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WO1995019759A1 - Procede pour solubiliser des agents pharmaceutiques difficilement solubles - Google Patents

Procede pour solubiliser des agents pharmaceutiques difficilement solubles Download PDF

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Publication number
WO1995019759A1
WO1995019759A1 PCT/US1995/001018 US9501018W WO9519759A1 WO 1995019759 A1 WO1995019759 A1 WO 1995019759A1 US 9501018 W US9501018 W US 9501018W WO 9519759 A1 WO9519759 A1 WO 9519759A1
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WO
WIPO (PCT)
Prior art keywords
peg
polyethylene glycol
difficultly soluble
process according
pharmaceutical actives
Prior art date
Application number
PCT/US1995/001018
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English (en)
Inventor
Dadi Jamshed Dhabhar
Original Assignee
The Procter & Gamble Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to CA002181241A priority Critical patent/CA2181241C/fr
Priority to AU16075/95A priority patent/AU706890B2/en
Priority to SK961-96A priority patent/SK96196A3/sk
Priority to BR9506564A priority patent/BR9506564A/pt
Priority to MX9602955A priority patent/MX9602955A/es
Priority to JP7519747A priority patent/JPH09508128A/ja
Application filed by The Procter & Gamble Company filed Critical The Procter & Gamble Company
Priority to EP95908124A priority patent/EP0741560A1/fr
Priority to PL95315635A priority patent/PL315635A1/xx
Priority to NZ279443A priority patent/NZ279443A/en
Publication of WO1995019759A1 publication Critical patent/WO1995019759A1/fr
Priority to NO963052A priority patent/NO963052L/no
Priority to FI962948A priority patent/FI962948L/fi

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Classifications

    • 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
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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

Definitions

  • the present invention relates to a process for enhancing the solubility of difficultly soluble pharmaceutical actives in a mixture of polyethylene glycol, polyvinylpyrrolidone, and propylene glycol.
  • Liquid, and especially concentrated liquid pharmaceutical compositions offer several advantages over solid compositions. Liquids are easy to swallow and provide an excellent vehicle for the uniform delivery of pharmaceutical actives. Moreover, liquids provide a rapid onset of pharmacologic action, since the composition does not first have to disintegrate and dissolve in the gastrointestinal tract. Likewise, concentrated liquid compositions offer certain distinct advantages. These compositions are ideally suited for incorporation into easy-to-swallow soft, flexible capsules. Encapsulation of this nature permits the accurate and uniform delivery of unit dose amounts of a pharmaceutical active, encompassing even those instances where relatively small amounts of a pharmaceutical active are to be delivered.
  • soft gelatin capsules are aesthetically appealing (especially when filled with a transparent liquid) and can be manufactured in a wide variety of sizes, shapes, and colors.
  • the current approach to this solubility problem is to force solubility into small volumes of solvent by means of a step-wise process incorporating heat.
  • This step-wise process consists of dissolving the difficultly soluble pharmaceutical active in polyethylene glycol with heat, followed by the addition of any additional pharmaceutical actives.
  • polyvinylpyrrolidone is dissolved in a solution of water and propylene glycol.
  • the polyvinylpyrrolidone solution is then added to the original batch solution to complete the process. Because the resultant concentrated liquid (or fill) is a supersaturated solution of the difficultly soluble pharmaceutical active, it is even more difficult to increase the resultant composition's concentration of the difficultly soluble active.
  • the present inventor has discovered that by using a polyvinylpyrrolidone with a specific viscosity average molecular weight of from about 5,000 to about 25,000 provides dissolution of significantly higher levels of the difficultly soluble pharmaceutical active.
  • an object of the present invention to describe a process which provides for increased solubility of difficultly soluble pharmaceutical actives.
  • a further object of the present invention is to enhance stability of the resultant composition by reducing the tendency of the difficultly soluble pharmaceutical active to precipitate out of solution.
  • the present invention relates to a process for enhancing the solubility of difficultly soluble pharmaceutical actives by combining and mixing until dissolved from about 1% to about 40% of at least one difficultly soluble pharmaceutical active in a solution comprising: i) from about 20% to about 70% of a polyethylene glycol; ii) from about 4% to about 20% of a polyvinylpyrrolidone having a viscosity average molecular weight from about 5,000 to about 25,000; and iii) from about 1% to about 10% of a propylene glycol.
  • the process preferably further comprises combining and mixing until dissolved the above solution with a separate admixture of from about 0.5% to about 20% of at least one additional pharmaceutical active in from about 1% to about 50% of an aqueous phase.
