CN1399542A

CN1399542A - Pharmaceutical carrier formulation

Info

Publication number: CN1399542A
Application number: CN00816307A
Authority: CN
Inventors: J·K·尤恩; R·W·桑德斯; M·B·法齐
Original assignee: American Cyanamid Co
Current assignee: Wyeth Holdings LLC
Priority date: 1999-09-27
Filing date: 2000-09-26
Publication date: 2003-02-26
Also published as: NO20021476D0; WO2001022942A1; MXPA02003190A; BR0014308A; ZA200203311B; CA2388471A1; HUP0202652A3; IL148543A0; PL354331A1; EA200200415A1; HK1044485A1; JP2003510267A; EP1216029A1; AR025867A1; AU7716100A; HUP0202652A2; NO20021476L; CZ20021082A3; KR20020064289A

Abstract

This invention provides carrier systems useful in preparing pharmaceutical formulations, the systems comprising, by weight percentage, from about 1 % to about 20 %, preferably from about 5 % to about 12 %, of a surfactant component; from about 55 % to about 93 %, preferably from about 60 % to about 85 %, of a component of one or more polyethylene glycols (PEG); and from about 1 % to about 25 %, preferably from about 5 % to about 15 %, of one or more sucrose fatty acid esters or polyvinylpyrrolidone (PVP) with a K value between about 15 and about 90, preferably with a K value of from about 16 to about 18, most preferably about 17, as defined in USP/NF, or a combination of one or more sucrose fatty acid esters or PVP, and, optionally, one or more pharmaceutically acceptable preservatives or antioxidants, such as BHA, BHT, ascorbyl palmitate or benzyl alcohol.

Description

Pharmaceutical carrier formulation

The present invention relates to the preparation of new pharmaceutical carrier, excipient or medicinal medium, described pharmaceutical carrier, excipient or medicinal medium can be used for the making up oil pharmaceutical composition of bioactive compound dissolubility and poorly water-soluble and/or the bioresorbable difference.The invention particularly relates to the oral Preparation of these chemical compounds.

Background of invention

The method of the liquid or the semisolid pharmaceutical formulation of a lot of preparation encapsulated has been described in this area.In Bull.Tech./Gattefosse Rep. (1996), 89, among the 27-38, people such as author Shah have described the hard gelatin capsule technology, particularly its application in improving poorly soluble or absorbability difference drug bioavailability.

United States Patent (USP) 4,620,974 (people such as Hersh) have told about the hard gelatin capsule of being made up of two medicated caps that are nested together and lubricant, wherein, comprise in the described lubricant with about 0.5-25% (weight ratio) concentration and be present in the Polyethylene Glycol that molecular weight in the described constituents mixt is approximately 200-900.

The method and apparatus of preparation minimum volume capsule is disclosed among the WO 96/40071 (Lamberti).WO 96/41622 people such as () Tanner has told about and has been applicable to the suspension that is encapsulated in the gelatine capsule, wherein especially comprises the liquid phase of the solid phase of solid particle and the solid phase that can suspend.

United States Patent (USP) 5,641,512 (Cimiluca) have been told about the Gelseal of encapsulation analgesic, wherein comprise xanthine derivative in the shell, as caffeine.

Disclose translucent basically semi-solid Gelseal packing material among EP 0 815 854 A1, described semisolid material is enough sticking, and it at room temperature can not be discharged from capsule with syringe.

United States Patent (USP) 4,744, told about Gelseal among 988 (Brox), it comprises the implant and at least a active substance of gelatin shell, softening agent, Polyethylene Glycol and rudimentary polyhydroxy-alcohol, it is characterized in that, comprise 4-40% Sorbitol or sorbitan in the described shell, the Polyethylene Glycol of employed half weight at least is that mean molecule quantity is 600 Polyethylene Glycol, and described capsule implant comprises the glycerol and/or 1 up to 20% (weight ratio), 2-propylene glycol.

Told about among the WO 95/19579 (Dhabhar) by the use mean molecule quantity and be approximately 5,000-25,000 polyvinylpyrrolidone with particular viscosity increases the method for insoluble drug dissolubility in Polyethylene Glycol and propylene glycol mixture.

United States Patent (USP) 4,578, the Unctuous compositions of antineoplastic agent has been described among 391 (people such as kawata), it comprises at least a oily microsolubility or water solublity antineoplastic agent, at least a fat or oil and at least a auxiliary agent that is increased in dissolubility in the oil medium are selected from the sucrose ester of crown ether, lecithin, Polyethylene Glycol, propylene glycol, vitamin E, polyoxyethylene alkyl ether and fatty acid.

WO 98/24430 (people such as Gautier) has told about anhydrous solubilization/stabilising system, it can be in water emulsifying or microemulsified increase the water solublity of hydrophobicity N-sulphonyl indolin derivatives with following array structure:

United States Patent (USP) 5,356,904 people such as () Freidinger disclose the method for using the oxytocin antagonist chemical compound with following formula structure: Or

Disclose the nitrogenous aromatics 5-unit ring with following array structure among the WO 95/03305 and condensed benzo-aza derivant, it is used as the arginine vasopressin antagonist on the pharmacology.

