CN1263461A - Pharmaceutical composition - Google Patents

Pharmaceutical composition Download PDF

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Publication number
CN1263461A
CN1263461A CN98806380A CN98806380A CN1263461A CN 1263461 A CN1263461 A CN 1263461A CN 98806380 A CN98806380 A CN 98806380A CN 98806380 A CN98806380 A CN 98806380A CN 1263461 A CN1263461 A CN 1263461A
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CN
China
Prior art keywords
azepine
steroid
alkene
ketone
androstane
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Pending
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CN98806380A
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Chinese (zh)
Inventor
A·F·帕尔
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Glaxo Group Ltd
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Glaxo Group Ltd
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Publication of CN1263461A publication Critical patent/CN1263461A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters

Abstract

The present invention discloses a novel solution comprising a therapeutically effective amount of a pharmaceutically active aza steroid, and a fatty acid ester of glycerol or propylene glycol. In another aspect, the present invention discloses a pharmaceutical composition comprising the solution of the invention. In another aspect, the present invention discloses a gelatin capsule filled with the composition of the present invention.

Description

Pharmaceutical composition
The present invention relates to the pharmaceutical composition that some contains 4-azasteroids and/or 6-azasteroids.The present invention is specifically related to contain the solution of steroid class 5-alpha reductase inhibitor.
Pharmaceutically active compound can be in a variety of forms, for example the Perle form administration.The method for preparing Perle is known for one of ordinary skill in the art.Referring to, " Perle " the 13rd chapter-part 2 of J.P.Stanley for example: the principle of industrialization pharmacy and practice.People such as L.Lachman edit, and the 3rd edition, 398-412 page or leaf, 1986; With, " the elasticity Perle: a kind of dosage form of uniqueness, pharmaceutical technology " of W.R.Ebert, the 1st volume, the 5th phase.
With regard to good solubility and the bioavailability of guaranteeing pharmaceutically active compound, be vital to the selection of excipient.Referring to, for example " its analysis of excipient and the use that Perle is commonly used " of A.Matso, " new medicament system and doser international symposium " 76-81 page or leaf (1991); K.Hutchison, " being encapsulated in the pharmacy superiority in the soft gel capsules " Spec.Pub.-R.Soc.Chem, 138 volumes, 86-97 page or leaf (1993).M.S.Patel etc., the development of soft gel preparation technology, " manufacturing chemistry man ", and in August, 1989 and I.R.Berry, the bioavailability that Perle improves, " D﹠C industry ", pp 32,102-108, (nineteen eighty-three JIUYUE).For example at K.Hutchison the soft gel preparation of oral administration " improve hydrophobic drug ", Spc.Pub.-R.Soc.Chem., 161 volumes, among the 133-147 (1995) the preparation to the hydrophobicity pharmaceutically active compound be described.
Adopted the hard gelatin capsule of liquid filling so far.Referring to, people's such as D.Cade " liquid filling and the hard gelatin capsule that seals " for example, drug development and pharmaceuticals industry, 12 (11-13): 2289-2300, (1986).
Azasteroids is the important pharmaceutically active compound of a class.Recognize specifically that now 4-azasteroids and 6-azasteroids are the inhibitor (after this claiming " 5AR inhibitor ") of testosterone-5 alpha-reductases.This compounds is considered to effectively to treat benign prostatauxe, carcinoma of prostate and other diseases.Referring to, for example United States Patent (USP) 4377584 (people such as Rasmusson), 4220775 (people such as Rasmusson), 4732897 (people such as Cainelli), 4760071 (Rasmusson), 4845104 (people such as Carlin), 4859681 (Rasmusson), 5302589 (people such as Frye), 5438061 (people such as Bergman), 5543406 (people such as Andrews), 5565467 (people such as Batchelor) and WO 95/07926 (people such as Batchelor).A kind of in this type of 5AR inhibitor, Finasteride (finasteride) is by Merck ﹠amp; Co., Inc. is with product " proscar (PROSCAR TM) " sell.These pharmaceutical active compounds are difficult for dissolving.Such solubility exerts an influence to bioavailability, can cause bioavailability to reduce and maybe can't expect.
