WO1993000072A1 - Process for solubilizing difficultly soluble pharmaceutical actives - Google Patents

Process for solubilizing difficultly soluble pharmaceutical actives Download PDF

Info

Publication number
WO1993000072A1
WO1993000072A1 PCT/US1992/004771 US9204771W WO9300072A1 WO 1993000072 A1 WO1993000072 A1 WO 1993000072A1 US 9204771 W US9204771 W US 9204771W WO 9300072 A1 WO9300072 A1 WO 9300072A1
Authority
WO
WIPO (PCT)
Prior art keywords
polyethylene glycol
solvent
polyvinylpyrrolidone
peg
mixtures
Prior art date
Application number
PCT/US1992/004771
Other languages
French (fr)
Inventor
Scott Douglas Coapman
Original Assignee
Richardson Vicks, Inc.
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
Application filed by Richardson Vicks, Inc. filed Critical Richardson Vicks, Inc.
Priority to EP92913574A priority Critical patent/EP0591346A1/en
Publication of WO1993000072A1 publication Critical patent/WO1993000072A1/en

Links

Classifications

    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—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
    • 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
    • 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

Definitions

  • the present invention relates to a process for solubilizing at least one difficultly soluble pharmaceutical active in a mixture of polyethylene glycol and polyvinylpyrrolidone.
  • the present invention also relates to a process for encapsulating these solubilized pharmaceutical compositions within soft gelatin shells, which are optionally transparent. Both the resulting compositions and their capsules provide an effective means for oral delivery of a wide variety of difficultly soluble pharmaceutical actives.
  • Liquid, and especially concentrated liquid pharmaceutical compositions offer many advantages over solid compositions. Liquids are easy to swallow and provide an excellent vehicle for the uniform delivery of pharmaceutical actives. Liquids provide a rapid onset of pharmacologic action, since the composition does not first have to disintegrate and dissolve in the gastrointestinal tract. Concentrated liquid compositions are ideally suited for encapsulation within a soft gelatin shell, to provide a portable and easy-to-swallow soft, flexible capsule. Encapsulation would also permit the accurate and uniform delivery of a unit dose of a pharmaceutical active, an advantage which becomes especially important when relatively small amounts of an active are to be delivered. Additionally, 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.
  • liquid compositions of the desired pharmaceutical active.
  • Many pharmaceutical actives are poorly soluble and therefore require relatively large volumes of solvent for dissolution.
  • the choice of solvents available for use in liquid compositions is limited by safety, compatibility, stability, and economic concerns.
  • the use of large volumes of solvents for solubilizing pharmaceutical actives is undesirable because the resulting solutions would be so dilute as to require impractically large dosages for delivering a therapeutically effective amount of active. It would thus be difficult, if not impossible, to encapsulate such large volumes into only one or two gelatin capsules and yet have them be of a reasonable size for easy swa lowing.
  • water-miscible co-solvents such as ethanol
  • these co-solvents may not be compatible with the desired pharmaceutical actives.
  • a more important disadvantage of water and volatile water-miscible co-solvents is that they are incompatible with soft gelatin capsules. Even though it may be possible to prepare soft gelatin capsules containing these solvents, over time the capsules gradually soften and deform, and develop leaks as these solvents dissolve the soft gelatin shell.
  • solubilizing system for pharmaceutical actives which would also be compatible with soft gelatin shells.
  • Many processes for solubilizing pharmaceutical actives employ heat.
  • heating the mixture is not always feasible or desirable because of stability concerns and the additional equipment, time, and costs associated with utilizing a heating process.
  • the solubilization process of the present invention overcomes the disadvantages of the prior art by not requiring the use of water as a solvent, except for the minor amounts of water normally present in the materials employed and/or which is absorbed from the environment.
  • the concentrated pharmaceutical compositions of the instant invention are substantially free of water.
  • the process of the present invention does not require a heating step.
  • Another object of the present invention is to provide a solubilization process which does not require water as a solvent or the use of a heating step.
  • a further object of the present invention is to provide a process for preparing soft gelatin capsules containing a solution of a difficultly soluble pharmaceutical active, in which the soft gelatin shell is optionally transparent.
  • a still further object of the present invention is to provide pharmaceutical compositions containing difficultly soluble pharmaceutical actives.
  • An even further object of the present invention is to provide soft gelatin capsules containing a solution of a difficultly soluble pharmaceutical active, in which the soft gelatin shell is optionally transparent.
  • the present invention relates to a process for solubilizing difficultly soluble pharmaceutical actives, comprising the steps of:
  • the present invention also relates to a process for preparing soft gelatin capsules containing a solution of a difficultly soluble pharmaceutical active, and to the compositions and the filled capsules themselves.
  • substantially free of water describes highly concentrated pharmaceutical compositions which, as initially prepared, do not contain any water, except for the minor amounts of water normally present in the materials employed in their preparation and/or which is gradually absorbed from the environment or the optional gelatin shell; i.e., less than from about 0.1% to about 8% water, prefereably less than from about 0.1% to about 6% water, more preferably less than from about 0.1% to about 4% water, and most preferably less than from about 0.1% to about 2% water.
  • the term "as initially prepared”, as used herein, is defined to mean the period of time from when the evaporation step is completed to about 5 minutes thereafter.
  • 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 380-420 and an average value of n between 8.2 and 9.1.
  • the polyethylene glycols useful herein are those which are liquids at room temperature or have a melting point slightly thereabove. Preferred are the polyethylene glycols having a molecular weight range from about 300 to about 1000 and corresponding n values from about 6 to about 20. More preferred are the polyethylene glycols having a molecular weight range from about 400 to about 1000 and corresponding n values from about 8 to about 20. Most preferred are the polyethylene glycols having a molecular weight range from about 600 to about 1000 and corresponding n values from about 12 to about 20. Most especially preferred is a polyethylene glycol having a molecular weight of about 600 and a corresponding n value of about 12.
  • mixtures of two or more polyethylene glycols of different average molecular weight range or n value can also be employed in the present invention.
  • Liquid and low-melting polyethylene glycols are commercially available from Union Carbide (Danbury, CT) under the CarbowaxR trademark.
  • S_g ⁇ "Carbowax ⁇ Polyethylene Glycols", Union Carbide Technical Bulletin f-4772M-ICD 11/86-20M, this reference being incorporated herein by reference in its entirety.
  • Polyethylene glycols having an average molecular weight below about 300 are not desirable for use in the instant invention since such polyethylene glycols tend to diffuse into, plasticize, and ultimately disrupt the soft gelatin shells which can be employed to encapsulate the compositions described herein.
  • 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 40% to about 50%.
  • the resulting highly concentrated liquid compositions of the present invention comprise from about 25% to about 87.5% polyethylene glycol, more preferably from about 37.5% to about 75%, and most preferably from about 50% to about 75%.
  • PVP polyvinylpyrrolidone
  • Polyvinylpyrrolidones are described in L. Blecher et al . in Handbook of Water-Soluble Gums & Resins. R.L. Davidson, Ed. (McGraw-Hill, New York, 1980) pp. 21/1-21/21, this reference being incorporated herein by reference in its entirety. Polyvinylpyrrolidone 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.
  • polyvinylpyrrolidone Both the soluble and insoluble forms of polyvinylpyrrolidone are commercially available from GAF Chemicals Company (Wayne, NJ) under the PlasdoneR and Polypiasdone R trademarks, respectively, and from BASF Aktiengesellschaft (Ludwigshafen, Germany) under the KollidonR trademark.
  • Soluble forms of polyvinylpyrrolidone include PlasdoneR K-25, PlasdoneR K-26/28, PlasdoneR K-29/32, PlasdoneR C-15, PlasdoneR C-30, PlasdoneR C-90, KollidonR 12 PF, KollidonR 17 PF, KollidonR 25, KollidonR 30, and KollidonR 90.
  • polyvinylpyrrolidone insoluble forms include Polyplasdone XL R , Polyplasdone XL R 10, KollidonR CL, and KollidonR CL-M. £ ⁇ £ “Tableting With PlasdoneR”, GAF Technical Bulletin 2302-110R1 (1986); "Polyplasdone XL R , Polyplasdone XL ⁇ IO”, GAF Technical Bulletin 2302-099 R2 (1984); and "KollidonR Grades, Polyvinylpyrrolidone for the Pharmaceutical
  • soluble forms of polyvinylpyrrolidone are preferred for use in the present invention.
  • Preferred are soluble polyvinyl- pyrrolidones having an average molecular weight in the range from about 2900 to about 1,100,000; more preferred are those having an average molecular weight in the range from about 9000 to about 45,000; and most preferred are those having an average molecular weight of about 29,000.
  • 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 polyvinylpyrrolidone, more preferably from about 1% to about 10%, and most preferably from about 1% to about
  • compositions of the instant invention comprise from about
  • 1.25% to about 35% of a soluble polyvinylpyrrolidone more preferably from about 1.25% to about 12.5%, and most preferably from about 1.25% to about 6.25%.
  • compositions of the instant invention contain at least one difficultly soluble pharmaceutical active as an essential component. In general, these actives have a solubility less than or equal to about 1 percent by weight in water at 25°C.
  • compositions useful classes 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.
  • analgesics such as 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,