  • diffusely soluble pharmaceutical active describes an active having a solubility of less than or equal to 1% by weight in water at 25°C. This term is defined to also include the descriptive terms “sparingly soluble”; “slightly soluble”; “very slightly soluble”; “practically insoluble, or insoluble”; and their equivalents as defined in the USP XXII. p.8 ( 1990), this reference being incorporated herein by reference in its entirety.
  • the highly concentrated liquid pharmaceutical compositions of the present invention comprise the following essential, as well as optional, components.
  • polyethylene glycol An essential component of the present compositions is a polyethylene glycol.
  • Polyethylene glycols generally are clear, viscous liquids or white solids which are soluble in water and many organic solvents. These polymers correspond to the general formula:
  • polyethylene glycol 400 which is also known by the CTFA designation, PEG-8, has an average molecular weight range from 3SO-420 and an average value of n between 8.2 and 9. 1. See CTFA Cosmetic Ingredient Dictionary. Third Edition (1982), pp. 201-203; and The Merck Index. Tenth Edition, entry 7441, p. 1092 (1983); these two references being incorporated herein by reference in their entirety.
  • Polyethylene glycols useful herein are mixtures of those which are liquids at room temperature or have a melting point slightly thereabove.
  • Preferred mixtures include those polyethylene glycols having a molecular weight range of from about 300 to about 1000 and corresponding n values of from about 6 to about 20. More preferred are those of polyethylene glycols having a molecular weight range of from about 400 to about 1000 and corresponding n values of from about 8 to about 20. Most preferred are those of polyethylene giycols having a molecular weight range of from about 600 to about 1000 and corresponding n values of from about 12 to about 20.
  • Liquid and low-melting poly ⁇ ethylene glycols are commercially available from Union Carbide (Danbury, CT) under the Carbowax® trademark.
  • the process for preparing the highly concentrated liquid compositions of the present invention comprises adding from about 20% to about 70% polyethylene glycol, more preferably from about 30% to about 60%, and most preferably from about 35% to about 55%.
  • polyethylene glycol more preferably from about 30% to about 60%, and most preferably from about 35% to about 55%.
  • PVP polyvinylpyrrolidone
  • Polyvi ⁇ nylpyrrolidone has different solubility characteristics based on its polymeric structure.
  • Long-chain polyvinylpyrrolidone which is also known as povidone, has good solubility in water and a number of organic solvents.
  • Cross-linked polyvinylpyrrolidone which is also known as crospovidone, is insoluble in virtually all common solvents.
  • Both the soluble and insoluble forms of polyvinylpyrrolidone are commercially available from GAF Chemicals Company (Wayne, NJ) under the Plasdone® and Polyplasdone® trademarks, respectively, and from BASF Aktiengesellschaft (Ludwigshafen, Germany) under the Kollidon® trademark.
  • Soluble forms of polyvinylpyrrolidone include Plasdone® K-25, Plasdone® K-26/28, Plasdone® K-29/32, Plasdone® C- 15, Plasdone® C-30, Plasdone® C-90, Kollidon® 12 PF, Kollidon® 17 PF, Kollidon® 25, Kollidon® 30, and Kollidon® 90.
  • Insoluble forms of polyvinylpyrrolidone include Polyplasdone XL®, Polyplasdone XL ®10, Kollidon® CL, and Kollidon® CL-M. See “Tableting With Plasdone®”, GAF Technical Bulletin 2302- 1 1 OR 1 ( 1986); "Polyplasdone XL®, Polyplasdone XL® 10", GAF Technical Bulletin 2302-099 R2 (1984); and "Kollidon® Grades, Polyvinylpyrrolidone for the Pharmaceutical Industry", BASF Technical Bulletin MEF 129e, Register 2, May 1986 (Bn); these references being incorporated herein by reference in their entirety.
  • soluble forms of polyvinylpyrrolidone are preferred for use in the present inven- tion.
  • Preferred are soluble polyvinyl- pyrrolidones having an viscosity average molecular weight in the range from about 5000 to about 25,000; more preferred are those having an viscosity average molecular weight in the range from about 5000 to about 15,000; and most preferred are those having an viscosity average molecular weight from about 5,000 to about 10,000.
  • mixtures of two or more soluble polyvinylpyrrolidones of different average molecular weight can be employed.
  • the process for preparing the highly concentrated liquid compositions of the instant invention comprises adding from about 1% to about 28% of a soluble polyvi ⁇ nylpyrrolidone, more preferably from about 1% to about 15%, and most preferably from about 2% to about 10%.