The mixture of glyceride has been used to dissolve Biliary Calculi, and glyceride mixture can be with trade name Capmul TMMCM available from Abitec (P.O.Box 569, Columbus, Ohio).Referring to, for example " harmless dissolving cholesterol calculus ", Medical World News, 28 pages (1978); U.Leuschner ﹠amp; D.Landgraf, " dissolving Biliary Calculi ", The Lancet, 2, the 8133 pages (1979) with monooctanoin; With people's " monooctanoin, a kind of lytic agent of residual cholesterol Biliary Calculi: its physical property and clinical practice " such as J.L.Thistle, the gastroenterology 78,1016-1022 page or leaf (1980).
Now the ester of glycerol and/or propylene glycol is applied to multiple different preparation.Referring to, for example United States Patent (USP) 4316917 (people such as Antoshkiw) and 4343823 (people such as Todd).
In brief, on the one hand, the invention discloses a kind of new solution that contains the fatty acid ester of the pharmaceutical active azasteroids for the treatment of effective dose and glycerol or propylene glycol.Described fatty acid preferably contains the carboxylic acid of 6-12 carbon atom.Preferred ester is a monoesters.
On the other hand, the invention discloses a kind of pharmaceutical composition that contains solution of the present invention.Compositions of the present invention is particularly suitable as the filling preparation that is used for gelatine capsule.
Again on the one hand, the invention discloses the gelatine capsule of filling with the present composition.
The tablet or the suspensoid of corresponding standard, compositions of the present invention has improved bioavailability.
Some can be used for steroid of the present invention is potent teratogenesis shape medicine.The steroid of powder of will dissociating earlier in manufacture process is converted into solution can make preparation process safer.The danger of Treatment Solution wants specific ionization solid littler.
In addition, some these type of steroids have oxidation tendency.Gelatin capsule formulation more can tolerate Oxidation, and this is because of the oxygen that penetrates the party regulation gelatin shell seldom.Referring to, people " Perle II: the oxygen permeability test of capsule shells " such as F.S.Hom for example, pharmaceutical science magazine (J.Pham.Sci.), 64 volumes, (No. 5), 851-887 page or leaf (1975).
Be applicable to that ester of the present invention is preferably derived from the carboxylic acid that contains 6-12 carbon atom.More preferably those are derived from the ester of sad (8 carbon atoms).Although the present invention can adopt an ester, diester and three esters, preferably adopt an ester.In addition, a described ester part can be the mixture that contains the mixture of different carbon numbers in the ester and/or comprise monoglyceride, diglyceride and triglyceride.Commercially available ester is such mixture often.For example, Capmul TM(all available from Abitec Corporation, Janesville Wisconsin) is this type of mixture for MCM and PG-8.Capmul TMThe composition of MCM is the mixture of fatty acid glyceride, and contains 95% monoesters of having an appointment, 1% glycerol, 2% free fatty and be less than 0.5% water, and derived from about 85% sad and 15% capric acid (all percentage ratios are weight percentage).PG-8 is the mixture of methyl glycol fatty acid ester, contains 96% monoesters of having an appointment, 0.05% diester, 1.3% free propylene glycol, and derived from sad.
Be applicable to that azasteroids of the present invention can be azasteroids or its acceptable solvent thing of any pharmaceutical active.The azasteroids of preferred type is as the 4-azepine class of 5 inhibitor (5AR inhibitor) and 6-azepine class steroid.For example, the disclosed arbitrary 5AR inhibitor of above-mentioned patent documentation.Preferred azasteroids is the 4-azasteroids.Concrete preferred 4-azasteroids comprises: Finasteride; 17-β-N-(2; two (trifluoromethyl) phenyl amino formoxyls of 5-)-4-azepine-5-α-androstane-1-alkene-3-ketone people's disclosed steroids in United States Patent (USP) 5565467 such as () Batchelor and 17-β-N-1-(3,4-methylene-dioxy-phenyl)-cyclohexyl carboxyamide base-4-azepine-5-α-androstane-1-alkene-3-ketone and 17-β-N-1-(right-chlorophenyl)-cyclopenta carbamoyl-4-azepine-5-α-androstane-1-alkene-3-ketone (being disclosed among the WO 95/07926) by people such as Batchelor.These steroids are to utilize the known method preparation of one of ordinary skill in the art, for example the method disclosed in the above-mentioned patent document.