EP 0 514 667 B1 (people such as Ogawa) have told about the benzo-aza derivant with following array structure:

It is used as vasodilator, depressor, diuretic and anticoagulant as vasopressin antagonists.

United States Patent (USP) 5,525,614 (people such as Blankley) have told about 1,2,3 of replacement with following general structure, the 4-tetrahydroisoquinoline: It has the angiotensin ii receptor antagonist characteristic and can treat effectively with vassopressin and secrete excessive relevant disease.

United States Patent (USP) 5,516,774 (people such as Albright) have told about tricyclic antidepressants vassopressin chemical compound, comprise that those have the chemical compound of pyrrolo-benzodiazepine core.United States Patent (USP) 5,700 provides other tricyclic antidepressants benzo-aza chemical compounds as vasopressin antagonists in 796 and 5,719,278.United States Patent (USP) 5,654 has been told about in 297 in vasopressin antagonists with the non-peptide core of bicyclo-and the United States Patent (USP) 5,686,445 and is disclosed the reactive compound that similarly has pyrido benzo oxygen azatropylidene and pyrido benzothiazepine core texture.

Summary of the invention

The invention provides new pharmaceutical carrier or vehicle system, it can be used in bioactive compound preparation and the preparation that utilizes this carrier system to prepare, and the method for preparing described carrier system and preparation.Make us especially interested be described new carrier system in mammal usefulness, the application in the preferred human encapsulated combination of oral medication preparation.

Usually, carrier system of the present invention comprises the compositions of representing with percetage by weight with following component:

(a), about 1%-20%, the preferably approximately surface active agent composition of 5%-12%, more preferably approximately 9%-14% or the approximately surfactant of 10.5%-13%;

(b), about 55%-93%, preferably approximately the 60%-85% mean molecule quantity is approximately 190-3450, one or more Polyethylene Glycol (PEG) component of preferred 400-1540; With

(c), about 1%-25%, 5%-15% preferably approximately, more preferably approximately 9%-14% or approximately 10%-13% one or more sucrose fatty acid ester or be approximately 15-90 as defined K value among the USP/NF, preferably approximately be 16-18, most preferably be approximately 17 polyvinylpyrrolidone (PVP) or the compositions of one or more sucrose fatty acid ester or PVP.

Described Polyethylene Glycol component can be made up of one or more PEG polymer, and described PEG polymer preferably can be by the PEG polymer between the PEG 200-PEG 4,000 of commercial channel acquisition, and promptly those mean molecule quantities are approximately the PEG polymer of 190-4800.More preferably mean molecule quantity is approximately 190-3450, most preferably is approximately the PEG polymer of 400-1540.Wherein, preferred PEG polymer is that mean molecule quantity is approximately the PEG 400 of 380-420 and the PEG 1,000 that mean molecule quantity is approximately 950-1050.In the PEG component, ratio high and low-molecular-weight PEG is preferably about 2.5: 1-1: 2.5, and more preferably about 1: 1.As an example, the preferred PEG mixture of polymers of the present invention comprises 1: 1 mixture of PEG 400 and PEG 1000.The mixture of preferred PEG component have or near the fusing point of accepting described preparation mammal physiological temp.The mixture that has the final component of about 140-1500 centipoise viscosity under 37 ℃ may be preferred, the mixture that more preferably has the final component of about 300-800 centipoise viscosity under 37 ℃.Aptly, the Polyethylene Glycol component can be the PEG 1000 of about 32%-36% and PEG400 or the PEG1000 of about 33%-35% and the PEG400 of 37.5%-43% of about 35%-46%.

The surfactant that can use in preparation of the present invention comprises but is not restricted to the polysorbate 20 (polyoxyethylene 20 sorbitan monolaurate) at The Extra Pharmacopoeia Thirtieth Edition 1341-1342 page definition by Martindale; polysorbate 60; polysorbate 40; polyoxyethylene sorbitan monoleate; sorbester p17 sorbitan oleate; a kind of ICI Americas; Wilmington; the Delaware product; sorbimacrogol oleate 100; polysorbate 85; Polysorbate 120; cholic acid and salt such as sodium taurocholate; the deoxidation sodium taurocholate; chenodeoxy cholic acid and ursodesoxycholic acid and pluronic or poloxamer such as Pluronic F68; Pluronic L44; the compositions of Pluronic L101 or above-mentioned one or more materials.Polyoxyethylene sorbitan monoleate itself or be preferred for the present invention with the compositions of one or more other surfactants.

Sucrose fatty acid ester used in the present invention comprise those by the commercial channel that obtain with the art-recognized ester that is used for the orally give pharmaceutical composition, comprise an ester, diester and three esters and composition thereof or the admixture of sucrose.The instantiation of ester used in the present invention is sucrose one lauric acid ester, sucrose mono-myristate, P-1570, sucrose monostearate, sucrose distearate, sucrose tristearate, sucrose three myristinates and sucrose tripalmitate or its compositions.