  • the ratio of the total amount of polyethylene glycol to polyvinylpyr ⁇ rolidone should be at least about 2.5: 1.
  • CH 3 CHOHCH 2 OH is well known in the art for its solvent and/or humectant properties.
  • a colorless and viscous liquid, propylene glycol is miscible with water, alcohols and many organic solvents.
  • Propylene glycol is described in Hawlev's Condensed Chemical Dictionary, pp. 970-971, (Revised by Richard J. Lewis, Sr.) (12th ed. 1993, herein incorporated by reference.
  • Propylene glycol suitable for use in the present invention is obtainable from any number of suppliers, Dow Chemical being one. Difficultly Soluble Pharmaceutical Actives
  • compositions of the instant invention contain at least one difficultly soluble pharmaceutical active as an essential component.
  • these actives have a solubility less than or equal to about 1 percent by weight in water at 25°C.
  • Useful classes of pharmaceutically-active compounds which can be incorporated into the present compositions include analgesics, anti-inflammatory agents, anti-pyretics, calcium channel blockers, beta-blockers, antibacterials, antidepressants, antidiabetics, anti-emetics, antihistamines, cerebral stimulants, sedatives, anti-parasitics, expectorants, diuretics, decongestants, antitussives, muscle relaxants, anti-Parkinsonian agents, bronchodilators, cardiotonics, antibiotics, antivirals, nutritional supplements (such as vitamins, minerals, fatty acids, amino acids, and the like), and mixtures thereof.
  • Difficultly soluble pharmaceutical actives selected from the non-narcotic analgesics/nonsteroidal anti-inflammatory drugs are especially useful in the present invention. Examples of such drugs are disclosed in U.S. Patent No. 4,522,828, to Sunshine et al., issued June 1 1, 1985; this patent being incorporated herein by reference in its entirety
  • Examples of preferred difficultly soluble pharmaceutical actives useful in the present invention include, but are not limited to, acetaminophen, acetylsalicylic acid, ibuprofen, fenbuprofen, fenoprofen, flurbiprofen, indomethacin, ketoprofen, naproxen, their p armaceutically-acceptable salts, and mixtures thereof.
  • Acetaminophen is especially preferred for use in the present invention.
  • the process for preparing the highly concentrated liquid compositions of the instant invention comprises adding from about 1% to about 40% of a difficultly soluble pharma ⁇ ceutical active, more preferably from about 15% to about 35%, and most preferably from about 25% to about 35%. Additional Pharmaceutical Actives
  • compositions of the instant invention can optionally contain one or more additional pharmaceutical actives having a solubility greater than the difficultly soluble pharmaceutical actives described above.
  • these actives have a solubility greater than about 1 percent by weight in water at 25°C.
  • additional pharmaceutical actives may also be selected from among the pharmaceutical categories previously mentioned
  • additional pharmaceutical actives useful in the present in ⁇ vention include, but are not limited to, pseudoephedrine and its salts such as pseu- doephedrine hydrochloride; dextromethorphan and its salts such as dextromethorphan hydrobromide; doxylamine and its salts such as doxylamine succinate; phenindamine and its salts such as phenindamine hydrogen tartrate; pheniramine and its salts such as pheniramine maleate; chlorpheniramine and its salts such as chlorpheniramine maleate; ephedrine and its salts such as ephedrine sulfate; triprolidine and its salts such as triprolidine hydrochloride; diphenhydramine and it salts such as diphenhydramine hydrochloride, diphenhydramine citrate, and diphenhydramine 8-chlorotheophyllinate; phenyltoxyiamine and its salts; guaifen
  • the process for preparing the highly concentrated liquid compositions of the instant invention comprises adding one or more of these optionally additional pharmaceutical actives at a concentration of from about 0 5% to about 20% Coolants
  • the present invention may optionally incorporate a cooling agent or a combination of cooling agents Suitable cooling agents are those described in U S Patent 4.136.163. January 23, 1979, to Watson et al., U S Patent 4.230.668. October 28, 1980, to Rowsell et al. and U S Patent 4.032.661. to Rowsell et al., all of which are herein incorporated by reference.
