containing enteric coating Piece group then goes out an identical effect after 4h.

The effect of this result Exenatide similar with being formulated is consistent.The formula for illustrating two-layered coating is feasible in clinic 's.

Embodiment 11

Dry method direct tablet compressing

Without granulation direct tablet compressing be simple economy tablet producing technology, can keep complete drug crystallization state and Stability in technique.For low dosage tabletting, one be exactly the problem of main component during direct tablet compressing homogeneity Problem.

Using direct compression method, trial prepares insulin and Exenatide tabletting respectively.Component list is shown in Table 20.Insulin And Exenatide powder crosses 200 mesh sieves, auxiliary material is added, is well mixed.Using gearing tabletting mode, while detect the hard of tabletting Degree, friability and thickness.

Table 20：Piece core component (unit：mg)

According to USP<905>Test the homogeneity of insulin or Exenatide batch mixing.The powder of same piece weight is taken after mixing at random Material, insulin or Exenatide content are surveyed using RP-HPLC.Mixed homogeneity is shown in Table 21.

Table 21：The homogeneity of direct compression method batch mixing

Batch	Medicine	Content/piece weight	Average value	RSD
					178-2	Exenatide	600μg/200mg	672±83	12.4%
176	Insulin	1mg(27U)/200mg	26±0.7	2.8%

As a result show, unit dose is that the batch mixing homogeneity of 1mg (account for piece weight 0.5%) insulin is to receive 's.And 0.6mg Exenatide homogeneity is poor.The water imbibition of Exenatide powder may add more by force the difficulty of homogeneity Degree.

Therefore, although direct tablet compressing process is feasible, heterogeneity such as water imbibition and particle diameter of medicine etc. can influence Homogeneity.

Embodiment 12

Non-solvent granulation in tabletting preparation process

Direct compression method problems faced be component homogeneous sex chromosome mosaicism, especially low dose of medicine, such as Ai Saina Peptide, and wet granulation can influence the stability of medicine.Therefore, employ a kind of non-solvent method of granulating and prepare insulin and Ai Sai That peptide tabletting.The component list of different batches and different pharmaceutical is shown in Table 22~26.

Insulin and Exenatide powder cross 200 mesh sieves, are suspended to afterwards in 8% PVP ethanol solutions.Suspension is slight Ultrasound is to without obvious bulky grain.In addition to superfine silica gel powder and magnesium stearate, all auxiliary materials are weighed, and are premixed in granulator.Medicine suspends Liquid adds auxiliary material mixture, granulation, crosses 18 mesh sieves, vacuum drying afterwards.Superfine silica gel powder and magnesium stearate are added after drying, is used Interlock tabletting.The hardness of tabletting, friability and thickness are detected simultaneously.

Table 22：Piece core component (the unit of the insulin containing 1mg：mg)

Table 23：Component (the unit of the label of the insulin containing 0.8mg：Mg, batch 182)

Table 24：Piece core component (the unit of the Exenatide containing 0.6mg：Mg, batch 178-1)

Table 25：Piece core component (the unit of the Exenatide containing 0.4mg：Mg, batch 183)

Table 26：Piece core component (unit containing 0.4mg Exenatides：Mg, batch 184)

Insulin or Exenatide content in tabletting are tested using RP-HPLC, according to USP<905>Evaluate the homogeneous of content Property.It the results are shown in Table 27：

Table 27：The content uniformity of insulin or Exenatide in 178~184 batch samples

Batch	Medicine	Content/piece weight	Average value	RSD
					178-1	Exenatide	600μg/220mg	583±6	1.0%
181	Insulin	1mg(27U)/300mg	28±0.2	0.8%
					182	Insulin	0.8mg(22U)/300mg	22±0.3	1.2%
183	Exenatide	400μg/300mg	424±14	3.3%
					184	Exenatide	400μg/300mg	393±9.4	2.4%

As a result show, the insulin or the content uniformity of Exenatide tabletting prepared using non-solvent method of granulating is can Receive.

Embodiment 13

Stability of the Exenatide in different formulations and preparation technology

The stability of Exenatide in different formulations is have rated, each formula is shown in Table 28.