Except these components, pharmaceutically acceptable antioxidant of other enhancing or protectiveness or antiseptic can be added in the present composition, preferably account for the about 0.1%-4% of described composition weight, more preferably account for the about 0.1%-3% of described composition weight.The example comprises ascorbic palmitate, benzyl alcohol, butylated hydroxyanisol (BHA), Yoshinox BHT (BHT) etc.The example of these components comprises that concentration is approximately the BHA of 0.3%-2.5% (%w/w) and the BHT that concentration is approximately 0.005%-0.15% (%w/w), the preferably mixture of BHA in these scopes and BHT in preparation of the present invention.Preferred BHA amount is approximately 0.5%-2.0% or is approximately 0.75%-1.5%.Preferred BHT amount is approximately 0.005%-0.02% or is approximately 0.075%-1.5%.Other instantiation is for wherein comprising those of about 0.2%BHT.

An instantiation of pharmaceutically suitable carrier of the present invention or vehicle system comprises based on %w/w:

A), the PEG 1000 of about 32%-36%;

B), the PEG400 (PEG400) of about 35%-46%;

C), the polyvidone of about 9%-14%;

D), the polyoxyethylene sorbitan monoleate of about 9%-14%;

E), the Yoshinox BHT (BHT) of about 0.005%-0.02%; With

F), the butylated hydroxyanisol (BHA) of about 0.5%-2.0%.

In a large amount of antioxidants of needs or the active example of antiseptic, component e) percent of BHT and BHA is appreciated that the corresponding each other increase in ground so that produce antioxidant/preservative component up to about 4% and f).

Should be appreciated that, the percent of chemical compound equals 100% in these carriers or each preparation of vehicle system, do not consider to have medicine or other pharmacology's components of pharmacological activity, as coloring agent, filler, pharmaceutically acceptable adjuvant, encapsulated with component or coating component etc.In the preferred instantiation of the present invention, with above-mentioned carrier system with have the pharmacological activity medicine and merge, then as with hard or Perle encapsulation.

Preferred another instantiation of the present invention comprises carrier or the vehicle system that is used for pharmaceutical composition, and it comprises based on %w/w:

A), the PEG 1000 of about 33%-35%;

B), the PEG400 (PEG400) of about 37.5%-43%;

C), the polyoxyethylene sorbitan monoleate of about 10.5%-13%;

D), the Yoshinox BHT (BHT) of about 0.075%-0.015%;

E), the butylated hydroxyanisol (BHA) of about 0.75%-1.5%; With

F), the polyvidone of about 10.0%-13%.

Carrier of the present invention or vehicle system can be used for preparing the pharmaceutical composition of numerous species chemical compound.These chemical compounds comprise those by various bicyclo-and tricyclic ring heart molecule, comprise bicyclo-and tricyclic heterocyclic derived compounds.Described examples for compounds comprises that those are in United States Patent (USP) 5,516,774; 5,654,297; 5,686,445; 5,700,796; With 5,719, disclosed chemical compound in 278, each document is incorporated herein for reference in full.Use about carrier system of the present invention and to be incorporated herein the WO 98/24430 people such as () Gautier that is also included within for reference, United States Patent (USP) 5,356,904 (people such as Freidinger), WO 95/03305, EP 0 514 667 Bl (people such as Ogawa) and United States Patent (USP) 5,525, disclosed chemical compound among 614 (people such as Blankley), each document is mentioned in the invention described above background.

Employed noticeable especially active pharmaceutical component or medicine are N-[4-(5H-pyrrolo-[2 among the present invention, 1-c] the basic carbonyl of [1,4] benzodiazepine 10 (11H))-the 3-chlorphenyl]-5-fluoro-2-methyl benzamide, also be known as VPA-985, or its officinal salt, it has structure: VPA-985 has the V2 receptor antagonist (vasopressin antagonists) that causes the mammal draining and do not drain essential electrolyte ability.The synthetic United States Patent (USP) 5,516 that is disclosed in of this chemical compound and salt thereof, among 774 (people such as Albright), the document is hereby incorporated by.

The most preferred that is used as active component in carrier of the present invention or the excipient preparation also has [2-chloro-4-(3-methylpyrazole-1-yl)-phenyl-(5H, 11H)-and pyrrolo-[2, l-c] [1,4] benzodiazepine -10-yl) ketone, or its officinal salt, it has structure:

Using the preparation of this chemical compound to can be used for treating people or other mammal needs in the method for disease, state or disease of vassopressin agonist activity.These Therapeutic Method comprise that treatment need be discharged into blood circulation with the Factor IX and the von Willebrand factor, are discharged into tectotype thrombinogen activator (t-PA) in the blood circulation or influence kidney water and the method for disease, state and the disease of urine concentration conservation.Described Therapeutic Method includes, but are not limited to treat people or other mammal diabetes, nocturnal enuresis, nocturia, urinary incontinence or hemorrhage and coagulation disease comprises hemophilia.This paper uses the method for described preparation also to comprise to promote people or other mammal temporary delay to urinate, control or treat unable temporary delay and urinate when this method also needing to be described as.Be appreciated that described method comprises the treatment that promotes that temporary delay is urinated, this method distinguishes over and is not included in and is known as in nocturnal enuresis and the nocturia treatment of diseases.

