CA2181241C - Process for solubilizing difficultly soluble pharmaceutical actives - Google Patents
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- CA2181241C CA2181241C CA002181241A CA2181241A CA2181241C CA 2181241 C CA2181241 C CA 2181241C CA 002181241 A CA002181241 A CA 002181241A CA 2181241 A CA2181241 A CA 2181241A CA 2181241 C CA2181241 C CA 2181241C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
Abstract
A process for improving the solubility of difficultly soluble pharmaceutical actives in a mixture of polyethy1ene glycol and propylene glycol by using a polyvinylpyrrolidone with a specific viscosity average molecular weight of from about 5,000 to about 25,000.
Description
PROCESS FOR SOLUBILIZING DIFFICULTLY SOLUBLE
PHARMACEUTICAL ACTIVES
TECHNICAL FIELD
The present invention relates to a process for enhancing the solubility of difficultly 1o soluble pharmaceutical actives in a mixture of polyethylene glycol, polyvinylpyrrolidone, and propylene glycol.
BACKGROUND OF THE INVENTION
Liquid, and especially concentrated liquid pharmaceutical compositions offer several advantages over solid compositions. Liquids are easy to swallow and provide an excellent vehicle for the uniform delivery of pharmaceutical actives.
Moreover, liquids provide a rapid onset of pharmacologic action, since the composition does not first have to disintegrate and dissolve in the gastrointestinal tract. Likewise, concentrated liquid compositions offer certain distinct advantages. These compositions are ideally suited for incorporation into easy-to-swallow soft, flexible capsules. Encapsulation of this nature 2o permits the accurate and uniform delivery of unit dose amounts of a pharmaceutical active, encompassing even those instances where relatively small amounts of a pharmaceutical active are to be delivered. In addition, 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.
These advantages notwithstanding, it is often difl:<cult to prepare such com-positions using the desired pharmaceutical active however. Many pharmaceutical actives are poorly soluble and, therefore, require relatively large volumes of solvent for dissolution, resulting in impractically large doses. Also, encapsulating such large volumes into easy-to-swallow gelatin capsules presents obvious difficulties, suggesting the 3o immediate importance of concentrated liquid compositions. Furthermore, the situation becomes even more complicated when multiple pharmaceutical actives are involved, and . particularly where the difficultly soluble pharmaceutical active is in combination with a water soluble pharmaceutical active(s).
The current approach to this solubility problem is to force solubility into small volumes of solvent by means of a step-wise process incorporating heat. This step-wise process consists of dissolving the diflicultly soluble pharmaceutical active in polyethylene glycol with heat, followed by the addition of any additional pharmaceutical actives. As a separate admixture, polyvinylpyrrolidone is dissolved in a solution of water and propylene glycol. Finally, the polyvinylpyrrolidone solution is then added to the original batch solution to complete the process. Because the resultant concentrated liquid (or fill) is a supersaturated solution of the difficultly soluble pharmaceutical active, it is even more difficult to increase the resultant composition's concentration of the difficultly soluble active.
The present inventor has discovered that by using a polyvinylpyrrolidone with a specific viscosity average molecular weight of from about 5,000 to about 25,000 provides to dissolution of significantly higher levels of the difficultly soluble pharmaceutical active.
1t is, therefore, an object of the present invention to describe a process which provides for increased solubility of difficultly soluble pharmaceutical actives. A further object of the present invention is to enhance stability of the resultant composition by reducing the tendency of the difficultly soluble pharmaceutical active to precipitate out of solution. These and other-objects of this invention will become apparent in light of the following discussion.
C OF TIC rrrtnrr The present invention relates to a process for enhancing the solubility of diffcultly soluble pharmaceutical actives by combining and mixing in the presence of heat until dissolved from about 1% to about 40% by weight of at least one diflycultly soluble pharmaceutical active in a solution comprising:
i) from about 20~/° to about 70% by wieght of a polyethylene glycol;
ii) from about 4% to about 20% by weight of a polyvinylpyrrolidone having a viscosity average molecular weight from about 5,000 to about 25,000; and iii) from about 1 % to about 10% by weight of a propylene glycol.