  • a particularly preferred cooling agent is N-ethyl-p-menthane- 3-carboxamide (WS-3 supplied by Sterling Organics), taught by the above incorporated U.S. Patent 4.136.163
  • Another particularly preferred cooling agent is 3-1 - menthoxypropane 1,2-diol (TK- 10 supplied by Takasago Perfumery Co., Ltd., Tokyo, Japan). This material is described in detail in U S Patent 4.459.425. July 10, 1984 to Amano et al. and incorporated herein by reference Other Optional Components
  • compositions of the instant invention include coolants, colorings, flavorings, preservatives, lubricants, flow-enhancers, filling aids, anti- oxidants, essences, and other aesthetically pleasing components.
  • the highly concentrated liquid pharmaceutical compositions are prepared using art-recognized principles and methodologies in mixing the ingredients together and in choosing the type of mixing equipment to be used.
  • the difficultly soluble pharmaceutical active polyethylene glycol, propylene glycol and polyvinylpyrrolidone
  • additional pharmaceutical actives may then be added to this batch solution or dissolved separately in an aqueous phase. The process is completed once all additional pharmaceutical actives have been added, whether by direct addition to the original batch solution and/or by indirectly transferring the separately formed admixture to the original batch.
  • Preselected amounts of the highly concentrated liquid pharmaceutical compositions of the present invention can also be encapsulated in a soft gelatin shell.
  • the soft gelatin shell is essentially transparent so as to enhance the aesthetic qualities of the capsule.
  • the soft gelatin shells comprise the following essential, as well as optional, components.
  • Gelatin is an essential component of the soft gelatin shells of the instant invention.
  • the starting gelatin material used in the manufacture of soft capsules is obtained by the partial hydrolysis of collagenous material, such as the skin, white connective tissues, or bones of animals.
  • Gelatin material can be classified as Type A gelatin, which is obtained from the acid-processing of porcine skins and exhibits an isoelectric point between pH 7 and pH 9; and Type B gelatin, which is obtained from the alkaline-processing of bone and animal (bovine) skins and exhibits an isoelectric point between pH 4.7 and pH 5.2.
  • Blends of Type A and Type B gelatins can be used to obtain a gelatin with the requisite viscosity and bloom strength characteristics for capsule manufacture.
  • Gelatin suitable for capsule manufacture is commercially available from the Sigma Chemical Company, St. Louis, Mo.
  • the soft gelatin shell of the capsules of the instant invention comprises from about 20% to about 60% gelatin, more preferably from about 25% to about 50% gelatin, and most preferably from about 40% to about 50% gelatin.
  • the gelatin can be of Type A, Type B, or a mixture thereof with bloom numbers ranging from about 60 to about 300.
  • Plasticizer
  • a plasticizer is another essential component of the soft gelatin shells of the instant invention.
  • One or more plasticizers is incorporated to produce a soft gelatin shell.
  • the soft gelatin thus obtained has the required flexibility characteristics for use as an encapsulation agent.
  • Useful plasticizers of the present invention include glycerin, sorbitan, sorbitol, or similar low molecular weight polyols, and mixtures thereof.
  • the shell of the present invention comprises from about 10% to about 35% plasticizer, preferably from about 10% to about 25% plasticizer, and most preferably from about 10% to about 20% plasticizer.
  • a preferred plasticizer useful in the present invention is glycerin. Water
  • the soft gelatin shells of the instant invention also comprise water as an essential component Without being limited by theory, the water is believed to aid in the rapid dissolution or rupture of the soft gelatin shell upon contact with the gastrointestinal fluids encountered in the body
  • the shell of the present invention as initially prepared, comprises from about 15% to about 50% water, more preferably from about 25% to about 40% water, and most preferably from about 30% to about 40% water.
  • Other Optional Components are preferably from about 15% to about 50% water, more preferably from about 25% to about 40% water, and most preferably from about 30% to about 40% water.