Table 28：The stability of Exenatide

Formula	Exenatide	Technique
			Exenatide powder	1mg	N/A
Directly mixed with auxiliary material	1mg	N/A
			With auxiliary material tabletting	1mg	Wet granulation
With auxiliary material tabletting	1mg	Direct tablet compressing
			With auxiliary material tabletting	1mg	Non-solvent is pelletized
Add auxiliary material and gelatin, mannitol tabletting	1mg	Wet granulation
			Add auxiliary material and PEG tablettings	1mg	Non-solvent is pelletized

Auxiliary material used is listed as follows in basic recipe：

Table 29：Solvent (unit in label：mg)

Sample is placed in culture dish, is placed in varying environment and is continued 10 days, including 60 DEG C, 25 DEG C and 92.5% are relatively wet Under degree, 4500lux illumination conditions, respectively at 0,5 and 10 day using RP-HPLC detection Exenatide contents.

The stability of different formulations is shown in Figure 10 A~10C.As a result show that Exenatide powder is relatively stable, in high temperature, high humidity And under illumination condition, it can still keep more than 95% within 10 days.Auxiliary material has similar stability after directly mixing, and shows in tabletting Auxiliary material and Exenatide are compatible.

However, the tabletting of wet granulation is highly unstable, the heavy losses at 5 days and 10 days.Add gelatin or mannitol Do not increase stability.When reducing the stability, especially high humility of Exenatide on the contrary, this is probably due to gelatin Or mannitol absorbs substantial amounts of moisture and caused under conditions of high humidity.

On the contrary, the tabletting pelletized using direct tablet compressing or non-solvent has preferable stability, with Ai Saina Peptide powder is similar.It is worth noting that, in non-solvent pelletization add low molecule amount PEG, stability still compared with Difference, this is probably to cause because Exenatide is partially dissolved in low molecule amount PEG.

Embodiment 14

Effect of the oral insulin to normal dogs

14.1 prepared by label

Matched according to table 30, being pelletized and being used using non-solvent interlocks tablet press machine compressed cores.Except insulin, PVP, micro mist Outside silica gel and magnesium stearate, remaining component is weighed and is well mixed in granulator in advance.Insulin powder is suspended in using 8% PVP ethanol solutions in, slight ultrasound.Suspension is added in auxiliary material and pelletized, is dried in vacuum overnight.Add superfine silica gel powder And magnesium stearate and it is well mixed after it is tabletted.The hardness of detection label, thickness, friability.

Table 30：Label matches (unit：mg)

14.2 bio-adhesive layer

Label uses 6%HPMC and 1.5%PEG6000 solution, is coated in coating pan (BY300A, Huanghai Sea instrument).Stick Layer weightening 4mg.

14.3 unidirectional releasing layer

Tabletting is further coated using semi-permeable cellulose acetate.First will using the sticky paper of circular 7mm diameters The side of the tabletting label of 10mm diameters covers, then molten using 3% cellulose acetate and 1.2% polyethylene glycol 2000 ethanol Liquid is coated.Tabletting drying at room temperature, the weightening of unidirectional releasing layer coating is 2mg.Finally sticky paper is peeled off, it is logical as unidirectional release Road.

14.4 enteric layers

Tabletting is further coated enteric layer.Coating suspensions include 8%L30D-55,2%PEG6000.Coating is in small package Carried out in clothing pot.Enteric layer weightening 20mg.

The blood sugar decreasing effect of 14.5 oral insulins

Using the effect of normal beasle dog evaluation oral insulin tabletting.

Healthy beasle dog 12,8~12kg of body weight, is responsible for nursing by animal center.Beasle dog is randomly divided into different control Treatment group, overnight fasting before experiment.Using the direct feeding tabletting of 10ml water.Feed is limited during experiment.Beasle dog experiment packet It is shown in Table 31.

Table 31：Oral insulin experiment packet situation

Group	n	Administration
			Blank group	3	Comfort piece
Hypodermic injection group	3	3.5U/ dogs, it is dissolved in 0.01N HCl
			50U	3	2 × 25U oral insulin tablettings

Different time takes blood, and blood glucose is tested using blood glucose meter.Figure 11 is shown in influence of the oral insulin to blood glucose.