  • 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 11, 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 pharmaceutically-acceptable salts, and mixtures thereof.
  • Acetaminophen is especially preferred for use in the compositions of 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 pharmaceutical active, more preferably from about 15% to about 35%, and most preferably from about 20% to about 30%.
  • the resulting highly concentrated liquid compositions of the instant invention comprise from about 1.25% to about 50% of a difficultly soluble pharmaceutical active, more preferably from about 18.75% to about 43.75%, and most preferably from about 25% to about 37.5%.
  • Solvents A solvent selected from the group consisting of the monohydric alcohols having from one to four carbon atoms, and mixtures thereof, is an essential component of the processes of the instant invention.
  • a sufficient quantity of solvent is utilized to aid in the solubilization of the essential components.
  • “sufficient” is meant a quantity of solvent that will ensure solubility of the components of the composition and yet not dilute the composition to the point where it occupies an unreasonably large volume.
  • the solvent is removed using standard evaporation techniques until the composition is substantially free from solvent.
  • substantially free from solvent is herein defined to mean that the compositions of the present invention comprise within after about 5 minutes of the evaporation step no more than from about 0.1% to about 6% of solvent after the evaporation step. Ethanol is most preferred as the solvent for use in the processes of the instant invention.
  • the process for preparing the highly concentrated liquid compositions of the instant invention comprises adding from about 1% to about 50% of solvent, more preferably from about 5% to about 40%, and most preferably from about 10% to about 30%.
  • the resulting highly concentrated liquid compositions of the instant invention comprise no more that from about 0.1% to about 6% solvent. Additional Pharmaceutical Actives
  • compositions of the instant invention can also 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.
  • Useful classes of additional pharmaceutically-active compounds include analgesics, anti-inflammatory agents, antipyretics, calcium channel blockers, beta-blockers, antibacterials, antidepressants, antidlabetlcs, anti-emetics, antihistamines, cerebral stimulants, sedatives, anti-parasitics, expectorants, diruetics, decongestants, antltussives, 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.
  • additional pharmaceutical actives useful in the present invention include, but are not limited to, pseudoephedrine and its salts such as pseudoephedrine hydrochloride; dextromethorphan and its salts such as dextromethorphan hydrobromide; doxylamine and its salts such as doxyla ine 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; phenyltoxyl- amine and its salts; guaifenesin; phenyl
  • Preferred additional pharmaceutical actives are dextromethorphan hydrobromide, doxylamine succinate, pseudoephe- drine hydrochloride, chlorpheniramine maleate, guaifenesin, tripro ⁇ lidine hydrochloride, diphenydramine hydrochloride and mixtures thereof.
  • the process for preparing the highly concentrated liquid compositions of the instant invention optionally comprises adding from about 0.5% to about 20% of a second pharmaceutical active, or mixtures thereof.
  • the resulting highly concentrated liquid compositions of the instant invention can optionally comprise from about 0.625% to about 25% of a second pharmaceutical active, or mixtures thereof.
  • compositions of the instant invention include 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, polyvinylpyrrolidone, and solvent are combined and mixed until dissolved to form a homogeneous solution.
  • Any optional components can either be added initially or after the essential components are combined.
  • the solvent is removed from the resulting homogeneous solution until the residual amount of solvent is present at no more than from about 0.1 percent to about 6 percent by weight of the composition.
  • the solvents can be removed using any art-recognized evaporation techniques including, but not limited to, rotary evaporation, spray-drying, flash evaporation, film evaporation, freeze-drying, thin film evaporation, forced circulation evaporation, wiped film evaporation, falling film evaporation, and the like.
  • the resulting solution of the difficultly soluble pharmaceutical active, and any optional components is substantially free from the added alcoholic solvent, i.e., contains no more that from about 0.1 percent to about 6 percent by weight of solvent. This resulting solution is suitable for encapsulation in a soft gelatin capsule using standard encapsulation techniques.
  • Soft Gelatin Capsules 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.
  • 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.
  • the solubilized pharmaceutical compositions of the present invention can be encapsulated 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., "Softgels: Manufacturing Considerations", Drugs and the Pharmaceutical Sciences. 41 (Specialized Drug Delivery Systems!. P. Tyle, Ed. (Marcel Dekker, Inc., New York, 1990) pp.409-449; F.S. Horn et al., "Capsules, Soft", Encyclopedia of Pharmaceutical Technology, vol. 2, J. Swarbrick and J.C. Boylan, eds. (Marcel Dekker, Inc., New York, 1990) pp.
  • Ingredients are identified by chemical or CTFA name.
  • a highly concentrated solution containing acetaminophen is prepared from the following ingredients.
  • Acetaminophen 26.00 Polyethylene Glycol 600 52.00
  • acetaminophen polyethylene glycol 600, polyvinyl- pyrrolidone, and ethanol are combined in a suitable vessel and mixed at room temperature until a homogeneous solution is obtained. Next, the ethanol is removed by rotary evaporation at room temperature.
  • the resulting acetaminophen composition is substantially free from ethanol and water, is suitable for oral administration, and contains about 32.10% acetaminophen, 64.20% polyethylene glycol 600, and about 3.70% polyvinylpyrrolidone.
  • a highly concentrated solution containing acetaminophen in combination with other pharmacutical actives is prepared from the following ingredients.
  • acetaminophen, pseudoephedrine hydrochloride, dextromethorphan hydrobromide, doxylamine succinate, polyethylene glycol 600, polyvinylpyrrolidone, and ethanol are combined in a suitable vessel and mixed at room temperature until a uniform solution is formed. Next, the ethanol is removed by rotary evaporation at room temperature.
  • the resulting pharmaceutical composition is substantially free from ethanol and water, is suitable for oral administration, and contains about 31.82% acetaminophen, 3.82% pseudoephedrine hydrochloride, 1.90% dextromethorphan hydrobromide, 0.48% doxylamine succinate, 58.80% polyethylene glycol 600, and 3.18% polyvinylpyrrolidone.
  • EXAMPLE IV EXAMPLE IV
  • a gelatin solution is prepared as described in Example II. Using standard encapsulation methodology, this gelatin solution is used to prepare soft gelatin capsules containing approximately 1000 mg of the pharmaceutical composition of Example III. The resulting soft gelatin pharmaceutical capsules are suitable for oral administration.
  • PlasdoneR K-29/32 Available as PlasdoneR K-29/32 from GAF Chemicals Co.
  • the acetaminophen, pseudoephedrine hydrochloride, dextro ⁇ methorphan hydrobromide, doxylamine succinate, polyethylene glycol 600, polyvinylpyrrolidone, propylene glycol, and ethanol are combined in a suitable vessel and mixed at room temperature until a homogeneous solution is formed. Next, the ethanol is removed by rotary evaporation.
  • the resulting pharmaceutical composition is substantially free from ethanol and water, is suitable for oral administration, and contains about 29.00% acetaminophen, 3.48% pseudoephedrine hydrochloride, 1.74% dextromethorphan hydrobromide, 0.72% doxylamine succinate, 58.09% polyethylene glycol 600, 2.32% polyvlnyl- pyrrolldone, and 4.64% propylene glycol.
  • a gelatin solution is prepared as described in Example II. Using standard encapsulation methodology, this gelatin solution is used to prepare soft gelatin capsules containing approximately 1000 mg of the pharmaceutical composition of Example V. The resulting soft gelatin pharmaceutical capsules are suitable for oral administration.
  • a highly concentrated solution containing acetaminophen in combination with other phamaceutical actives is prepared from the following ingredients.
  • acetaminophen, pseudoephedrine hydrochloride, dextro ⁇ methorphan hydrobromide, guaifenesin, polyethylene glycol 600, polyvinylpyrrolidone, propylene glycol, and ethanol are combined in a suitable vessel and mixed at room temperature until a homogeneous solution is formed. Next, the ethanol is removed by rotary evaporation.
  • the resulting pharmaceutical composition is substantially free from ethanol and water, is suitable for oral administration, and contains about 27.77% acetaminophen, 3.34% pseudoephedrine hydrochloride, 1.11% dextromethorphan hydrobromide, 11.11% guaifenesin, 49.99% polyethylene glycol 600, 2.22% polyvinylpyrrolidone, and 4.45% propylene glycol.
  • EXAMPLE VIII Soft Gelatin Capsule Containing a Solubilized Pharmaceutical Composition
  • a gelatin solution is prepared as described in Example II. Using standard encapsulation methodology, this gelatin solution is used to prepare soft gelatin capsules containing approximately 1000 mg of the pharmaceutical composition of Example VII. The resulting soft gelatin pharmaceutical capsules are suitable for oral administration.
  • a highly concentrated solution containing acetaminophen in combination with other phamaceutical actives is prepared from the following ingredients.
  • acetaminophen, pseudoephedrine hydrochloride, dextro ⁇ methorphan hydrobromide, chlorpheniramine maleate, polyethylene glycol 600, polyvinylpyrrolidone, propylene glycol, and ethanol are combined in a suitable vessel and mixed at room temperature until a homogeneous solution is formed. Next, the ethanol is removed by rotary evaporation.
  • the resulting pharmaceutical composition is substantially free from ethanol and water, is suitable for oral administration, and contains about 31.58% acetaminophen, 3.79% pseudoephedrine hydrochloride, 1.90% dextromethorphan hydrobromide, 0.25% chlorpheniramine maleate, 54.90% polyethylene glycol 600, 2.53% polyvinylpyrrolidone, and 5.05% propylene glycol.
  • composition A gelatin solution is prepared as described in Example II. Using standard encapsulation methodology, this gelatin solution is used to prepare soft gelatin capsules containing approximately 1000 mg of the pharmaceutical composition of Example IX. The resulting soft gelatin pharmaceutical capsules are suitable for oral administration.