  • the solubilized pharmaceutical compositions of the present invention can be en ⁇ capsulated within any conventional soft gelatin shell that is capable of substantially containing the composition for a reasonable period of time
  • the soft gelatin shells of the instant invention can be prepared by combining appropriate amounts of gelatin, water, plasticizer, and any optional components in a suitable vessel and agitating and/or stirring while heating to about 65°C until a uniform solution is obtained
  • This soft gelatin shell preparation can then be used for encapsulating the desired quantity of the solubilized fill composition employing standard encapsulation methodology to produce one-piece, hermetically-sealed, soft gelatin capsules
  • the gelatin capsules are formed into the desired shape and size so that they can be readily swallowed
  • the soft gelatin capsules of the instant invention are of a suitable size for easy swallowing and typically contain from about 100 mg to about 2000 mg of the solubilized pharmaceutical active composition
  • Soft gelatin capsules and encapsulation methods are described in P K Wilkinson et al , "Soft
  • a highly concentrated solution containing acetaminophen in combination with other pharmaceutical actives is prepared from the following ingredients' Ingredients Weight %
  • a solution of the polyethylene glycols, propylene glycol, and polyvinylpyrrolidone is prepared by mixing and warming these compositions to 70°C Acetaminophen is then dissolved into this solution, stirring and heating the solution to 120°C in the presence of nitrogen Once the acetaminophen is dissolved the solution is removed from the heat In a separate container, pseudoephedrine HC1, dextromethorphan HBr and doxylamine succinate are dissolved in water at room temperature by stirring Finally, this separate admixture is combined with the original batch solution and mixed until uniform Examples II-III are further examples of concentrated solutions containing acetaminophen in combination with other pharmaceutical actives and are manufactured in a manner substantially similar to Example I
  • Acetaminophen 31 25 Pseudoephedrine HC1 2 88 Dextromethorphan HBr 1 44 Doxylamine Succinate 0 60 Polyethylene Glycol 600 24 38
  • a highly concentrated solution containing acetaminophen and guaifenesin in combination with other pharmaceutical actives is prepared from the following ingredients Ingredients Weight %
  • a solution of polyethylene glycols, propylene glycol, and polyvinylpyrrolidone is prepared by mixing and warming to 70°C Acetaminophen is then dissolved into this solution, stirring and heating the solution to 120°C in the presence of nitrogen Once the acetaminophen is dissolved and the solution removed from heat, the guaifenesin is next added and dissolved.
  • pseudoephedrine HC1, dextromethorphan HBr and doxylamine succinate are dissolved in water at room temperature by stirring Finally, this separate admixture is combined with the original batch solution and mixed until uniform.
  • Example V is a further example of a concentrated solution containing aceta ⁇ minophen and guaifenesin in combination with other pharmaceutical actives and is manufactured in a manner substantially similar to Example IV Ingredients Weight %
  • a highly concentrated solution containing acetaminophen is prepared from the following ingredients
  • a solution of the polyethylene glycols, propylene glycol, and polyvinylpyrrolidone is prepared by mixing and warming these components to 70°C. Acetaminophen is then dissolved into this solution, stirring and heating the solution to 120°C in the presence of nitrogen gas. Once the acetaminophen is dissolved, the solution is removed from the heat. Finally, a measured quantity of the aqueous phase is combined with the original batch solution and mixed until uniform.
  • a highly concentrated solution containing acetaminophen and pseudoephedrine HC1 is prepared from the following ingredients Ingredients Weight %
  • Acetaminophen 3 1.25 Pseudoephedrine HC1 2.88 Polyethylene Glycol 600 25.45 Polyethylene Glycol 1000 23. 1 1 Propylene Glycol 4.33 Polyvinylpyrrolidone 1 8 17
  • a solution of the polyethylene glycols, propylene glycol, and polyvinylpyrrolidone is prepared by mixing and warming these components to 70°C. Acetaminophen is then dissolved into this solution, stirring and heating the solution to 120°C in the presence of nitrogen gas. Once the acetaminophen is dissolved, the solution is removed from the heat. In a separate container, pseudoephedrine HC1 is dissolved in water at room temperature by stirring. Finally, this separate admixture is combined with the original batch solution and mixed until uniform.
  • a soft gelatin capsule is first prepared form the following ingredients: Ingredients Weight %
  • the above ingredients are combined in a suitable vessel and heated with mixing at about 65°C to form a uniform solution.
  • the resulting solution is used to prepare soft gelatin capsules containing approximately 1040 mg. of the compositions of Examples I-VII.
  • the resulting soft gelatin capsules are suitable for oral administration.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention se rapporte à un procédé pour améliorer la solubilité d'agents pharmaceutiques difficilement solubles dans un mélange de polyéthylèneglycol et de propylèneglycol, en utilisant une polyvinylpyrrolidone ayant un poids moléculaire moyen en viscosité spécifique compris entre 5000 et environ 25000.
PCT/US1995/001018 1994-01-24 1995-01-24 Procede pour solubiliser des agents pharmaceutiques difficilement solubles WO1995019759A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
AU16075/95A AU706890B2 (en) 1994-01-24 1995-01-24 Process for solubilizing difficultly soluble pharmaceutical actives
SK961-96A SK96196A3 (en) 1994-01-24 1995-01-24 Process for solubilizing difficultly soluble pharmaceutical actives
BR9506564A BR9506564A (pt) 1994-01-24 1995-01-24 Processo para solubilizar ativos farmacêuticos de dificil solubilidade
MX9602955A MX9602955A (es) 1994-01-24 1995-01-24 Procedimiento para solubizar activos farmaceuticos dificilmente solubles.