As a result prove that oral insulin tabletting significantly reduces blood sugar level, it is similar with injection of insulin, and blank group blood glucose Keep constant.

The blood sugar level of normal individual is normally controlled in narrow range.In normal beasle dog, oral insulin tabletting The blood glucose of induction reduces similar to the intensity and pattern of insulin injection.

Embodiment 15

Laser ablation process in tabletting preparation process

15.1 prepared by label

Matched according to table 32, using gearing tabletting compressed cores.In addition to Exenatide, superfine silica gel powder and magnesium stearate, its Remaining component is weighed and is well mixed.Exenatide is suspended in 8% PVP ethanol solutions, as adhesive.After granulation Vacuum drying.22 mesh sieves are crossed, add superfine silica gel powder and magnesium stearate, tabletting after being well mixed.Detect the hardness of label, thickness, Friability.

Table 32：Core tablet formula (unit：mg)

15.2 bio-adhesive layer

Label uses 3%HPMC E0 and 0.6%L30D-55 suspension, is wrapped in coating pan (BY300A, Huanghai Sea instrument) Clothing.Coating tablet is in 40 DEG C of dry 14h, adhesion layer weightening 3mg.

15.3 unidirectional releasing layer

Tabletting is further coated using semi-permeable cellulose acetate.When hand-manipulated, the tabletting label of 9mm diameters is first First side is covered with the sticky paper of 7mm diameters of circle, then using 3% cellulose acetate and 1.2% polyethylene glycol 2000 (solvent acetone and formic acid, 9: 1V/V) solution coating.Sticky paper is peeled off after drying, as unidirectional release channel.

During laser boring, tabletting is covered without sticky paper, but tabletting is integrally coated using cellulose acetate solution, after coating 40 DEG C of tabletting be dried overnight.Go out the hole of 7mm diameters in wafer surface ablation using laser ablation apparatus (CMS) afterwards, with Effect when hand-manipulated is similar.Shown by the stability test of 2h in simulate the gastric juice, it is glutinous that laser boring will not destroy biology The integrality of attached layer.

In manual operations or laser drilling process, the weightening of unidirectional releasing layer is 2~3mg.

The absorption of 15.4 oral Exenatides

The effect of manual pasting or the unidirectional delivery formulations of oral Exenatide of laser boring is evaluated using normal beasle dog.

Healthy beasle dog 12,8~12kg of body weight, is responsible for nursing by animal center.Beasle dog is randomly divided into different control Treatment group, overnight fasting before experiment.Using the direct feeding tabletting of 10ml water.Feed is limited during experiment.Different time points use The anticoagulant tube of test tube of hepari takes blood.Beasle dog experiment packet is shown in Table 33.

Table 33：Oral Exenatide experimental animal packet

Group	n	Administration
			Blank group	3	Comfort piece
Hypodermic injection group	3	60 μ g/ dogs, are dissolved in 10mM sodium acetate solutions, pH4.5
			Paster group	3	1mg, oral Exenatide tabletting, drilling after manual pasting
Laser boring group	3	1mg, oral Exenatide tabletting, laser boring

Different time points take blood, and serum is taken after 3000rpm centrifugations 10min, -20 DEG C of freezings of blood serum sample, is tried using ELISA Agent box (Phoenix) tests blood concentration.

Sample sets Exenatide plasma concentration curve is shown in Figure 12.Exenatide prepared by manual pasting drilling or laser boring The drug absorption of unidirectional release tabletting is similar.

Embodiment 16

Insulin dose is transfused the effect of dog to growth hormone release inhibiting hormone

16.1 prepared by label

Matched according to table 34, using crawl tabletting compressed cores.In addition to insulin, superfine silica gel powder and magnesium stearate, remaining Component is weighed and is well mixed.Pelletized using 8% PVP ethanol solutions (25%) as adhesive.It was dried in vacuo after granulation Night.Particle crosses 22 mesh sieves, according to the piece of every again needs, each weighs required grain amount, is then respectively adding insulin, micro- Powder silica gel and magnesium stearate, tabletting after being well mixed.The hardness of detection label, thickness, friability.