Abstract

The present invention relates to a process for solubilizing at least one difficultly soluble pharmaceutical active in a mixture of polyethylene glycol and polyvinylpyrrolidone. The process does not require water as a solvent or the use of a heating step. In further embodiments, the present invention also relates to a process for encapsulating these solubilized pharmaceutical compositions within soft gelatin shells, which are preferably transparent. Both the resulting compositions and their capsules provide an effective means for oral delivery of a wide variety of difficultly soluble pharmaceutical actives.

Description

PROCESS FOR SOLUBILIZING DIFFICULTLY SOLUBLE PHARMACEUTICAL ACTIVES
TECHNICAL FIELD The present invention relates to a process for solubilizing at least one difficultly soluble pharmaceutical active in a mixture of polyethylene glycol and polyvinylpyrrolidone. In further embodiments, the present invention also relates to a process for encapsulating these solubilized pharmaceutical compositions within soft gelatin shells, which are optionally transparent. Both the resulting compositions and their capsules provide an effective means for oral delivery of a wide variety of difficultly soluble pharmaceutical actives.
BACKGROUND OF THE INVENTION Liquid, and especially concentrated liquid pharmaceutical compositions offer many advantages over solid compositions. Liquids are easy to swallow and provide an excellent vehicle for the uniform delivery of pharmaceutical actives. Liquids provide a rapid onset of pharmacologic action, since the composition does not first have to disintegrate and dissolve in the gastrointestinal tract. Concentrated liquid compositions are ideally suited for encapsulation within a soft gelatin shell, to provide a portable and easy-to-swallow soft, flexible capsule. Encapsulation would also permit the accurate and uniform delivery of a unit dose of a pharmaceutical active, an advantage which becomes especially important when relatively small amounts of an active are to be delivered. Additionally, 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.
However, despite these advantages of liquid compositions, it is not always possible to prepare a liquid composition of the desired pharmaceutical active. Many pharmaceutical actives are poorly soluble and therefore require relatively large volumes of solvent for dissolution. Also, the choice of solvents available for use in liquid compositions is limited by safety, compatibility, stability, and economic concerns. Furthermore, the use of large volumes of solvents for solubilizing pharmaceutical actives is undesirable because the resulting solutions would be so dilute as to require impractically large dosages for delivering a therapeutically effective amount of active. It would thus be difficult, if not impossible, to encapsulate such large volumes into only one or two gelatin capsules and yet have them be of a reasonable size for easy swa lowing.
One approach to overcoming these solubility problems has been to incorporate water, water-miscible co-solvents, and surfactants into the compositions. See, U.S. Patent No. 4,794,117, to Corbiere, issued December 27, 1988 which discloses the solubilization of hydrophobic pharmaceuticals in aqueous solutions of polyethylene glycol at controlled pH; U.S. Patent No. 4,690,823, to Lohner et al., issued September 1, 1987 which discloses the solubilization of ibuprofen in a mixture of polyethylene glycol and a surfactant; U.S. Patent No. 3,784,684, to Bossert et al., issued January 8, 1974 which discloses the solubilization1 of a pharmaceutical active in a mixture of polyethylene glycol and an alcohol having 2-8 carbons and 1-3 hydroxy groups; PCT Application No. W088/02625, to Yu et al., published April 21, 1988 which discloses the solubilization of an ionized or partly-ionized pharmaceutical active in a mixture of water, polyethylene glycol, and polyvinylpyrrolidone; and European Patent Application No. 152,292, to Rogers, published August 21, 1985 which discloses acetaminophen formulations containing polyethylene glycol, an acrylic acid resin, and a surfactant.
In many instances it may not be possible or desirable to incorporate water, water-miscible co-solvents, or surfactants into a pharmaceutical composition. For example, water-miscible co-solvents, such as ethanol, have the disadvantage of being relatively volatile, thereby resulting in concentration changes in the actives over time. Also, these co-solvents may not be compatible with the desired pharmaceutical actives. A more important disadvantage of water and volatile water-miscible co-solvents is that they are incompatible with soft gelatin capsules. Even though it may be possible to prepare soft gelatin capsules containing these solvents, over time the capsules gradually soften and deform, and develop leaks as these solvents dissolve the soft gelatin shell. Thus, it would be highly desirable to develop a solubilization process which does not require the use of water; and in processes where water-miscible co-solvents are used, it would be highly desirable to develop a process in which the water-miscible solvents are ultimately removed from the final compositions.
Previous investigators have attempted to circumvent these incompatibility problems by modifying the composition of the capsule shell. For example, U.S. Patent No. 3,865,603, to Szymanski et al., issued February 11, 1975 discloses gelatin compositions which are extended with chemically modified fluidity starches; U.S. Patent No. 2,580,683, to Kreuger, issued January 1, 1952 discloses gelatin compositions modified by the addition of non-hygroscopic water soluble substances; and Japanese Patent No. 84044096, to Morishita, issued January 26, 1984 discloses gelatin shells modified with tannic acid, and sugar and/or sugar derivatives. However, it may not always be desirable, feasible or economical to modify the soft gelatin shell with such additives. Thus, it would be highly desirable to find a solubilizing system for pharmaceutical actives which would also be compatible with soft gelatin shells. Many processes for solubilizing pharmaceutical actives employ heat. However, heating the mixture is not always feasible or desirable because of stability concerns and the additional equipment, time, and costs associated with utilizing a heating process. Thus, it would be highly desirable to develop a solubilization process not requiring the use of heat.
The solubilization process of the present invention overcomes the disadvantages of the prior art by not requiring the use of water as a solvent, except for the minor amounts of water normally present in the materials employed and/or which is absorbed from the environment. Thus, the concentrated pharmaceutical compositions of the instant invention are substantially free of water. Importantly, the process of the present invention does not require a heating step.
It is therefore an object of the present invention to provide a process for solubilizing difficultly soluble pharmaceutical actives. Another object of the present invention is to provide a solubilization process which does not require water as a solvent or the use of a heating step. A further object of the present invention is to provide a process for preparing soft gelatin capsules containing a solution of a difficultly soluble pharmaceutical active, in which the soft gelatin shell is optionally transparent. A still further object of the present invention is to provide pharmaceutical compositions containing difficultly soluble pharmaceutical actives. An even further object of the present invention is to provide soft gelatin capsules containing a solution of a difficultly soluble pharmaceutical active, in which the soft gelatin shell is optionally transparent.
These and other objects of this invention will become apparent in light of the following disclosure.
SUMMARY OF THE INVENTION The present invention relates to a process for solubilizing difficultly soluble pharmaceutical actives, comprising the steps of:
(a) combining and mixing until dissolved
(i) from about 1% to about 40% of at least one difficultly soluble pharmaceutical active, (ii) from about 20% to about 70% of a polyethylene glycol,
(iii) from about 1% to about 28% of a polyvinyl- pyrrolidone, and (iv) from about 1% to about 50% of a solvent selected from the group consisting of monohydric alcohols having from 1 to 4 carbon atoms and mixtures thereof, wherein the ratio of said polyethylene glycol to said polyvinylpyrrolidone is at least about 2.5:1; and
(b) evaporating said solvent to obtain a composition containing from about 0.1% to about 6% by weight of said solvent.
The present invention also relates to a process for preparing soft gelatin capsules containing a solution of a difficultly soluble pharmaceutical active, and to the compositions and the filled capsules themselves.
All percentages and ratios used herein are by weight and all measurements are at 25°C, unless otherwise indicated. DETAILED DESCRIPTION OF THE INVENTION The term "difficultly soluble pharmaceutical active", as used herein, 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 term "substantially free of water", as used herein, describes highly concentrated pharmaceutical compositions which, as initially prepared, do not contain any water, except for the minor amounts of water normally present in the materials employed in their preparation and/or which is gradually absorbed from the environment or the optional gelatin shell; i.e., less than from about 0.1% to about 8% water, prefereably less than from about 0.1% to about 6% water, more preferably less than from about 0.1% to about 4% water, and most preferably less than from about 0.1% to about 2% water. The term "as initially prepared", as used herein, is defined to mean the period of time from when the evaporation step is completed to about 5 minutes thereafter.
Concentrated Liquid Pharmaceutical Compositions The highly concentrated liquid pharmaceutical compositions of the present invention comprise the following essential, as well as optional, components. Polyethylene Glvcol
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:
H(OCH2CH2)nOH where n is greater than or equal to 4. Polyethylene glycols are described in G.M. Powell, III in Handbook of Water-Soluble Gums & Resins. R.L. Davidson, Ed. (McGraw-Hill, New York, 1980) pp. 18/1-18/31, this reference being incorporated herein by reference in its entirety. Polyethylene glycols, which are also known as "PEGs" or "polyoxyethylenes", are designated by both their average molecular weight range and their average "n" value as in the above designated formula. For example, polyethylene glycol 400, which is also known by the CTFA designation, PEG-8, has an average molecular weight range from 380-420 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.
The polyethylene glycols useful herein are those which are liquids at room temperature or have a melting point slightly thereabove. Preferred are the polyethylene glycols having a molecular weight range from about 300 to about 1000 and corresponding n values from about 6 to about 20. More preferred are the polyethylene glycols having a molecular weight range from about 400 to about 1000 and corresponding n values from about 8 to about 20. Most preferred are the polyethylene glycols having a molecular weight range from about 600 to about 1000 and corresponding n values from about 12 to about 20. Most especially preferred is a polyethylene glycol having a molecular weight of about 600 and a corresponding n value of about 12. Moreover, mixtures of two or more polyethylene glycols of different average molecular weight range or n value can also be employed in the present invention. Liquid and low-melting polyethylene glycols are commercially available from Union Carbide (Danbury, CT) under the CarbowaxR trademark. S_g§ "Carbowax^ Polyethylene Glycols", Union Carbide Technical Bulletin f-4772M-ICD 11/86-20M, this reference being incorporated herein by reference in its entirety.
Polyethylene glycols having an average molecular weight below about 300 are not desirable for use in the instant invention since such polyethylene glycols tend to diffuse into, plasticize, and ultimately disrupt the soft gelatin shells which can be employed to encapsulate the compositions described herein.
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 40% to about 50%. After the evaporation step, the resulting highly concentrated liquid compositions of the present invention comprise from about 25% to about 87.5% polyethylene glycol, more preferably from about 37.5% to about 75%, and most preferably from about 50% to about 75%. Polyvinylpyrrolidone
An essential component of the present compositions is polyvinylpyrrolidone ("PVP"), which is a polymer of N-vinyl-2-pyrrolidone having the following formula:
Figure imgf000009_0001
Polyvinylpyrrolidones are described in L. Blecher et al . in Handbook of Water-Soluble Gums & Resins. R.L. Davidson, Ed. (McGraw-Hill, New York, 1980) pp. 21/1-21/21, this reference being incorporated herein by reference in its entirety. Polyvinylpyrrolidone 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 PlasdoneR and PolypiasdoneR trademarks, respectively, and from BASF Aktiengesellschaft (Ludwigshafen, Germany) under the KollidonR trademark. Soluble forms of polyvinylpyrrolidone include PlasdoneR K-25, PlasdoneR K-26/28, PlasdoneR K-29/32, PlasdoneR C-15, PlasdoneR C-30, PlasdoneR C-90, KollidonR 12 PF, KollidonR 17 PF, KollidonR 25, KollidonR 30, and KollidonR 90. Insoluble forms of polyvinylpyrrolidone include Polyplasdone XLR, Polyplasdone XLR10, KollidonR CL, and KollidonR CL-M. £§£ "Tableting With PlasdoneR", GAF Technical Bulletin 2302-110R1 (1986); "Polyplasdone XLR, Polyplasdone XL^IO", GAF Technical Bulletin 2302-099 R2 (1984); and "KollidonR Grades, Polyvinylpyrrolidone for the Pharmaceutical
Industry", BASF Technical Bulletin MEF 129e, Register 2, May 1986
(Bn); these references being incorporated herein by reference in thei entirety. The soluble forms of polyvinylpyrrolidone are preferred for use in the present invention. Preferred are soluble polyvinyl- pyrrolidones having an average molecular weight in the range from about 2900 to about 1,100,000; more preferred are those having an average molecular weight in the range from about 9000 to about 45,000; and most preferred are those having an average molecular weight of about 29,000. Moreover, 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 polyvinylpyrrolidone, more preferably from about 1% to about 10%, and most preferably from about 1% to about
5%.
After the evaporation step, the resulting highly concentrated liquid compositions of the instant invention comprise from about
1.25% to about 35% of a soluble polyvinylpyrrolidone, more preferably from about 1.25% to about 12.5%, and most preferably from about 1.25% to about 6.25%.
An important requirement of the processes and compositions of the instant invention is that the polyethylene glycol component(s) and the polyvinylpyrrolidone component(s) are present in a proper ratio. Preferably, the ratio of the total amount of polyethylene glycol to polyvinylpyrrolidone should be at least about 2.5:1. Difficultly Soluble Pharmaceutical Actives The compositions of the instant invention contain at least one difficultly soluble pharmaceutical active as an essential component. In general, 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 11, 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 pharmaceutically-acceptable salts, and mixtures thereof. Acetaminophen is especially preferred for use in the compositions of 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 pharmaceutical active, more preferably from about 15% to about 35%, and most preferably from about 20% to about 30%.
After the evaporation step, the resulting highly concentrated liquid compositions of the instant invention comprise from about 1.25% to about 50% of a difficultly soluble pharmaceutical active, more preferably from about 18.75% to about 43.75%, and most preferably from about 25% to about 37.5%. Solvents A solvent selected from the group consisting of the monohydric alcohols having from one to four carbon atoms, and mixtures thereof, is an essential component of the processes of the instant invention. A sufficient quantity of solvent is utilized to aid in the solubilization of the essential components. By "sufficient" is meant a quantity of solvent that will ensure solubility of the components of the composition and yet not dilute the composition to the point where it occupies an unreasonably large volume. After mixing and solubilization of the the components of the instant invention, the solvent is removed using standard evaporation techniques until the composition is substantially free from solvent. The term "substantially free from solvent" is herein defined to mean that the compositions of the present invention comprise within after about 5 minutes of the evaporation step no more than from about 0.1% to about 6% of solvent after the evaporation step. Ethanol is most preferred as the solvent for use in the processes of the instant invention. The process for preparing the highly concentrated liquid compositions of the instant invention comprises adding from about 1% to about 50% of solvent, more preferably from about 5% to about 40%, and most preferably from about 10% to about 30%.
After the evaporation step, the resulting highly concentrated liquid compositions of the instant invention comprise no more that from about 0.1% to about 6% solvent. Additional Pharmaceutical Actives
The compositions of the instant invention can also contain one or more additional pharmaceutical actives having a solubility greater than the difficultly soluble pharmaceutical actives described above. In general, these actives have a solubility greater than about 1 percent by weight in water at 25°C. Useful classes of additional pharmaceutically-active compounds include analgesics, anti-inflammatory agents, antipyretics, calcium channel blockers, beta-blockers, antibacterials, antidepressants, antidlabetlcs, anti-emetics, antihistamines, cerebral stimulants, sedatives, anti-parasitics, expectorants, diruetics, decongestants, antltussives, 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.
Examples of additional pharmaceutical actives useful in the present invention include, but are not limited to, pseudoephedrine and its salts such as pseudoephedrine hydrochloride; dextromethorphan and its salts such as dextromethorphan hydrobromide; doxylamine and its salts such as doxyla ine 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; phenyltoxyl- amine and its salts; guaifenesin; phenylpropanolamine hydrochloride; and mixtures thereof. Preferred additional pharmaceutical actives are dextromethorphan hydrobromide, doxylamine succinate, pseudoephe- drine hydrochloride, chlorpheniramine maleate, guaifenesin, tripro¬ lidine hydrochloride, diphenydramine hydrochloride and mixtures thereof.
The process for preparing the highly concentrated liquid compositions of the instant invention optionally comprises adding from about 0.5% to about 20% of a second pharmaceutical active, or mixtures thereof.
After the evaporation step, the resulting highly concentrated liquid compositions of the instant invention can optionally comprise from about 0.625% to about 25% of a second pharmaceutical active, or mixtures thereof.
Optional Components
Other components which can be incorporated into the compositions of the instant invention include colorings, flavorings, preservatives, lubricants, flow-enhancers, filling aids, anti- oxidants, essences, and other aesthetically pleasing components.
Process for Solubilizing Difficultly Soluble Pharmaceutical Actives
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. In a preferred manner of execution, the difficultly soluble pharmaceutical active, polyethylene glycol, polyvinylpyrrolidone, and solvent are combined and mixed until dissolved to form a homogeneous solution. Any optional components can either be added initially or after the essential components are combined.