Described chemical compound can be by hereinafter described method is synthetic.

(2-chloro-4-fluorophenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone

Oxalyl chloride (2.60g) is added to dichloromethane (50ml) suspension of 2-chloro-4-fluobenzoic acid (3.44g).Adding two dimethyl formamides also at room temperature stirred this mixture 18 hours.Resulting solution evaporation is obtained the viscosity grease (3.72g) of crude product 2-chloro-4-fluorobenzoyl chloride.

Dichloromethane (25ml) solution of crude product 2-chloro-4-fluorobenzoyl chloride (3.68g) under agitation is added to ice-cooled 10 in batches, 11-dihydro-5H-pyrrolo-[2,1-c] in the solution of [1,4] benzodiazepine (2.76g), diisopropylethylamine (2.47g) and dichloromethane (50ml).After at room temperature placing 18 hours, reactant mixture water and saturated sodium bicarbonate aqueous solution washing.The dichloromethane solution anhydrous sodium sulfate drying filters the dichloromethane eluting of also further using several volumes by hydrated sodium silicate magnesium short column.The organic facies that merges concentrates on electric hot plate and adds hexane gradually until crystallization occurring.After the cooling,, obtain title compound (3.85g), m.p.110-112 ℃ by overanxious collection crystallization.[2-chloro-4-(3-methyl-pyrazol-1-yl)-phenyl]-(5H, 11H)-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (isomer A) and [2-chloro-4-(5-methyl-pyrazol-1-yl)-phenyl]-(5H, 11H)-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (isomer B)

Method 1: in 60% sodium hydride in oil in dimethyl formamide (25ml) (0.3g uses the hexane defat), add 3-methylpyrazole (0.55g).After the hydrogen discharging is calmed down, add (2-chloro-4-fluorophenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (1.7g).Reactant mixture heated 18 hours in sand-bath (125 ℃ of internal temperatures).Then, the reactant mixture impouring is diluted with saturated brine solution on ice and further.Precipitated solid is by removing by filter.Dissolving crude product is used anhydrous sodium sulfate drying in dichloromethane, filter and further use the dichloromethane eluting of several volumes then by hydrated sodium silicate magnesium short column.The eluent that merges refluxes on electric hot plate and adds hexane gradually until observing opaque solution.After cooling, obtain amorphous solid.When this material passes through second hydrated sodium silicate magnesium post filtration and vacuum evaporating solvent, obtain the amorphous glass thing (1.11g) of regional isomer 9A and 9B mixture (about 9: 1), MS, m/z:403.2 (M+H) ⁺

Method 2: under 0 ℃ and nitrogen environment, dropping 3-methylpyrazole (5.50g) in anhydrous dimethyl formamide (250ml) suspension of 60% sodium hydride (3.00g) of the hexane wash to refrigerative stirring in advance under.This mixture is warmed to room temperature.After gas discharging stops, adding (2-chloro-4-fluorophenyl)-(5H, 11H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (17.0g) solid, and with reactant mixture be heated to 130 ℃ 1 hour.In reactant mixture impouring frozen water, by filtering collecting precipitation and drying.Resolution of precipitate is used anhydrous sodium sulfate drying in dichloromethane, and filters by the silica gel short column, uses eluent ethyl acetate.The filtrate vacuum evaporation that merges obtains residue foam thing (18.5g).Also (10: 90-25: 75) the gradient mixture eluting comes purification and separated region isomer, obtains the regional isomer of two purification with ethyl acetate-hexane by low-pressure column chromatography chromatography on silica gel;

Isomer A, the colourless amorphous solid of [2-chloro-4-(3-methyl-pyrazol-1-yl)-phenyl]-(5H, 11H)-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (13.5g); MS (EI), m/z:402 (M) ⁺With sample (0.5g) crystallization in ether, recrystallization in ethanol then obtains the colourless crystallization solid of regional isomer A (0.275g), m.p.141-143 ℃.

Isomer B, the colourless amorphous solid of [2-chloro-4-(5-methyl-pyrazol-1-yl)-phenyl]-(5H, 11H)-pyrrolo-[2,1-c] [1,4] benzodiazepine -10-yl)-ketone (1.93g).With sample crystallization in ether, recrystallization in methanol then obtains the colourless spicule (1.4g) of regional isomer B, m.p.160-163 ℃; MS (EI), m/z:402 (M) ⁺, MS (+FAB), m/z:403 (M+H) ⁺

In order to obtain the administration concordance, the preferred present composition exists with unit dosage form.Also prepare easily and use although it will be understood by those skilled in the art that semisolid of the present invention or gel, suitable unit dosage forms preferably includes tablet or capsule.Described unit dosage forms can comprise 0.1-1000mg and preferred 2-50mg active constituent compound of the present invention.Further more preferably, unit dosage forms comprises about 5-25mg medicinal activity compound of the present invention.Preparation of the present invention can be with the dosage range or the preferred dosage range orally give with the 0.1-10mg/kg active component of about 0.01-100mg/kg active component.Described compositions can give 1-6 time every day, more preferably every day 1-4 time.