The process preferably further comprises combining and mixing until dissolved the above solution with a separate admixture of from about 0.5% to about 20% bf at least one additional pharmaceutical active in from about l% to about 50% of an aqueous phase.
All percentages and ratios used herein are by weight and all measurements are at 30 25°C, unless otherwise indicated.
DETAILED DESCRIPTION OF THE INVENTION
The term "difftcuttly 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";
35 "very slightly soluble"; "practically insoluble, or insoluble"; and their equivalents as defined B
PHARMACEUTICAL ACTIVES
TECHNICAL FIELD
The present invention relates to a process for enhancing the solubility of difficultly 1o soluble pharmaceutical actives in a mixture of polyethylene glycol, polyvinylpyrrolidone, and propylene glycol.
BACKGROUND OF THE INVENTION
Liquid, and especially concentrated liquid pharmaceutical compositions offer several advantages over solid compositions. Liquids are easy to swallow and provide an excellent vehicle for the uniform delivery of pharmaceutical actives.
Moreover, liquids provide a rapid onset of pharmacologic action, since the composition does not first have to disintegrate and dissolve in the gastrointestinal tract. Likewise, concentrated liquid compositions offer certain distinct advantages. These compositions are ideally suited for incorporation into easy-to-swallow soft, flexible capsules. Encapsulation of this nature 2o permits the accurate and uniform delivery of unit dose amounts of a pharmaceutical active, encompassing even those instances where relatively small amounts of a pharmaceutical active are to be delivered. In addition, 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.
These advantages notwithstanding, it is often difl:<cult to prepare such com-positions using the desired pharmaceutical active however. Many pharmaceutical actives are poorly soluble and, therefore, require relatively large volumes of solvent for dissolution, resulting in impractically large doses. Also, encapsulating such large volumes into easy-to-swallow gelatin capsules presents obvious difficulties, suggesting the 3o immediate importance of concentrated liquid compositions. Furthermore, the situation becomes even more complicated when multiple pharmaceutical actives are involved, and . particularly where the difficultly soluble pharmaceutical active is in combination with a water soluble pharmaceutical active(s).
The current approach to this solubility problem is to force solubility into small volumes of solvent by means of a step-wise process incorporating heat. This step-wise process consists of dissolving the diflicultly soluble pharmaceutical active in polyethylene glycol with heat, followed by the addition of any additional pharmaceutical actives. As a separate admixture, polyvinylpyrrolidone is dissolved in a solution of water and propylene glycol. Finally, the polyvinylpyrrolidone solution is then added to the original batch solution to complete the process. Because the resultant concentrated liquid (or fill) is a supersaturated solution of the difficultly soluble pharmaceutical active, it is even more difficult to increase the resultant composition's concentration of the difficultly soluble active.
The present inventor has discovered that by using a polyvinylpyrrolidone with a specific viscosity average molecular weight of from about 5,000 to about 25,000 provides to dissolution of significantly higher levels of the difficultly soluble pharmaceutical active.
1t is, therefore, an object of the present invention to describe a process which provides for increased solubility of difficultly soluble pharmaceutical actives. A further object of the present invention is to enhance stability of the resultant composition by reducing the tendency of the difficultly soluble pharmaceutical active to precipitate out of solution. These and other-objects of this invention will become apparent in light of the following discussion.
C OF TIC rrrtnrr The present invention relates to a process for enhancing the solubility of diffcultly soluble pharmaceutical actives by combining and mixing in the presence of heat until dissolved from about 1% to about 40% by weight of at least one diflycultly soluble pharmaceutical active in a solution comprising:
i) from about 20~/° to about 70% by wieght of a polyethylene glycol;
ii) from about 4% to about 20% by weight of a polyvinylpyrrolidone having a viscosity average molecular weight from about 5,000 to about 25,000; and iii) from about 1 % to about 10% by weight of a propylene glycol.
The process preferably further comprises combining and mixing until dissolved the above solution with a separate admixture of from about 0.5% to about 20% bf at least one additional pharmaceutical active in from about l% to about 50% of an aqueous phase.