Next, the solvent is removed from the resulting homogeneous solution until the residual amount of solvent is present at no more than from about 0.1 percent to about 6 percent by weight of the composition. The solvents can be removed using any art-recognized evaporation techniques including, but not limited to, rotary evaporation, spray-drying, flash evaporation, film evaporation, freeze-drying, thin film evaporation, forced circulation evaporation, wiped film evaporation, falling film evaporation, and the like. The resulting solution of the difficultly soluble pharmaceutical active, and any optional components, is substantially free from the added alcoholic solvent, i.e., contains no more that from about 0.1 percent to about 6 percent by weight of solvent. This resulting solution is suitable for encapsulation in a soft gelatin capsule using standard encapsulation techniques.
Soft Gelatin Capsules Preselected amounts of the highly concentrated liquid pharmaceutical compositions of the present invention can also be encapsulated in a soft gelatin shell. Optionally, 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
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. For a general description of gelatin and gelatin-based capsules, see Remingtons's Pharmaceutical Sciences. 16th ed., Mack Publishing Company, Easton, Pa. (1980), page 1245 and pages 1576-1582; and U.S. Patent 4,935,243, to Borkan et al., issued June 19, 1990; these two references being incorporated herein by reference in their entirety.
The soft gelatin shell of the capsules of the instant invention, as initially prepared, 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, as initially prepared, 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.
Optional Components
Other optional components which can be incorporated into the soft gelatin shells include colorings, flavorings, preservatives, anti-oxidants, essences, and other aesthetically pleasing components. Soft Gelatin Shell Preparation and Encapsulation
The solubilized pharmaceutical compositions of the present invention can be encapsulated 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., "Softgels: Manufacturing Considerations", Drugs and the Pharmaceutical Sciences. 41 (Specialized Drug Delivery Systems!. P. Tyle, Ed. (Marcel Dekker, Inc., New York, 1990) pp.409-449; F.S. Horn et al., "Capsules, Soft", Encyclopedia of Pharmaceutical Technology, vol. 2, J. Swarbrick and J.C. Boylan, eds. (Marcel Dekker, Inc., New York, 1990) pp. 269-284; M.S. Patel et al., "Advances in Softgel Formulation Technology", Manufacturing Chemist, vol. 60, no. 7, pp. 26-28 (July 1989); M.S. Patel et al., "Softgel Technology", Manufacturing Chemist, vol. 60, no. 8, pp. 47-49 (August 1989); R.F. Jimerson, "Softgel (Soft Gelatin Capsule) Update", Drug Development and Industrial Pharmacy (Interphex '86 Conference), vol. 12, no. 8 & 9, pp. 1133-1144 (1986); and W.R. Ebert, "Soft Elastic Gelatin Capsules: A Unique Dosage Form", Pharmaceutical Technology, vol. 1, no. 5, pp. 44-50 (1977); these references are incorporated by reference herein in their entirety. The resulting soft gelatin capsule is soluble in water and in gatrointestinal fluids. Upon swallowing the capsule, the gelatin shell rapidly dissolves or ruptures in the gastrointestinal tract thereby introducing the pharmaceutical actives into the physiological system. fXAMPLIS The following examples further describe and demonstrate embodiments within the scope of the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
Ingredients are identified by chemical or CTFA name.
EXAMPLE I Solubilized Acetaminophen Composition
A highly concentrated solution containing acetaminophen is prepared from the following ingredients.
Ingredient Weight %
Acetaminophen 26.00 Polyethylene Glycol 600 52.00
Polyvinylpyrrolidone^ 3.00
Ethanol 95% USP QS100
1 Available as PlasdoneR K-29/32 from GAF Chemicals Co.
The acetaminophen, polyethylene glycol 600, polyvinyl- pyrrolidone, and ethanol are combined in a suitable vessel and mixed at room temperature until a homogeneous solution is obtained. Next, the ethanol is removed by rotary evaporation at room temperature.
The resulting acetaminophen composition is substantially free from ethanol and water, is suitable for oral administration, and contains about 32.10% acetaminophen, 64.20% polyethylene glycol 600, and about 3.70% polyvinylpyrrolidone.
EXAMPLE II Soft Gelatin Capsule Containing A Solubilized Acetaminophen Composition A soft gelatin mixture is first prepared from the following ingredients.
Ingredient Weight %
Gelatin 47.00
Glycerin 15.00 water QS100
The above ingredients are combined in a suitable vessel and heated with mixing at about 65°C to form a uniform solution. Using standard encapsulation methodology, the resulting solution is used to prepare soft gelatin capsules containing approximately 1000 mg o the acetaminophen composition of Example I. The resulting soft gelatin acetaminophen capsules are suitable for oral administration. EXAMPLE III
Solubilized Pharmaceutical Composition
A highly concentrated solution containing acetaminophen in combination with other pharmacutical actives is prepared from the following ingredients.
Figure imgf000018_0001
1 Available as PlasdoneR K-29/32 from GAF Chemicals Co.
The acetaminophen, pseudoephedrine hydrochloride, dextromethorphan hydrobromide, doxylamine succinate, polyethylene glycol 600, polyvinylpyrrolidone, and ethanol are combined in a suitable vessel and mixed at room temperature until a uniform solution is formed. Next, the ethanol is removed by rotary evaporation at room temperature. The resulting pharmaceutical composition is substantially free from ethanol and water, is suitable for oral administration, and contains about 31.82% acetaminophen, 3.82% pseudoephedrine hydrochloride, 1.90% dextromethorphan hydrobromide, 0.48% doxylamine succinate, 58.80% polyethylene glycol 600, and 3.18% polyvinylpyrrolidone. EXAMPLE IV
Soft Gelatin Capsule Containing A Solubilized Acetaminophen Composition
A gelatin solution is prepared as described in Example II. Using standard encapsulation methodology, this gelatin solution is used to prepare soft gelatin capsules containing approximately 1000 mg of the pharmaceutical composition of Example III. The resulting soft gelatin pharmaceutical capsules are suitable for oral administration.
EXAMPLE V Solubilized Pharmaceutical Composition A highly concentrated solution containing acetaminophen in combination with other phamaceutical actives is prepared from the following ingredients.
Ingredient Weight %
Acetaminophen 23.20 Pseudoephedrine Hydrochloride 2.78
Dextromethorphan Hydrobromide 1.39
Doxylamine Succinate 0.58
Polyethylene Glycol 600 46.47
Polyvinylpyrrolidone! 1.86 Propylene Glycol 3.72
Ethanol 95% USP QS100
1 Available as PlasdoneR K-29/32 from GAF Chemicals Co. The acetaminophen, pseudoephedrine hydrochloride, dextro¬ methorphan hydrobromide, doxylamine succinate, polyethylene glycol 600, polyvinylpyrrolidone, propylene glycol, and ethanol are combined in a suitable vessel and mixed at room temperature until a homogeneous solution is formed. Next, the ethanol is removed by rotary evaporation. The resulting pharmaceutical composition is substantially free from ethanol and water, is suitable for oral administration, and contains about 29.00% acetaminophen, 3.48% pseudoephedrine hydrochloride, 1.74% dextromethorphan hydrobromide, 0.72% doxylamine succinate, 58.09% polyethylene glycol 600, 2.32% polyvlnyl- pyrrolldone, and 4.64% propylene glycol.
EXAMPLE VI Soft Gelatin Capsule Containing a Solubilized Pharmaceutical Composition
A gelatin solution is prepared as described in Example II. Using standard encapsulation methodology, this gelatin solution is used to prepare soft gelatin capsules containing approximately 1000 mg of the pharmaceutical composition of Example V. The resulting soft gelatin pharmaceutical capsules are suitable for oral administration. EXAMPLE VII Solubilized Pharmaceutical Composition
A highly concentrated solution containing acetaminophen in combination with other phamaceutical actives is prepared from the following ingredients.
Figure imgf000020_0001
1 Available as PlasdoneR K-29/32 from GAF Chemicals Co.
The acetaminophen, pseudoephedrine hydrochloride, dextro¬ methorphan hydrobromide, guaifenesin, polyethylene glycol 600, polyvinylpyrrolidone, propylene glycol, and ethanol are combined in a suitable vessel and mixed at room temperature until a homogeneous solution is formed. Next, the ethanol is removed by rotary evaporation. The resulting pharmaceutical composition is substantially free from ethanol and water, is suitable for oral administration, and contains about 27.77% acetaminophen, 3.34% pseudoephedrine hydrochloride, 1.11% dextromethorphan hydrobromide, 11.11% guaifenesin, 49.99% polyethylene glycol 600, 2.22% polyvinylpyrrolidone, and 4.45% propylene glycol.
EXAMPLE VIII Soft Gelatin Capsule Containing a Solubilized Pharmaceutical Composition A gelatin solution is prepared as described in Example II. Using standard encapsulation methodology, this gelatin solution is used to prepare soft gelatin capsules containing approximately 1000 mg of the pharmaceutical composition of Example VII. The resulting soft gelatin pharmaceutical capsules are suitable for oral administration. EXAMPLE IX Solubilized Pharmaceutical Composition
A highly concentrated solution containing acetaminophen in combination with other phamaceutical actives is prepared from the following ingredients.
Figure imgf000021_0001
1 Available as PlasdoneR K-29/32 from GAF Chemicals Co.
The acetaminophen, pseudoephedrine hydrochloride, dextro¬ methorphan hydrobromide, chlorpheniramine maleate, polyethylene glycol 600, polyvinylpyrrolidone, propylene glycol, and ethanol are combined in a suitable vessel and mixed at room temperature until a homogeneous solution is formed. Next, the ethanol is removed by rotary evaporation. The resulting pharmaceutical composition is substantially free from ethanol and water, is suitable for oral administration, and contains about 31.58% acetaminophen, 3.79% pseudoephedrine hydrochloride, 1.90% dextromethorphan hydrobromide, 0.25% chlorpheniramine maleate, 54.90% polyethylene glycol 600, 2.53% polyvinylpyrrolidone, and 5.05% propylene glycol.
EXAMPLE X Soft Gelatin Capsule Containing a Solubilized Pharmaceutical
Composition A gelatin solution is prepared as described in Example II. Using standard encapsulation methodology, this gelatin solution is used to prepare soft gelatin capsules containing approximately 1000 mg of the pharmaceutical composition of Example IX. The resulting soft gelatin pharmaceutical capsules are suitable for oral administration.
WHAT IS CLAIMED IS:

Claims

1. A process for solubilizing difficultly soluble pharmaceutical actives, comprising the steps of:
(a) combining and mixing until dissolved
(i) from about 1% to about 40% of at least one difficultly soluble pharmaceutical active, preferably from about 15% to about 35%, most preferably from about 20% to about 30%. (ii) from about 20% to about 70% of a polyethylene glycol, (iii) from about 1% to about 28% of a polyvinylpyrrolidone, and (iv) from about 1% to about 50% of a solvent selected from the group consisting of the monohydric alcohols having from 1 to 4 carbon atoms and mixtures thereof, preferably wherein said solvent is ethanol, wherein the ratio of said polyethylene glycol to said polyvinylpyrrolidone is at least about 2.5:1; and (b) evaporating said solvent to obtain a composition containing from about 0.1% to about 6% by weight of said solvent.
2. A process according to Claim 1 wherein said polyethylene glycol is added in an amount from about 30% to about 60% and said polyvinylpyrrolidone is added in an amount from about 1% to about 10% and preferably wherein said polyethylene glycol is added in an amount from about 40% to about 50% and said polyvinylpyrrolidone is added in an amount from about 1% to about 5%.
3. A process according to Claim 2 wherein said difficultly soluble pharmaceutical active is selected from the group consisting of acetaminophen, acetylsalicylic acid, ibuprofen, fenbuprofen, fenoprofen, flurbiprofen, indomethacin, naproxen, and mixtures thereof, and preferably wherein said active is acetaminophen.
4. A process according to Claim 3 wherein said polyethylene glycol is selected from the group consisting of PEG-6, PEG-8, PEG-9, PEG-10, PEG-12, PEG-14, PEG-16, PEG-18, PEG-20, and mixtures thereof, preferably wherein said polyethylene glycol is PEG-12; and wherein said polyvinylpyrrolidone has an average molecular weight of about 9,000 to about 45,000, preferably about 29,000.
5. A process according to Claim 1 which further comprises combining in step (a) from about 0.5% to about 20% of a second pharmaceutical active selected from the group consisting of dextromethorphan hydrobromide, doxylamine succinate, pseudoephedrine hydrochloride, chlorpheniramine maleate, guaifenesin, triprolidine hydrochloride, diphenhydramine hydrochloride, and mixtures thereof.
6. A process for preparing soft gelatin capsules of a highly-concentrated • liquid, pharmaceutical composition, comprising the steps of:
(a) combining and mixing until dissolved
(i) from about 1% to about 40% of at least one difficultly soluble pharmaceutical active,
(ii) from about 20% to about 70% of a polyethylene glycol,
(iii) from about 1% to about 28% of a polyvinyl¬ pyrrolidone, and
(iv) from about 1% to about 50% of a solvent selected from the group consisting of monohydric alcohols having from one to four carbon atoms and mixtures thereof, preferably wherein said solvent is ethanol, wherein the ratio of said polyethylene glycol to said polyvinylpyrrolidone is at least about 2.5:1;
(b) evaporating said solvent to obtain a composition containing from about 0.1% to about 6% by weight of said solvent; and
(e) encapsulating the evaporated composition in a soft gelatin shell .
7. A process according to Claim 6 wherein said difficultly soluble pharmaceutical active is selected from the group consisting of acetaminophen, acetylsalicylic acid, ibuprofen, fenbuprofen, fenoprofen, flurbiprofen, indomethacin, naproxen, and mixtures thereof, and preferably wherein said active is acetaminophen.
8. A process according to Claim 7 which further comprises combining in step (a) from about 0.5% to about 20% of a second pharmaceutical active selected from the group consisting of dextromethorphan hydrobromide, doxylamine succinate, pseudoephedrine hydrochloride, chlorpheniramine maleate, guaifenesin, triprolidine hydrochloride, diphenhydramine hydrochloride, and mixtures thereof.
9. A highly-concentrated liquid, pharmaceutical composition prepared in accordance with the process of any of Claims 1-5.
10. A soft gelatin capsule prepared in accordance with the process of any of Claims 6-8.
11. A highly-concentrated liquid, pharmaceutical composition which is substantially free from solvent, comprising:
(a) from about 1.25% to about 50% of at least one difficultly soluble pharmaceutical active;
(b) from about 25% to about 87.5% of a polyethylene glycol ;
(c) from about 1.25% to about 35% of a polyvinyl¬ pyrrolidone; and
(d) from about 0.1% to about 8% water; wherein the ratio of said polyethylene glycol to said polyvinylpyrrolidone is at least about 2.5:1.
PCT/US1992/004771 1991-06-27 1992-06-08 Process for solubilizing difficultly soluble pharmaceutical actives WO1993000072A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP92913574A EP0591346A1 (en) 1991-06-27 1992-06-08 Process for solubilizing difficultly soluble pharmaceutical actives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US07/722,056 US5141961A (en) 1991-06-27 1991-06-27 Process for solubilizing difficulty soluble pharmaceutical actives
US722,056 1991-06-27

Publications (1)

Publication Number Publication Date
WO1993000072A1 true WO1993000072A1 (en) 1993-01-07

Family

ID=24900343

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1992/004771 WO1993000072A1 (en) 1991-06-27 1992-06-08 Process for solubilizing difficultly soluble pharmaceutical actives

Country Status (8)