Table 34：Label matches (unit：mg)

16.2 bio-adhesive layer

16.3 unidirectional releasing layer

Tabletting is further coated using semi-permeable cellulose acetate.The tabletting label of 10mm diameters is first with circle The sticky paper of 7mm diameters covers side, then using 3% cellulose acetate and the (solvent acetone of 1.2% polyethylene glycol 2000 And formic acid, 9: 1V/V) solution coating.40 DEG C are dried overnight.Unidirectional releasing layer weightening 2mg, afterwards peels off sticky paper, as unidirectional Release channel.

Effect of 16.4 oral insulins to blood glucose

Using the effect of the beasle dog evaluation oral insulin of growth hormone release inhibiting hormone infusion.

Healthy beasle dog 12,8~12kg of body weight, is responsible for nursing by animal center.Beasle dog is randomly divided into different control Treatment group, overnight fasting before experiment.The direct feeding tabletting of 10ml water is used after infusion growth hormone release inhibiting hormone 4h.Limited during experiment into Food.Beasle dog experiment packet is shown in Table 35.

Table 35：Oral insulin experimental animal is grouped

Group	n	Administration
			Blank group	3	Comfort piece
Injection group	3	Subcutaneous insulin injections, 3.5U/ dogs, molten and 0.01N HCl
			25U	3	25U tablettings, it is a piece of

25Ux2	4	25U tablettings, two panels
			50U	3	50U tablettings, it is a piece of

Different time points take blood, and blood glucose meter surveys blood glucose, and the blood sugar decreasing effect of oral insulin is shown in Table 13.

As a result show, oral insulin tabletting can significantly reduce blood glucose, similar to insulin injection.The oral pancreas islet of 25U For element compared with the oral insulin of 50U or 25U × 2, blood glucose decline has dose dependent.The oral insulin of 50U or 25U × 2 Blood glucose declines almost equivalent.

Embodiment 17

The influence that bio-adhesive polymer discharges and absorbed to Exenatide

17.1 prepared by label

Exenatide tabletting uses alcohol granulation, and method is the same.Proportioning is shown in Table 36.Exenatide powder is suspended in 8% PVP absolute ethyl alcohols in, ultrasound is to without obvious bulky grain.In addition to superfine silica gel powder and magnesium stearate, remaining component is weighed and made It is well mixed in grain machine.Exenatide suspension is added in auxiliary material mixture and pelletized, is dried in vacuo after crossing 18 mesh sieves.Add micro- Powder silica gel and magnesium stearate, tabletting after being well mixed.The hardness of detection label, thickness, friability.

Table 36：Core tablet formula (unit：mg)

17.2 bio-adhesive layer

Label is using 3%HPMC E50 and 0.6%L30D-55 water slurry (50% ethanol) in coating pan (BY300A, Huang Extra large instrument) in be coated.Or using 2.6%HPMC, 0.8%L30D-55 and 0.6%PEG suspension (50% ethanol) coating, bag Garment piece is in 40 DEG C of dry 14h, 3~4mg of adhesion layer weightening.

17.3 unidirectional releasing layer

Tabletting is further coated using semi-permeable cellulose acetate.Coating solution is 3.2% ethyl cellulose, 0.6% 85% ethanol solution of polyethylene glycol 2000 and 0.2% triacetin.40 DEG C are dried overnight after coating, unidirectional releasing layer weightening 2mg。

Tabletting uses laser boring, in the side of 9mm diameter tablettings cutting 7mm holes, as unidirectional release channel.

The absorption of 17.4 Exenatides

Using the assimilation effect of normal beasle dog evaluation Exenatide tabletting.

Healthy beasle dog 12,8~12kg of body weight, is responsible for nursing by animal center.Beasle dog is randomly divided into different control Treatment group, overnight fasting before experiment.Using the direct feeding tabletting of 10ml water.Feed is limited during experiment.Beasle dog experiment packet It is shown in Table 37.