JP7519747A JPH09508128A (ja) 1994-01-24 1995-01-24 難溶性医薬活性剤の溶解方法
CA002181241A CA2181241C (fr) 1994-01-24 1995-01-24 Procede pour solubiliser des agents pharmaceutiques difficilement solubles
EP95908124A EP0741560A1 (fr) 1994-01-24 1995-01-24 Procede pour solubiliser des agents pharmaceutiques difficilement solubles
PL95315635A PL315635A1 (en) 1994-01-24 1995-01-24 Method of solubilising hardly pharmaceutically active substances
NZ279443A NZ279443A (en) 1994-01-24 1995-01-24 Solubilizing difficultly soluble pharmaceutical agents using a mixture of polyethylene glycol, polyvinylpyrrolidone and propylene glycol
NO963052A NO963052L (no) 1994-01-24 1996-07-22 Fremgangsmåte for å solubilisere vanskelig opplöselige farmasöytisk aktive komponenter
FI962948A FI962948L (fi) 1994-01-24 1996-07-23 Menetelmä vaikealiukoisten farmaseuttisesti aktiivisten aineiden liuottamiseksi

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US18557694A 1994-01-24 1994-01-24
US08/185,576 1994-01-24

Publications (1)

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WO1995019759A1 true WO1995019759A1 (fr) 1995-07-27

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PCT/US1995/001018 WO1995019759A1 (fr) 1994-01-24 1995-01-24 Procede pour solubiliser des agents pharmaceutiques difficilement solubles

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EP (1) EP0741560A1 (fr)
JP (1) JPH09508128A (fr)
CN (1) CN1138827A (fr)
AU (1) AU706890B2 (fr)
BR (1) BR9506564A (fr)
CA (1) CA2181241C (fr)
CZ (1) CZ210496A3 (fr)
FI (1) FI962948L (fr)
MX (1) MX9602955A (fr)
NO (1) NO963052L (fr)
NZ (1) NZ279443A (fr)
PL (1) PL315635A1 (fr)
SK (1) SK96196A3 (fr)
WO (1) WO1995019759A1 (fr)

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997048390A1 (fr) * 1996-06-20 1997-12-24 Mcneil-Ppc Analgesiques combinant acetaminophene et meclozine
WO1998058637A1 (fr) * 1996-06-20 1998-12-30 Mcneil-Ppc Analgesique a base d'acetaminophene et de diphenhydramine
WO1999036060A1 (fr) 1998-01-20 1999-07-22 Applied Analytical Industries, Inc. Compositions liquides orales
US5962461A (en) * 1996-08-07 1999-10-05 Ascent Pediatrics, Inc. Pleasant-tasting aqueous liquid composition of a bitter-tasting drug
JPH11514013A (ja) * 1996-08-05 1999-11-30 エスセーエール ファルマトップ 新規なパラセタモールの安定な液体配合物とその製造方法
WO2000041692A3 (fr) * 1999-01-11 2000-11-30 Procter & Gamble Compositions possedant une stabilite amelioree
WO2000041694A3 (fr) * 1999-01-11 2000-11-30 Procter & Gamble Compositions possedant une stabilite amelioree
EP1059084A2 (fr) * 1999-06-10 2000-12-13 McNEIL-PPC, INC. Composition pharmaceutique liquide à absorption rapide, contenant une amine et un agent antiinflammatoire non-stéroidièn
WO2001015688A1 (fr) * 1999-09-02 2001-03-08 Banner Pharmacaps, Inc. Gels mous contenant de l'ibuprofene
GB2354710A (en) * 1999-07-29 2001-04-04 So Ge Val Sa Paracetamol solution in polyethylene glycol and/or polypropylene glycol for farm animals
WO2001066115A3 (fr) * 2000-03-07 2002-02-14 Bayer Ag Solutions d'acide acetylsalicylique
EP1196147A1 (fr) * 1999-07-16 2002-04-17 aaiPharma Inc. Compositions buvables
KR20020069387A (ko) * 2001-02-26 2002-09-04 진양제약주식회사 호박산독실아민 조성물 및 이 조성물을 함유한 연질캅셀제제
WO2003047502A1 (fr) * 2001-12-07 2003-06-12 Santos Ma Joyce Bedelia B Composition pharmaceutique liquide aqueuse a gout masque
US6846495B2 (en) 1999-01-11 2005-01-25 The Procter & Gamble Company Compositions having improved delivery of actives