The present composition can be with preparations such as other conventional carrier or excipient such as filler, disintegrating agent, auxiliary agent, binding agent, lubricant, flavoring agents.

Preferably, preparation of the present invention is packed into after producing in can such as soft or the hard gelatin capsule.During preparation of the present invention can be formulated as liquid or semi-solid preparation and incapsulates.Similarly, by using the component and/or the temperature of optimum range, described preparation can be mixed with gel or solid preparation before encapsulated.

Carrier system of the present invention also can be at other the poorly soluble chemical compound that comprises as active medicine or component, include, but are not limited to (the Yamanouchi Pharmaceutical Company of disclosed chemical compound among the EP0709386, Ltd), comprise compound N-[1,1 '-biphenyl]-2-base-4-[(4,5-dihydro-glyoxal ethyline is [4,5-d] [1] benzo-aza -6 (1H)-yl) carbonyl also] use in the pharmaceutical composition of Benzoylamide (CAS Reg.No.179528-39-3 YM 087) or its officinal salt.The method of useful in preparing drug formulations

The present invention also comprises the method that the biology of utilizing type described herein or pharmacological activity component prepare preparation.The inventive method comprises step:

A), PEG and surface active agent composition are merged, preferably mix or stir producing first carrier mixture simultaneously;

B), the temperature of first carrier mixture is increased to about 75-95 ℃, 80-90 ℃ scope preferably approximately;

C), add active pharmaceutical component or medicament and produce first pharmaceutical composition mixture;

D), with first pharmaceutical composition mixture preferably under about 115-170 ℃ temperature, more preferably under about 130-150 ℃ temperature, most preferably under about 135-145 ℃ temperature, stir, preferably heat simultaneously until first pharmaceutical composition mixture clarification;

E), if desired, first pharmaceutical composition is cooled to the about 75-95 of temperature ℃, preferably approximately 80-90 ℃;

F), add a certain amount of sucrose fatty acid ester and/or the last pharmaceutical composition mixture of polyvidone generation, the preferred stirring simultaneously until last pharmaceutical composition mixture change clarification.

Under the situation of using optional antioxidant or antiseptic such as BHA, BHT etc., can use the following step:

A), PEG component (as the mixture of PEG400 and PEG1000) and surface active agent composition (as polyoxyethylene sorbitan monoleate) are merged, preferably mix or stir producing first carrier mixture simultaneously;

C), optional antioxidant or antiseptic be added to produce second carrier mixture in first carrier mixture, with its stirring or mix and become clear solutions until second carrier mixture;

D), add active component and produce first pharmaceutical composition mixture;

E), with first pharmaceutical composition mixture preferably under about 115-170 ℃ temperature, more preferably under about 130-150 ℃ temperature, most preferably under about 135-145 ℃ temperature, stir, preferably heat simultaneously until first pharmaceutical composition mixture and become clarification;

F), first pharmaceutical composition randomly is cooled to the about 75-95 of temperature ℃, preferably approximately 80-90 ℃;

G), add a certain amount of sucrose fatty acid ester and/or the last pharmaceutical composition mixture of polyvidone generation, the preferred stirring simultaneously until last pharmaceutical composition mixture change clarification.

The viscosity and the form that it will be understood by those skilled in the art that last preparation can be controlled with component in the scope of the invention and the temperature range in the course of processing.For example, liquid or semi-solid preparation can prepare with more liquid PEG, surfactant and PVP in the scope of the invention.More gel sample, heavy-gravity or semi-solid combination can and have the PVP component combined preparation of higher K value with higher molecular weight PEG component.And if last compositions need be milled or other processed, so described component can be cooled to and be lower than its fusing point.In order to produce more starting composition pelletizing, fluid composition of the present invention can be sprayed to refrigerative coating Teflon ^The surface on form little solid ball, they are coating or collect so that further processing independently.

Hereinafter utilize compound N-[4-(5H-pyrrolo-[2,1-c] [1,4] benzodiazepine -10 (11H)-Ji carbonyl)-the 3-chlorphenyl]-5-fluoro-2-methyl benzamide (VPA-985) provides the specific non-limiting example of preparation in the scope of the invention as non-limiting explanation embodiment.Being appreciated that can be by using other active component or the comparable preparation of its preparation of compositions.

Embodiment 150mg/ capsule: the oral formulations of 10% medicine loading

Replace the polyoxyethylene sorbitan monoleate in embodiment 1 said preparation, also can separately or combine with one another and/or unite and use other Polysorbate serial as polysorbas20,40 and 60 with polyoxyethylene sorbitan monoleate.