In the weight of solution of the present invention, the content of azasteroids is preferably 0.0025-2.5% (weight), more preferably 0.025-1.5% (weight).
Can also contain antioxidant in the described compositions.The antioxidant that is suitable for comprises: Yoshinox BHT (BHT), butylated hydroxyanisol (BHA) and ascorbic acid.Preferred antioxidant is Yoshinox BHT.Antioxidant can use separately or share.Antioxidant or antioxidant mixture preferably account for the 0.001-0.5% (weight) of the present composition.
Pharmaceutical composition of the present invention is especially suitable for use as the filling preparation of gelatine capsule, first-selected Perle.
Experiment
In following experiment, in a plurality of solubility tests, adopt pharmaceutical active 4-azasteroids.(2, two (trifluoromethyl) phenyl amino formoxyls of 5--4-azepine-5-α-androstane-1-alkene-3-ketone is as the pharmaceutical active steroid with 17-β-N-.In this steroid is disclosed in patent ' 467, and can be according to known method (comprise patent the described method in ' 467) preparation.
By excessive steroid being suspended in the dissolubility that to measure steroid in different aqueous of about 1mL and the organic media.Move the gained suspension and make it not be subjected to illumination in the rotary water-bath transfer of 25 ℃ Vankel .When balance period (usually in 1-12 days) finishes, with 0.22 μ filter membrane, remove unnecessary solid through centrifugal filtration.Get the gained supernatant subsequently and measure the concentration of steroid with respect to external standard.The concentration of steroid is by the HPLC algoscopy, adopts the Hewlett Packard1090 series II/M that has DOS Chem work station to measure in the supernatant.The HPLC condition is summarised in the following table 1.Solubility results in different aqueous mediums is summarised in the following table 2, and the solubility results in organic media is summarised in the table 3.Table 4 has been summarized the dissolubility in the different components that contains chelating agent (2-HP-).Table 5 has been summarized at different oils and Capmul TMDissolubility among the MCM.Table 6 has been summed up at Capmul TMMCM and mean molecule quantity are the dissolubility in 400 Polyethylene Glycol (PEG400) mixture.In the following harmony in the exterior test, Mili Q TM+ water is reverse osmosis water, and CMC is a carboxymethyl cellulose, and THF is an oxolane, and DMSO is a dimethyl sulfoxide, and PG is a propylene glycol, Labrafil TMIt is the mixture (deriving from Semen Maydis oil or almond oil partial alcoholysis) of unsaturated polyester glycolysis glycerol; it is made up of glyceride and macrogol ester; SDS is a sodium lauryl sulphate, and " model duodenum bile salts " is the mixture of NaGC, goose deoxidation NaGC (sodium glycochenodesoxycholate), glycodesoxycholic acid sodium, sodium taurocholate, Taurochenodeoxycholic Acid sodium, Taurodeoxycholate sodium (sodiumtaurodesoxycholate), sodium chloride, lecithin and phosphate buffer.Tween 80 is polyethylene glycol oxide (a 20) Arlacel-80.PEG 400 is available from Union Carbide, Molescusol TMBe the 2-HP-, and Intralipid TMIt is the mixture of soybean oil, phospholipid, glycerol USP and water for injection.Except as otherwise noted, all % all are weight percentage, and for example " v/v " is meant percent by volume.Table 1 HPLC condition
Chromatographic column 250×4.6mm?Zorbax?RxC18
Mobile phase A.0.1%v/vTFA B.0.05%v/vTFA, be dissolved in the acetonitrile
Percentage composition In 20 minutes by 40%B to 95%B (put and stay 10 minutes)
Flow velocity 1.0ml/min
Detect optical wavelength 210/240
Furnace temperature 35℃
The dissolubility of table 2 in aqueous medium
Medium Concentration (mg/ml)
Milli?Q + water ＜0.0039
0.1N?HCl ＜0.0039
0.5% carboxymethyl cellulose ＜0.0039
1％Labrafil Highly degraded
0.02％SDS ＜0.0039
0.01% docusate sodium ＜0.0039
0.1% Tween 80 ＜0.0039
0.1% Tween 80/0.02%SDS ＜0.0039
Model duodenum cholate ?0.0386
The dissolubility of table 3. in organic media
Medium Concentration (mg/ml)
Propylene glycol 6.21
PEG400 3.27
PEG400,0.1% Tween 80 3.91
Propylene carbonate 6.24
Ethyl acetate 14.49
THF 225.44
Acetonitrile 7.44
Acetone 46.97
DMSO 130.40
Benzylalcohol ＞34
Ethanol 45.59
70% ethanol water 2.73
Isopropyl alcohol 29.98