WO2007065846A2 (fr) * 2005-12-09 2007-06-14 Basf Se Utilisation de copolymeres blocs de lactame polyvinylique et d'oxyde de polyalkylene comme solubilisants dans des composes peu solubles dans l'eau
US8158686B2 (en) 2005-11-04 2012-04-17 Basf Se Use of copolymers as solubilizers for slightly water-soluble compounds
US20120301544A1 (en) * 2010-01-19 2012-11-29 Accucaps Industries Limited Pharmaceutical formulations of loratadine for encapsulation and combinations thereof
US8637076B2 (en) 2006-06-01 2014-01-28 Cima Labs Inc. Prednisolone salt formulations
WO2014132163A1 (fr) * 2013-02-28 2014-09-04 Pfizer Inc. Stabilité améliorée de compositions liquides nouvelles
WO2016063057A1 (fr) * 2014-10-21 2016-04-28 Reckitt Benckiser Llc Nouvelle formulation pharmaceutique
US11278506B2 (en) 2015-10-09 2022-03-22 Rb Health (Us) Llc Pharmaceutical formulation
US11896566B2 (en) * 2010-01-19 2024-02-13 Catalent Ontario Limited Pharmaceutical formulations of naproxen for soft gel encapsulation and combinations thereof
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EP1959935A2 (fr) * 2005-10-26 2008-08-27 Banner Pharmacaps Inc. Systeme matriciel double a liberation controlee a base d'excipients hydrophiles, pour garnir une gelule
JP2008184430A (ja) * 2007-01-30 2008-08-14 Ss Pharmaceut Co Ltd ソフトカプセル
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EP2827862B1 (fr) 2012-03-20 2023-12-27 Eagle Pharmaceuticals, Inc. Formulations de bendamustine
TWI586379B (zh) * 2015-06-29 2017-06-11 永信藥品工業股份有限公司 一種製作難溶藥物固體劑型的方法
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WO1998058637A1 (fr) * 1996-06-20 1998-12-30 Mcneil-Ppc Analgesique a base d'acetaminophene et de diphenhydramine
WO1997048390A1 (fr) * 1996-06-20 1997-12-24 Mcneil-Ppc Analgesiques combinant acetaminophene et meclozine
JPH11514013A (ja) * 1996-08-05 1999-11-30 エスセーエール ファルマトップ 新規なパラセタモールの安定な液体配合物とその製造方法
US5962461A (en) * 1996-08-07 1999-10-05 Ascent Pediatrics, Inc. Pleasant-tasting aqueous liquid composition of a bitter-tasting drug
EP1049459A4 (fr) * 1998-01-20 2005-04-20 Applied Analytical Ind Inc Compositions liquides orales
WO1999036060A1 (fr) 1998-01-20 1999-07-22 Applied Analytical Industries, Inc. Compositions liquides orales
EP1049459A1 (fr) * 1998-01-20 2000-11-08 Applied Analytical Industries, Inc. Compositions liquides orales
WO2000041692A3 (fr) * 1999-01-11 2000-11-30 Procter & Gamble Compositions possedant une stabilite amelioree
WO2000041694A3 (fr) * 1999-01-11 2000-11-30 Procter & Gamble Compositions possedant une stabilite amelioree
AU771478B2 (en) * 1999-01-11 2004-03-25 Procter & Gamble Company, The Compositions having improved stability
US6846495B2 (en) 1999-01-11 2005-01-25 The Procter & Gamble Company Compositions having improved delivery of actives
EP1059084A2 (fr) * 1999-06-10 2000-12-13 McNEIL-PPC, INC. Composition pharmaceutique liquide à absorption rapide, contenant une amine et un agent antiinflammatoire non-stéroidièn
US7060730B2 (en) 1999-06-10 2006-06-13 Cathy Klech Gelotte Rapidly absorbed liquid compositions
EP1059084A3 (fr) * 1999-06-10 2002-11-06 McNEIL-PPC, INC. Composition pharmaceutique liquide à absorption rapide, contenant une amine et un agent antiinflammatoire non-stéroidièn
EP1196147A4 (fr) * 1999-07-16 2005-04-20 Aaipharma Inc Compositions buvables