(%w/w) every capsule 20,000

(mg) capsule batch (g)

Active component 10.42 50.00 1000.00

Inactive ingredients

PEG1000，NF 30.96 148.61 2,972.16

Polyvidone USP K-17 10.00 48.00 960.00

Polyoxyethylene sorbitan monoleate, NF 10.00 48.00 960.00

BHT，NF 0.09 0.42 8.32

BHA，NF 0.87 4.16 83.2

PEG 400, NF ²In right amount extremely in right amount extremely in right amount extremely

100 480.00 9,600

1, weigh polyoxyethylene sorbitan monoleate, PEG400 and PEG1000 are added in the suitable blender, and the agitator of installing with the top stirs and is warmed to 85 ± 5 ℃.

2, BHT and BHA are added in the described blender very lentamente in case block formation.85 ± 5 ℃ of following continuous stirring, form until clear solutions.

3, active component is added under 85 ± 5 ℃ very lentamente in the described blender in case block formation.Slowly be warming up to 125 ± 5 ℃ and stir and to dissolve fully until active component.

4, in step 4, described solution is cooled to 60 ± 5 ℃.

5, in step 5, add polyvidone lentamente, USP, (Plasdone C-15 is ISP) in case block formation for K-17.

Allow described solution be warmed to 85 ± 5 ℃.Stirring is clarified until described solution becomes.

6, under 38 ± 5 ℃, as passing through to use Hoglinger and Karg (H﹠amp; K) 800L encapsulated device is made solution (in step 10) is encapsulated into No. 1 capsule with 480mg.In encapsulation process, with cooling nitrogen cooling capsule body by dry ice.

7, with the described capsule of gelatin solution ring seal.

Embodiment 250mg/ capsule: the oral formulations of 10% medicine loading

Replace employed surfactant (poloxamer 188) in the said preparation, also can use other polymer such as Pluronic L44, Plurnic L101 in the described series.

(%w/w) every capsule 20,000

(mg) capsule batch (g)

Active component 10.42 50.00 1000.00

Inactive ingredients:

Polyvidone USP K-17 10.00 48.00 960.00

(Plasdone?C-15，ISP)

Poloxamer 188, NF 12.00 57.60 1152.00

BHT?NF 0.09 0.42 8.32

BHA?NF 0.87 4.16 83.20

PEG 400 NF are an amount of extremely in right amount extremely in right amount extremely

100 480.00 9600g

In said preparation, except with the displaced polyoxyethylene sorbitan monoleate of 12% poloxamer, said preparation preparation as embodiment 1 prescription (50mg/ capsule).Encapsulation weight is 480mg.

Embodiment 350mg/ capsule

Embodiment 4 provides and has united the preparation that contains two or more surfactants.

(%w/w) every capsule 20,000

(mg) capsule batch (g)

Active component 10.64 51.07 1,021.44

Inactive ingredients:

PEG?1000，NF 28.60 137.28 2,745.60

Polyvidone USP K-17 10.00 48.00 960.00

(Plasdone?C-15，ISP)

Polysorbate 40, NF 5.00 24.00 480.00

Poloxamer 188, NF 10.00 48.00

BHT，NF 0.09 0.43 8.64

BHA，NF 0.87 4.18 83.52

PEG 400, and NF is an amount of extremely in right amount extremely in right amount extremely

100 480.00 9600.00

Except in step 1, add two kinds of surfactants with PEG 400 and PEG 1000, outside polysorbate 40 and the poloxamer 188, the preparation of embodiment 3 is prepared as embodiment 1 (50mg/ capsule).Encapsulation weight is 480mg.Embodiment 425mg/ capsule: the oral formulations of 5% medicine loading

(%w/w) every capsule 20,000

(mg) capsule batch (g) active component 5.49 25.00 500.00 Inactive ingredients:PEG 1000, NF 32.66 148.61 2,972.16 polyvidone USP K-17 10.55 48.00 960.00 (Plasdone C-15, ISP) polyoxyethylene sorbitan monoleate, NF 10.55 48.00 960.00BHT, NF 0.09 0.42 8.32BHA, NF 0.91 4.16 83.2PEG 400, NF ²In right amount extremely in right amount extremely in right amount extremely

100 455.00 9,100

Except in step 3, come outside the lytic activity component with the heating-up temperature of 120 ± 5 ℃ of 115 ± 5 ℃ of replacements, the preparation of embodiment 4 as above 50mg/ capsule is equally prepared.Encapsulation weight is 455mg.Embodiment 5100mg/ capsule: the oral formulations of 15% medicine loading

(%w/w) every capsule 20,000

(mg) capsule batch (g) active component 15.38 100.00 2,000.00 Inactive ingredients:PEG 1000, and NF 28.98 188.35 3, and 767.05 polyvidone USP K-17 10.00 65.00 1,300.00 (Plasdone C-15, ISP) ³Polyoxyethylene sorbitan monoleate, NF 9.45 61.39 1,227.91BHT, NF 0.08 0.53 10.64BHA, NF 0.82 5.32 106.42PEG 400, NF is an amount of extremely in right amount extremely in right amount extremely