The dissolubility of table 4 in 2-HP-solution
Medium Concentration (mg/ml)
10％Molecusol ?0.03
20％Molecusol ?0.12
40％Molecusol ?0.79
40％Molecusol /25％PEG?400/5％PG ?0.08
40％Molecusol / 50% moisture PEG 400 ?0.56
The dissolubility of table 5. in different oleaginous base systems
Medium Concentration (mg/ml)
Oleum sesami ?0.52
Safflower oil ?0.39
Oleum Glycines ?0.44
Oleum Gossypii semen ?0.53
Semen Maydis oil ?0.56
Semen Ricini oil ?2.01
Olive oil ?0.44
Oleum Arachidis hypogaeae semen ?0.46
Mineral oil ?0.007
1% span 20/Oleum Gossypii semen ?0.62
10% benzylalcohol/Oleum Gossypii semen ?2.77
Intralipid20％ ?0.009
Capmul TM?MCM ?28.24
Table 6 is at Capmul TMDissolubility in MCM and the PEG mixture
Be dissolved in the Capmul among the PEG 400 TMMCM(％) Concentration (mg/ml)
10 ?6.95
25 ?10.01
50 ?14.11
100 ?28.24
Dissolubility data shows that the steroid utmost point indissoluble of the above-mentioned type is separated.Above-mentioned data show is at Capmul TMDissolubility among the MCM is apparently higher than tested other system.
Subsequently, use Capmul TMThe MCM preparation is adapted at the filling preparation of use in the gelatine capsule.In order to prepare 0.01,0.05,0.5,2.5,5.0 and the 10.0mg Perle, with Capmul TMMCM is heated to about 26-28 ℃.Add Yoshinox BHT NF subsequently, mixture is stirred until dissolving.Add steroid and mixing again, the temperature of maintenance and monitoring mixture is no more than 40 ℃ to guarantee it, until dissolving.Before in incapsulating solution is outgased.
By being mixed, gelatin NF, glycerol USP, sorbitol (sorbitol special) and pure water USP can prepare gelatin.With the gained mixture at the pressurized reactor internal heating to the gelatin fusion.Subsequently gelatin is maintained molten state until being used for encapsulation.
Adopt rotary punch die method (die process) to carry out encapsulation.Hot gelatin is dosed in the encapsulation machine, and this machine has two spreader material-storing boxs, and they cast in gelatin on the drum cooler, forms two gelatin bars thus.With the fractional distillation cocos nucifera oil gelatin bar inboard is lubricated, and lubricate the outside with the fractional distillation cocos nucifera oil that contains 0.1% lecithin NF.The fractional distillation cocos nucifera oil prevents that gelatin from adhering on the equipment, and lecithin NF prevents that capsule from sticking together after manufacturing, before the drying.Subsequently the gelatin bar is transported on the encapsulation roller bearing machine.Form the periphery that capsular die cavity is positioned at adjacent two roll shaft machines, two roll shaft machine rotations are also drawn Shen gelatin bar therebetween.To fill in injection of solution to the two gelatine capsule bar by the counting displacement pump, and make solution diffusion and be filled in the die cavity.After capsule is filled, by encapsulation roll shaft machine simultaneously with its shaping, seal and cut down from the gelatin bar.After this capsule is transported in the rotation basket drier.
By can fully removing the moisture in the capsule so that handle at rotation basket drier inner drying.Transfer to it in pallet subsequently and make its drying, be no more than 2% (w/w) until the moisture of filling solution.Be meant that moisture reaches 2% o'clock required time drying time.
Prepare and contain 0.01,0.05,0.5,2.5,5.0 or steroid, the 0.035mg Yoshinox BHT NF of 10.0mg and be enough to make the filled compositions total amount to reach the Capmul of 350mg TM6 batches of MCM, but the capsular total loading of 10mg is 500mg.
Utilize standard method that the relative bioavailability of above-mentioned composition is assessed again.The volunteer is received in the Perle of the present invention or the medicine in the conventional tablet randomly.Collect pharmacokinetic parameter (AUC, C between blood sample and the contrast therapy group Max, T Max).Compare with the relative bioavailability of the 10%-20% of same amount steroid in the tablet, the relative bioavailability of Perle of the present invention is 80% to 90%.
Can be by the application that this description and claim constitute as the basis for priority of any follow-up related application.Claims of follow-up application can relate to the new feature of said technical characterictic or its in conjunction with feature, and can be with for example and be not subjected to limiting mode to comprise one or more following claim.