Country Link
US (1) US5141961A (en)
EP (1) EP0591346A1 (en)
AU (1) AU2191192A (en)
CA (1) CA2109623C (en)
IE (1) IE922096A1 (en)
MX (1) MX9203447A (en)
PT (1) PT100634A (en)
WO (1) WO1993000072A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994025008A1 (en) * 1993-04-29 1994-11-10 The Procter & Gamble Company Pharmaceutical compositions containing polyvinylpyrrolidone and a tri-ester and process of manufacture thereof
WO2000041693A2 (en) * 1999-01-11 2000-07-20 The Procter & Gamble Company Compositions having improved delivery of actives
WO2014132163A1 (en) 2013-02-28 2014-09-04 Pfizer Inc. Enhanced stability of novel liquid compositions
CN104490882A (en) * 2014-11-29 2015-04-08 郑州后羿制药有限公司 Traditional Chinese veterinary medicine for treating duck infectious serositis diseases and preparation method thereof

Families Citing this family (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0623018B1 (en) * 1992-01-17 1995-12-27 ALFATEC-PHARMA GmbH Process for the manufacture of soft gelatin capsules by a drip-feed method
US5376688A (en) * 1992-12-18 1994-12-27 R. P. Scherer Corporation Enhanced solubility pharmaceutical solutions
US5484606A (en) * 1994-01-24 1996-01-16 The Procter & Gamble Company Process for reducing the precipitation of difficulty soluble pharmaceutical actives
CZ210496A3 (en) * 1994-01-24 1996-12-11 Procter & Gamble Method improving solution process of difficult-to dissolve pharmaceutically active compounds
US5510389A (en) * 1994-03-02 1996-04-23 The Procter & Gamble Company Concentrated acetaminophen solution compositions
IT1269583B (en) * 1994-04-26 1997-04-08 Bayer Italia Spa PHARMACEUTICAL PREPARATIONS BASED ON A SOLUTION OF KETOPROFENE IN SOFT GELATINE CAPSULES AND METHOD FOR THEIR PRODUCTION
US5563177A (en) * 1995-01-30 1996-10-08 American Home Products Corporation Taste masking guaifenesin containing liquids
US5641512A (en) * 1995-03-29 1997-06-24 The Procter & Gamble Company Soft gelatin capsule compositions
IT1294205B1 (en) * 1997-07-23 1999-03-24 Farmigea Spa PROCEDURE FOR THE SOLUBILIZATION IN WATER AND IN AQUEOUS VEHICLES OF PHARMACOLOGICALLY ACTIVE SUBSTANCES
US6365180B1 (en) * 1998-01-20 2002-04-02 Glenn A. Meyer Oral liquid compositions
US6287594B1 (en) 1998-01-20 2001-09-11 Edward S. Wilson Oral liquid compositions
US6596298B2 (en) * 1998-09-25 2003-07-22 Warner-Lambert Company Fast dissolving orally comsumable films
US20030206942A1 (en) * 1998-09-25 2003-11-06 Neema Kulkarni Fast dissolving orally consumable films containing an antitussive and a mucosa coating agent
US20030211136A1 (en) * 1998-09-25 2003-11-13 Neema Kulkarni Fast dissolving orally consumable films containing a sweetener
US20050037065A1 (en) * 1999-05-27 2005-02-17 Drugtech Corporation Nutritional formulations
US6251426B1 (en) * 1999-09-02 2001-06-26 Banner Pharmacaps, Inc. Ibuprofen-containing softgels
US6346231B1 (en) * 1999-10-06 2002-02-12 Joar Opheim Flavored gelatin capsule and method of manufacture
WO2002036077A2 (en) * 2000-11-06 2002-05-10 Andrx Pharmaceuticals, Inc. Once a day antihistamine and decongestant formulation
KR20020069387A (en) * 2001-02-26 2002-09-04 진양제약주식회사 Mixing method of composition containing doxylamine succinate and soft capsule preparation containing the composition
WO2003013481A1 (en) * 2001-08-03 2003-02-20 Bakulesh Mafatlal Khamar The process of manufacturing pharmaceutical composition with increased content of poorly soluble pharmaceutical ingredients
US7138133B2 (en) 2001-10-10 2006-11-21 The Procter & Gamble Company Orally administered liquid compositions
KR100446153B1 (en) * 2001-10-24 2004-08-30 한국유나이티드제약 주식회사 Formulation of a soluble ibuprofen and its process
DE10153934A1 (en) * 2001-11-06 2003-05-22 Basf Ag Process for the crystallization of profenes
US8092831B2 (en) * 2002-11-08 2012-01-10 Andrx Pharmaceuticals, Llc Antihistamine and decongestant system
US20040146537A1 (en) * 2003-01-28 2004-07-29 Ramachandran Radhakrishnan Oily wax matrix suspension formulation comprising pharmacologically active agents
BG65674B1 (en) * 2003-07-10 2009-06-30 Нихфи Ад Liquid form of combined medicamentous preparation for the treatment of colds and flue diseases
US20060013834A1 (en) * 2004-02-24 2006-01-19 Medicis Pediatrics, Inc. Room temperature stable aqueous liquid pharmaceutical composition
US20050249802A1 (en) * 2004-05-06 2005-11-10 The Procter & Gamble Company Softgel encapsulated pharmaceutical compositions comprising concentrated active ingredients
US20060062811A1 (en) * 2004-09-21 2006-03-23 Szymczak Christopher E Medicinal cooling emulsions
US20070053868A1 (en) 2005-03-08 2007-03-08 Banner Pharmacaps, Inc. Solvent system for enhancing the solubility of pharmaceutical agents
KR20080017065A (en) * 2005-06-03 2008-02-25 엘란 파마 인터내셔널 리미티드 Nanoparticulate acetaminophen formulations
US8637076B2 (en) * 2006-06-01 2014-01-28 Cima Labs Inc. Prednisolone salt formulations
US20070281014A1 (en) * 2006-06-01 2007-12-06 Cima Labs, Inc. Prednisolone salt formulations
DE102007000521A1 (en) * 2007-10-18 2009-04-23 Renate Conrad cough preparation
WO2009091622A1 (en) * 2008-01-18 2009-07-23 Dow Global Technologies Inc. Method to enhance aqueous solubility of poorly soluble actives using methoxypolyethylene glycol
US8518438B2 (en) * 2011-01-14 2013-08-27 Enspire Group, Llc Highly concentrated liquid acetaminophen solutions
TWI544922B (en) 2011-05-19 2016-08-11 愛爾康研究有限公司 High concentration olopatadine ophthalmic composition
US8969416B2 (en) 2012-03-29 2015-03-03 Enspire Group LLC Polyvinylpyrrolidone-containing acetaminophen liquid formulations
CN105209084B (en) 2013-03-13 2018-07-03 艾利丹尼森公司 Improved bond properties
JP6539274B2 (en) 2013-08-12 2019-07-03 ファーマシューティカル マニュファクチュアリング リサーチ サービシズ，インコーポレーテッド Extruded immediate release abuse deterrent pills
WO2015071841A1 (en) 2013-11-12 2015-05-21 Druggability Technologies Holdings Limited Complexes of dabigatran and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them
WO2015095391A1 (en) 2013-12-17 2015-06-25 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
JP6371463B2 (en) 2014-07-17 2018-08-08 ファーマシューティカル マニュファクチュアリング リサーチ サービシズ，インコーポレーテッド Immediate release abuse deterrent liquid filler form
AU2015336065A1 (en) 2014-10-20 2017-05-04 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
EP3247362A4 (en) 2014-11-17 2018-10-10 Context Biopharma Inc. Onapristone extended-release compositions and methods
KR101763145B1 (en) 2015-02-23 2017-08-01 한국화학연구원 Oral preparation having micelles that encapsulate nonsteroidal antiinflammatory drugs
AU2016326657B2 (en) 2015-09-25 2019-10-24 Context Biopharma, Inc. Methods of making onapristone intermediates
WO2017085687A1 (en) 2015-11-20 2017-05-26 West-Ward Pharmaceuticals International Limited Stable formulation of phenobarbital sodium injection
JP2019503353A (en) * 2015-12-15 2019-02-07 コンテキスト・バイオファーマ・インコーポレイテッド Amorphous onapristone composition and method of making the same
WO2018102369A1 (en) 2016-11-30 2018-06-07 Arno Therapeutics, Inc. Methods for onapristone synthesis dehydration and deprotection
TW202100140A (en) * 2019-03-11 2021-01-01 美商Ｒ Ｐ 先靈爾科技公司 Improved api stability in softgels