100 650.00 13,000.00

Except in step 3, come outside the lytic activity component with the heating-up temperature of 120 ± 5 ℃ of 145 ± 5 ℃ of replacements, said preparation as above 50mg/ capsule is equally prepared.Encapsulation weight in No. 0 hard gelatin capsule is 650mg.Embodiment 6150mg: be encapsulated in No. 00 capsule

(%w/w) every capsule 20,000

(mg) capsule batch (g) active component 16.48 149.97 2,999.36 Inactive ingredients:PEG 1000, NF 26.3 239.33 4,786.60 polyvidone USP K-17 15 136.50 2,730.00 (Plasdone C-15, ISP) polyoxyethylene sorbitan monoleate, NF 9.32 84.81 1,696.24BHT, NF 0.08 0.73 14.56BHA, NF 0.81 7.37 147.42PEG 400, NF is an amount of extremely in right amount extremely in right amount extremely

100 910.00 18,200.00

Except in step 3, come outside the lytic activity component with the heating-up temperature of 145 ± 5 ℃ of 150 ± 5 ℃ of replacements, the preparation of embodiment 6 is prepared as the 50mg/ capsule.Encapsulation weight in No. 00 hard gelatin capsule is 910mg.

Following specific embodiment 7-11 shown in the following table 1 can prepare as mentioned above, produces that PEG400, the PEG1000 contain 10% active component and variable concentrations and K value are respectively two kinds of PVP components of 15 and 90 and as the preparation of the compositions of the BHA of auxiliary agent and BHT.

Table 1

Embodiment PEG PEG PVP PVP BHT BHA NATC activity

Sequence number 400 1000 K15 K90 components

(％) (％) (％) (％) (％) (％) (％) (％)

7 55.40 20.00 10.00 0.00 0.20 2.00 2.40 10.00

8 40.40 35.00 10.00 0.00 0.20 2.00 2.40 10.00

9 75.40 0.00 5.00 5.00 0.20 2.00 2.40 10.00

10 65.40 10.00 0.00 10.00 0.20 2.00 2.40 10.00

11 40.40 35.00 5.00 5.00 0.20 2.00 2.40 10.00 similarly, the following example 12-32 can be by method described herein, with PEG400, PEG1000, K value be 17 PVP, active component, as the BHA and the BHT of antioxidant or antiseptic and other component preparation of classifying " other " as.

12 40.40 35.00 10.00 10.00 2.00 0.20 Ns of sulphur gallbladders of active BHA other other sequence number 400 1000 K-17 components of BHT of table 2 embodiment PEG PEG PVP

Acid sodium

2.4013 75.40-5.00 10.21 2.00 0.20 Ns of sulphur gallbladder PVP

Acid sodium K-90

2.40 5.0014 42.59 35.00 10.00 10.21 2.00 0.2015 34.35 28.23 10.00 10.21 2.00 0.20 poloxamers 188-

15.0016 42.59 20.00 10.00 10.21 2.00 0.20 poloxamers 188-

15.0017 37.10 30.49 10.00 10.21 2.00 0.20 poloxamers 188-

10.0018 35.72 29.36 10.00 10.21 2.00 0.20 poloxamers 188-

12.5019 34.35 28.23 10.00 10.21 2.00 0.20 poloxamers 188-

15.0020 37.10 30.49 10.00 10.21 2.00 0.20 poloxamers 188-

10.0021 34.35 28.23 10.00 10.21 2.00 0.20 poloxamers 188-

15.0022 35.72 29.36 10.00 10.21 2.00 0.20 poloxamers 188-

12.5023 36.86 30.30 10.00 10.64 2.00 0.20 Pluronic?L44 -

10.0024 36.86 30.30 10.00 10.64 2.00 0.20 Pluronic?L101 -

10.0025 39.61 32.55 10.00 10.64 2.00 0.20 polysorbate40s-

5.0026 41.25 33.91 10.00 10.64 2.00 0.20 polysorbate40s-

2.0027 39.61 32.55 10.00 10.64 2.00 0.20 polysorbas20s-

5.0028 41.25 33.91 10.00 10.64 2.00 0.20 polysorbas20s-

2.0029 34.12 28.04 10.00 10.64 2.00 0.20 polysorbate40 poloxamers 188

5.00 10.0030 36.86 30.30 10.00 10.64 2.00 0.20 polysorbate40s-

10.0031 36.86 30.30 10.00 10.64 2.00 0.20 Tween 80s-

10.0032 34.12 28.04 10.00 10.64 2.00 0.20 Tween 80 poloxamers 188

5.00 10.00

Claims

1, a kind of compositions, it comprises (w/w%):

A), about 1%-20%, the preferably approximately surface active agent composition of 5%-12%;

B), about 55%-93%, preferably approximately the mean molecule quantity of 60%-85% is approximately one or more Polyethylene Glycol (PEG) component of 190-3450; With

C), approximately one or more sucrose fatty acid ester of 1%-25% or the polyvinylpyrrolidone that the K value is approximately 15-90, perhaps one or more sucrose fatty acid ester or K value are approximately the compositions of the polyvinylpyrrolidone of 15-90.