Claims (17)

1. solution wherein contains the pharmaceutical active azasteroids for the treatment of effective dose and the fatty acid ester of glycerol or propylene glycol.
2. the described solution of claim 1, wherein said steroid is 4-azepine or 6-azasteroids.
3. the described solution of claim 2, wherein said steroid is the carbonyl-4-azepine androstane-1-alkene-3-ketone of 17-beta substitution or the carbonyl-6-azepine androstane-4-alkene-3-ketone of 17-beta substitution.
4. the described solution of claim 3, wherein said steroid is the carbonyl-4-azepine androstane-1-alkene-3-ketone of 17-beta substitution.
5. the described solution of claim 4; wherein said steroid is 17-β-N-(tert-butyl)-carbamoyl-4-azepine-5-α-androstane-1-alkene-3-ketone, 17-β-N-(2; two (trifluoromethyl) phenyl amino formoxyls of 5-)-4-azepine-5-α-androstane-1-alkene-3-ketone, 17-β-N-1-(3,4-methylene-dioxy-phenyl)-cyclohexyl carboxyamide base-4-azepine-5-α-androstane-1-alkene-3-ketone or 17-β-N-(1-(right-chlorophenyl)-cyclopenta carbamoyl-4-azepine-5-α-androstane-1-alkene-3-ketone.
6. the described solution of claim 5, wherein said steroid are 17-β-N-(2, two (trifluoromethyl) phenyl amino formoxyls of 5-)-4-azepine-5-α-androstane-1-alkene-3-ketone.
7. each described solution of claim 1-6, wherein said steroid is the 0.0025%-2.5% (weight) of solution weight.
8. the described solution of claim 7, wherein said steroid is the 0.025%-1.5% (weight) of this solution.
9. each described solution of claim 1-8, wherein said ester is derived from the carboxylic acid that contains 6-12 carbon atom.
10. the described solution of claim 9, wherein said ester is derived from the carboxylic acid that contains 8 carbon atoms.
11. each described solution of claim 1-10, wherein said ester is a monoesters.
12. a pharmaceutical composition wherein contains each described solution of aforesaid right requirement.
13. the described compositions of claim 12 wherein also contains antioxidant.
14. the described compositions of claim 13, wherein said antioxidant are Yoshinox BHT, butylated hydroxyanisol, ascorbic acid or its mixture.
15. the compositions of claim 13 or 14, wherein said antioxidant account for the 0.001%-0.5% (weight) of said composition weight.
16. the gelatine capsule of a liquid filling wherein contains each described compositions of claim 12-15.
17. the described gelatine capsule of claim 16, wherein said capsule is a Perle.
CN98806380A 1997-08-19 1998-08-17 Pharmaceutical composition Pending CN1263461A (en)

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GB9717428.8 1997-08-19

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AU (1) AU9343098A (en)
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CA (1) CA2295016A1 (en)
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US8900631B2 (en) 2011-04-28 2014-12-02 Health Science Funding, LLC Dosage form to increase prasterone bioavailability
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KR101679992B1 (en) * 2015-12-31 2016-11-28 주식회사 유유제약 Pharmaceutical composition comprising dutasteride and propylene glycol monolaurate and preparation method of the same

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CN103169712A (en) * 2011-12-20 2013-06-26 重庆华邦制药有限公司 Dutasteride preparation used for increasing bioavailability and preparation method
CN103169712B (en) * 2011-12-20 2017-10-27 重庆华邦制药有限公司 Improve dutasteride's preparation of bioavilability and preparation method thereof

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KR20010014080A (en) 2001-02-26
WO1999008666A2 (en) 1999-02-25
CO4960657A1 (en) 2000-09-25
EP1007010A2 (en) 2000-06-14
AU9343098A (en) 1999-03-08
JP2002511101A (en) 2002-04-09
MA26531A1 (en) 2004-12-20
PE105699A1 (en) 1999-11-25
AR016629A1 (en) 2001-07-25
ZA987392B (en) 2000-02-17
WO1999008666A3 (en) 1999-04-15

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