EP1196147A1 (fr) * 1999-07-16 2002-04-17 aaiPharma Inc. Compositions buvables
GB2354710A (en) * 1999-07-29 2001-04-04 So Ge Val Sa Paracetamol solution in polyethylene glycol and/or polypropylene glycol for farm animals
GB2354710B (en) * 1999-07-29 2004-05-12 So Ge Val Sa Paracetamol solution in polyethylene glycol and/or polypropylene glycol for farm animals
WO2001015688A1 (fr) * 1999-09-02 2001-03-08 Banner Pharmacaps, Inc. Gels mous contenant de l'ibuprofene
US6251426B1 (en) 1999-09-02 2001-06-26 Banner Pharmacaps, Inc. Ibuprofen-containing softgels
WO2001066115A3 (fr) * 2000-03-07 2002-02-14 Bayer Ag Solutions d'acide acetylsalicylique
KR20020069387A (ko) * 2001-02-26 2002-09-04 진양제약주식회사 호박산독실아민 조성물 및 이 조성물을 함유한 연질캅셀제제
WO2003047502A1 (fr) * 2001-12-07 2003-06-12 Santos Ma Joyce Bedelia B Composition pharmaceutique liquide aqueuse a gout masque
US8158686B2 (en) 2005-11-04 2012-04-17 Basf Se Use of copolymers as solubilizers for slightly water-soluble compounds
US8632763B2 (en) 2005-11-04 2014-01-21 Basf Se Use of a copolymer in the form of a solubiliser for a poorly water-soluble compound
WO2007065846A2 (fr) * 2005-12-09 2007-06-14 Basf Se Utilisation de copolymeres blocs de lactame polyvinylique et d'oxyde de polyalkylene comme solubilisants dans des composes peu solubles dans l'eau
WO2007065846A3 (fr) * 2005-12-09 2007-11-29 Basf Ag Utilisation de copolymeres blocs de lactame polyvinylique et d'oxyde de polyalkylene comme solubilisants dans des composes peu solubles dans l'eau
US8637076B2 (en) 2006-06-01 2014-01-28 Cima Labs Inc. Prednisolone salt formulations
US11896566B2 (en) * 2010-01-19 2024-02-13 Catalent Ontario Limited Pharmaceutical formulations of naproxen for soft gel encapsulation and combinations thereof
US20120301544A1 (en) * 2010-01-19 2012-11-29 Accucaps Industries Limited Pharmaceutical formulations of loratadine for encapsulation and combinations thereof
US12138248B2 (en) 2010-01-28 2024-11-12 Eagle Pharmaceuticals, Inc. Formulations of bendamustine
WO2014132163A1 (fr) * 2013-02-28 2014-09-04 Pfizer Inc. Stabilité améliorée de compositions liquides nouvelles
AU2014222418B2 (en) * 2013-02-28 2016-06-23 Pf Consumer Healthcare 1 Llc Enhanced stability of novel liquid compositions
AU2016208390B2 (en) * 2013-02-28 2017-04-13 Pf Consumer Healthcare 1 Llc Enhanced stability of novel liquid compositions
US9744133B2 (en) 2013-02-28 2017-08-29 Pfizer Inc. Enhanced stability of novel liquid compositions
US9308166B2 (en) 2013-02-28 2016-04-12 Pfizer Inc. Enhanced stability of novel liquid compositions
WO2016063057A1 (fr) * 2014-10-21 2016-04-28 Reckitt Benckiser Llc Nouvelle formulation pharmaceutique
US11278506B2 (en) 2015-10-09 2022-03-22 Rb Health (Us) Llc Pharmaceutical formulation
US12257218B2 (en) 2015-10-09 2025-03-25 Rb Health (Us) Llc Pharmaceutical formulation

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NO963052L (no) 1996-09-24
AU1607595A (en) 1995-08-08
FI962948A0 (fi) 1996-07-23
NO963052D0 (no) 1996-07-22
MX9602955A (es) 1997-06-28
CZ210496A3 (en) 1996-12-11
PL315635A1 (en) 1996-11-25
JPH09508128A (ja) 1997-08-19
SK96196A3 (en) 1997-03-05
BR9506564A (pt) 1997-09-02
FI962948L (fi) 1996-07-23
AU706890B2 (en) 1999-07-01
CA2181241A1 (fr) 1995-07-27
CA2181241C (fr) 2000-04-25
NZ279443A (en) 1998-04-27
EP0741560A1 (fr) 1996-11-13
CN1138827A (zh) 1996-12-25

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