2, the compositions of claim 1, it comprises (w/w%):

A), the surface active agent composition of about 5%-12%;

B), the mean molecule quantity of about 60%-85% is approximately one or more Polyethylene Glycol components of 400-1540; With

C), approximately 5%-15% one or more sucrose fatty acid ester or be approximately 15-90 as defined K value among the USP/NF, preferably the K value is approximately the polyvinylpyrrolidone (PVP) of 16-18, the perhaps compositions of one or more sucrose fatty acid ester or PVP.

3, the compositions of claim 1; wherein; described surface active agent composition comprises polysorbate 20, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monoleate, sorbester p17 sorbitan oleate, sorbimacrogol oleate 100, polysorbate 85, Polysorbate 120, sodium taurocholate, deoxidation sodium taurocholate, chenodeoxy cholic acid, ursodesoxycholic acid, pluronic or poloxamer, or its compositions.

4, the compositions of claim 1, wherein said one or more Polyethylene Glycol components comprise that ratio is approximately 2.5: 1-1: 2.5 PEG400 and the mixture of PEG1000.

5, the compositions of claim 1, the K value of wherein said polyvinylpyrrolidone component is approximately 17.

6, the compositions of claim 1, it further comprises one or more antioxidants or the preservative component of about 0.1%-4%.

7, the compositions of claim 6, wherein said one or more antioxidants or antiseptic are selected from ascorbic palmitate, benzyl alcohol, butylated hydroxyanisol (BHA) or Yoshinox BHT (BHT), or its compositions.

8, the compositions of claim 7, wherein said one or more antioxidants or antiseptic comprise the BHA of about 0.3%-2.5% and the BHT of about 0.005%-0.15%.

9, a kind of pharmaceutical composition, it comprises (w/w%):

A), the surface active agent composition of about 1%-20%;

B), the mean molecule quantity of about 55%-93% is approximately one or more Polyethylene Glycol (PEG) component of 190-3450;

C), approximately one or more sucrose fatty acid ester of 1%-25% or the polyvinylpyrrolidone that the K value is approximately 15-90, perhaps one or more sucrose fatty acid ester or K value are approximately the compositions of the polyvinylpyrrolidone of 15-90; With

D), one or more antioxidants or the preservative component of about 0.1%-4%.

10, the compositions of claim 9, wherein said one or more antioxidants or antiseptic are selected from ascorbic palmitate, benzyl alcohol, butylated hydroxyanisol or Yoshinox BHT, or its compositions.

11, the compositions of claim 9; wherein said surface active agent composition comprises polysorbate 20, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monoleate, sorbester p17 sorbitan oleate, sorbimacrogol oleate 100, polysorbate 85, Polysorbate 120, sodium taurocholate, deoxidation sodium taurocholate, chenodeoxy cholic acid, ursodesoxycholic acid, pluronic or poloxamer, or its compositions.

12, the compositions of claim 9, wherein said one or more antioxidants or antiseptic are selected from ascorbic palmitate, benzyl alcohol, butylated hydroxyanisol or Yoshinox BHT, or its compositions.

13, a kind of compositions, it comprises (w/w%):

A), the PEG1000 of about 32%-36%;

B), the PEG400 of about 35%-46%;

C), the polyvidone of about 9%-14%;

D), the polyoxyethylene sorbitan monoleate of about 9%-14%;

E), the Yoshinox BHT of about 0.005%-0.02%; With

F), the butylated hydroxyanisol of about 0.5%-2.0%.

14, the compositions of claim 13, it comprises (w/w%):

A), the PEG1000 of about 33%-35%;

B), the PEG400 of about 37.5%-43%;

C), the polyoxyethylene sorbitan monoleate of about 10.5%-13%;

D), the Yoshinox BHT of about 0.075%-0.015%;

E), the butylated hydroxyanisol of about 0.75%-1.5%; With

F), the polyvidone of about 10.0%-13%.

15, the arbitrary method for compositions of a kind of preparation claim 1-8, this method comprises:

D), with first pharmaceutical composition mixture preferably under about 115-170 ℃ temperature, more preferably under about 130-150 ℃ temperature, most preferably under about 135-145 ℃ temperature, stir, preferably heat simultaneously until first pharmaceutical composition mixture and become clarification;

16, the arbitrary method for compositions of a kind of preparation claim 9-12, this method comprises:

C), optional antioxidant or antiseptic be added to produce second carrier mixture in first carrier mixture, then with its stirring or mix and become clear solutions until second carrier mixture;

D), add active component and produce first pharmaceutical composition mixture;