Table 37：Oral Exenatide experiment packet

Group	n	Administration
			Blank group	3	Comfort piece
Hypodermic injection group	3	60 μ g/ dogs, are dissolved in 10mM sodium acetate solutions, pH4.5
			Exenatide group	3	0.4mg × 2 piece, 65%HPMC coatings
Exenatide group	3	0.4mg × 2 piece, 80%HPMC coatings

Different time points take blood, and serum is taken after 3000rpm centrifugations 10min, -20 DEG C of freezings of blood serum sample, is tried using ELISA Agent box (Phoenix) tests blood concentration.Sample sets Exenatide plasma concentration curve is shown in Figure 14.

As a result show that bio-adhesive layer is essential in tabletting, and the content of bio-adhesive polymer can significantly affect The release of Exenatide and assimilation effect.

Claims

1. a kind of administration composition, it is characterised in that the composition of the administration composition is：

A is loaded with the solid pharmaceutical preparation of effective therapeutic component, sorbefacient and pharmaceutic adjuvant；

The therapeutic component includes bioactive macromolecule, and bioactive macromolecule selects from Exenatide and its salt and insulin Select one kind；

The sorbefacient is sodium caprate；

Content of the sodium caprate in administration composition is 100 ~ 200mg；

The bio-adhesive layer that b is made up of bio-adhesive polymer and enteric polymer；

The bio-adhesive layer content accounts for the 0.5~10% of administration composition gross mass；

The content of bio-adhesive polymer accounts for the 80~90% of bio-adhesive layer gross mass in the bio-adhesive layer；

The bio-adhesive polymer selects from carbomer, polycarbophil, hydroxypropyl methyl cellulose and chitosan and its salt It is one or more of；

The semi-permeable formula coatings of c, make the therapeutic component in preparation and sorbefacient have unidirectional releasability；

The semi-permeable formula coatings contain semi permeable material；Semi permeable material selects one from cellulose acetate and its salt Kind is several；

The semi-permeable formula coatings content accounts for the 0.5~10% of administration composition gross mass；

Contain plasticizer in the semi-permeable formula coatings；

The unidirectional release channel area with unidirectional releasability covers the 20~90% of the preparation side gross area；

The semi-permeable formula coatings of c are between a solid pharmaceutical preparations and b bioadhesive layers；

D enteric layers；

The administration composition prepares solid pharmaceutical preparation by non-solvent granulating process；

The preparation method of described administration composition comprises the steps of：

B) semi-permeable layer coating is carried out to solid pharmaceutical preparation, the individual event release channel in the semi-permeable coatings makes in solid pharmaceutical preparation Therapeutic component and sorbefacient there is unidirectional releasability；

The unidirectional release channel of the solid pharmaceutical preparation side is formed by laser ablation process；

C) solid pharmaceutical preparation is coated using the bio-adhesive polymer with bio-adhesive characteristic；

d）It is coated using enteric layer.

2. administration composition according to claim 1, it is characterised in that therapeutic component and sorbefacient are from solid pharmaceutical preparation In rate of release it is almost synchronous.

3. administration composition according to claim 1, it is characterised in that therapeutic component and sorbefacient are delivered to people Or the mucomembranous surface of animal.

4. administration composition according to claim 1, it is characterised in that sufferer is administered by oral way.

5. administration composition according to claim 1, it is characterised in that said composition is prepared into capsule, tablet, pill, powder End or graininess.

6. administration composition according to claim 1, it is characterised in that the non-solvent medium choosing in non-solvent granulating process From ethanol, isopropanol, butanol, acetone or ethyl acetate.

7. administration composition according to claim 1, it is characterised in that solid prepared by described non-solvent granulating process Preparation can keep the stability of therapeutic component at room temperature.

A kind of 8. preparation method of administration composition according to described in claim 1 or 2, it is characterised in that the administration combination The preparation method of thing comprises the steps of：

B) carry out semi-permeable layer coating to solid pharmaceutical preparation, the individual event release channel in coating make therapeutic component in solid pharmaceutical preparation and Sorbefacient has unidirectional releasability；

d）It is coated using enteric layer.