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2237619A1 (en) * 1973-07-20 1975-02-14 Scherer Ltd R P
DE2546371A1 (en) * 1975-10-16 1977-04-21 Sandoz Ag Solid digitalis glycoside medicaments - contg. polyalkylene glycol and/or a vinyl pyrrolidone (co)polymer
EP0042076A2 (en) * 1980-06-13 1981-12-23 A. Nattermann & Cie. GmbH Process for filling hard capsules with pharmaceutical products containing phospholipids and being highly viscous at room temperature
EP0152292A2 (en) * 1984-02-08 1985-08-21 R.P. Scherer Corporation Acetaminophen gelatin capsules
EP0193287A2 (en) * 1985-02-19 1986-09-03 Nippon Kayaku Kabushiki Kaisha Etoposide preparations
GB2184654A (en) * 1985-12-18 1987-07-01 Bayer Ag Dihydropyridine spray
WO1988002625A1 (en) * 1986-10-17 1988-04-21 R.P. Scherer Corporation Solvent system for an ionizable pharmaceutical agent
US4777050A (en) * 1987-03-23 1988-10-11 Schering Corporation Controlled-release dosage form comprising acetaminophen, pseudoephedrine and dexbrompheniramine

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3851051A (en) * 1970-07-17 1974-11-26 Scherer R Corp Soft gelatin capsule containing high water content fill
US4198391A (en) * 1973-07-20 1980-04-15 R. P. Scherer Ltd. Pharmaceutical compositions
US4067960A (en) * 1975-06-20 1978-01-10 R. P. Scherer Limited Pharmaceutical compositions containing cardiac glycoside
JPS5942635B2 (en) * 1980-12-27 1984-10-16 旭フアイバ−グラス株式会社 Matuto manufacturing method
GB8305693D0 (en) * 1983-03-02 1983-04-07 Scherer Ltd R P Pharmaceutical compositions
DE3307353C2 (en) * 1983-03-02 1985-01-31 R.P. Scherer GmbH, 6930 Eberbach Soft gelatin capsule containing polyethylene glycol and process for their production
DE3437599A1 (en) * 1984-10-13 1986-04-17 Dolorgiet GmbH & Co KG, 5205 St Augustin SOFT GELATINE CAPSULES CONTAINING IBUPROFEN AND METHOD FOR THE PRODUCTION THEREOF
US4764378A (en) * 1986-02-10 1988-08-16 Zetachron, Inc. Buccal drug dosage form
DE3629386A1 (en) * 1986-08-29 1988-03-03 Scherer Gmbh R P GELATINE CAPSULES AND METHOD FOR THEIR PRODUCTION
GB2185887B (en) * 1987-02-18 1989-12-06 Farmitalia Carlo Erba Ltd Temazepam composition
US4968509A (en) * 1987-07-27 1990-11-06 Mcneilab, Inc. Oral sustained release acetaminophen formulation and process
US4820522A (en) * 1987-07-27 1989-04-11 Mcneilab, Inc. Oral sustained release acetaminophen formulation and process
US4900775A (en) * 1988-02-29 1990-02-13 Gaf Chemicals Corporation Solubilization of complexes of water-insoluble organic compounds by aqueous solutions of polyvinylpyrrolidone

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2237619A1 (en) * 1973-07-20 1975-02-14 Scherer Ltd R P
DE2546371A1 (en) * 1975-10-16 1977-04-21 Sandoz Ag Solid digitalis glycoside medicaments - contg. polyalkylene glycol and/or a vinyl pyrrolidone (co)polymer
EP0042076A2 (en) * 1980-06-13 1981-12-23 A. Nattermann & Cie. GmbH Process for filling hard capsules with pharmaceutical products containing phospholipids and being highly viscous at room temperature
EP0152292A2 (en) * 1984-02-08 1985-08-21 R.P. Scherer Corporation Acetaminophen gelatin capsules
EP0193287A2 (en) * 1985-02-19 1986-09-03 Nippon Kayaku Kabushiki Kaisha Etoposide preparations
GB2184654A (en) * 1985-12-18 1987-07-01 Bayer Ag Dihydropyridine spray
WO1988002625A1 (en) * 1986-10-17 1988-04-21 R.P. Scherer Corporation Solvent system for an ionizable pharmaceutical agent
US4777050A (en) * 1987-03-23 1988-10-11 Schering Corporation Controlled-release dosage form comprising acetaminophen, pseudoephedrine and dexbrompheniramine

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994025008A1 (en) * 1993-04-29 1994-11-10 The Procter & Gamble Company Pharmaceutical compositions containing polyvinylpyrrolidone and a tri-ester and process of manufacture thereof
WO2000041693A2 (en) * 1999-01-11 2000-07-20 The Procter & Gamble Company Compositions having improved delivery of actives
WO2000041693A3 (en) * 1999-01-11 2000-11-30 Procter & Gamble Compositions having improved delivery of actives
US6846495B2 (en) 1999-01-11 2005-01-25 The Procter & Gamble Company Compositions having improved delivery of actives
KR100511730B1 (en) * 1999-01-11 2005-08-31 더 프록터 앤드 갬블 캄파니 Compositions having improved delivery of actives
CN105007891A (en) * 2013-02-28 2015-10-28 辉瑞公司 Enhanced stability of novel liquid compositions
KR20150111358A (en) * 2013-02-28 2015-10-05 화이자 인코포레이티드 Enhanced stability of novel liquid compositions
WO2014132163A1 (en) 2013-02-28 2014-09-04 Pfizer Inc. Enhanced stability of novel liquid compositions
JP2016510019A (en) * 2013-02-28 2016-04-04 ファイザー・インク Novel liquid composition with enhanced stability
US9308166B2 (en) 2013-02-28 2016-04-12 Pfizer Inc. Enhanced stability of novel liquid compositions
AU2014222418B2 (en) * 2013-02-28 2016-06-23 Pf Consumer Healthcare 1 Llc Enhanced stability of novel liquid compositions
KR101695580B1 (en) * 2013-02-28 2017-01-13 화이자 인코포레이티드 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
JP2017078084A (en) * 2013-02-28 2017-04-27 ファイザー・インク Novel liquid composition with enhanced stability
US9744133B2 (en) 2013-02-28 2017-08-29 Pfizer Inc. Enhanced stability of novel liquid compositions
KR20190136139A (en) * 2013-02-28 2019-12-09 화이자 인코포레이티드 Enhanced stability of novel liquid compositions
KR102218334B1 (en) 2013-02-28 2021-02-19 화이자 인코포레이티드 Enhanced stability of novel liquid compositions
CN104490882A (en) * 2014-11-29 2015-04-08 郑州后羿制药有限公司 Traditional Chinese veterinary medicine for treating duck infectious serositis diseases and preparation method thereof

Also Published As

Publication number Publication date
AU2191192A (en) 1993-01-25
CA2109623C (en) 1997-12-16
CA2109623A1 (en) 1993-01-07
IE922096A1 (en) 1992-12-30
EP0591346A1 (en) 1994-04-13
US5141961A (en) 1992-08-25
PT100634A (en) 1993-09-30
MX9203447A (en) 1992-12-01

Similar Documents

Publication Publication Date Title
US5141961A (en) Process for solubilizing difficulty soluble pharmaceutical actives
US5484606A (en) Process for reducing the precipitation of difficulty soluble pharmaceutical actives
AU706890B2 (en) Process for solubilizing difficultly soluble pharmaceutical actives
US5431916A (en) Pharmaceutical compositions and process of manufacture thereof
CA2214399C (en) Soft gelatin capsule with a gelatin shell comprising xanthine derivative
US5510389A (en) Concentrated acetaminophen solution compositions
AU701771B2 (en) Gelatin capsules containing a high concentrated acetaminophen solution
WO2009066146A2 (en) Stable solutions of sparingly soluble actives
JP2016094462A (en) Pharmaceutical formulations of naproxen for soft gel encapsulation and combinations thereof
EP1684732A2 (en) Ibuprofen-containing soft gelatin capsules
WO2003013481A1 (en) The process of manufacturing pharmaceutical composition with increased content of poorly soluble pharmaceutical ingredients
HUT74909A (en) Process for solubilizing difficultly soluble pharmaceutical actives
MXPA97007393A (en) Soft gelatine capsule with a gelatin cover comprising xant derivative
JPH01258619A (en) Novel sodium picosulfate pharmaceutical having rapid intraintestinal diffusion
KR20050075075A (en) Transparent soft capsules containg highly concentrated acetaminophen

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BB BG BR CA CS FI HU JP KP KR LK MG MN MW NO PL RO RU SD

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU MC NL SE BF BJ CF CG CI CM GA GN ML MR SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2109623

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 1992913574

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1992913574

Country of ref document: EP

WWR Wipo information: refused in national office

Ref document number: 1992913574

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1992913574

Country of ref document: EP