All percentages and ratios used herein are by weight and all measurements are at 30 25°C, unless otherwise indicated.
DETAILED DESCRIPTION OF THE INVENTION
The term "difftcuttly 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";
35 "very slightly soluble"; "practically insoluble, or insoluble"; and their equivalents as defined B
in the USP XXII, p.8 (1990).
Concentrated Liauid Pharmaceutical Compositions The highly concentrated liquid pharmaceutical compositions of the present invention comprise the following essential, as well as optional, components.
Polyethylene Glycol An essential component of the present compositions is a polyethylene glycol.
Polyethylene glycols generally are clear, viscous liquids or white solids which are soluble in water and many organic solvents. These polymers correspond to the general formula:
H(OCHZCHZ)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. 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 CFTA Cosmetic In;~redient Dictionary, Third Edition (1982), pp. 201-203; and The Merck Index. Tenth Edition, entry 7441, p. 1092 (1983).
Polyethylene glycols useful herein are mixtures of those which are liquids at room temperature or having a melting point slightly thereabove. Preferred mixtures include those polyethylene glycols having a molecular weight range of from about 300 to about 1000 and corresponding n values of from about 6 to about 20. More preferred are those of polyethylene glycols having a molecular weight range of from about 400 to about 1000 and corresponding n values of from about 8 to about 20. Most preferred are those of pblyethylene glycols having a molecular weight range of from about 600 to about 1000 and corresponding n values of from about 12 to about 20. Liquid and low-melting polyethylene glycols are commercially available from Union Carbide (Danbury, CT) under the Carbowax~ trademark. See "Carbowax~ Polyethylene Glycols", Union Carbide Technical Bulletin f 4772M-ICD 11/86-20M.
Polyethylene glycols having an average molecular weight below about 300 are B
Concentrated Liauid Pharmaceutical Compositions The highly concentrated liquid pharmaceutical compositions of the present invention comprise the following essential, as well as optional, components.
Polyethylene Glycol An essential component of the present compositions is a polyethylene glycol.
Polyethylene glycols generally are clear, viscous liquids or white solids which are soluble in water and many organic solvents. These polymers correspond to the general formula:
H(OCHZCHZ)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. 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 CFTA Cosmetic In;~redient Dictionary, Third Edition (1982), pp. 201-203; and The Merck Index. Tenth Edition, entry 7441, p. 1092 (1983).
Polyethylene glycols useful herein are mixtures of those which are liquids at room temperature or having a melting point slightly thereabove. Preferred mixtures include those polyethylene glycols having a molecular weight range of from about 300 to about 1000 and corresponding n values of from about 6 to about 20. More preferred are those of polyethylene glycols having a molecular weight range of from about 400 to about 1000 and corresponding n values of from about 8 to about 20. Most preferred are those of pblyethylene glycols having a molecular weight range of from about 600 to about 1000 and corresponding n values of from about 12 to about 20. Liquid and low-melting polyethylene glycols are commercially available from Union Carbide (Danbury, CT) under the Carbowax~ trademark. See "Carbowax~ Polyethylene Glycols", Union Carbide Technical Bulletin f 4772M-ICD 11/86-20M.
Polyethylene glycols having an average molecular weight below about 300 are B
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.
T'he 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 to about 55%.
Polvvin~pvrrolidone An essential component of the present compositions is polyvinylpyrrolidone ("PVP"), which is a polymei of N-vinyl-2-pyrrolidone having the following formula:
,s ~°
cH Ct~
L-Polyvinylpyrrolidones are described in.Lc Blecher et al: in Handbook of Water-Soluble Gums & Resins, R.L. Davidson, Ed. (McGraw-Hill, New York, 1980)pp.
21/21. 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 Plasdone~ and Polyplasdone~ trademarks, respectively, and from BASF
Aktiengesellschaft (Ludwigshafen, Germany) under the Kollidon~ trademark.
Soluble forms ofpolyvinylpyrrolidone include Plasdone~ K-25, Plasdone~ K-26/28, Plasdone~
K-29/32, Plasdone~ C-15, Plasdone~ C-30, Plasdone~ C-90, Kollidon~ 12 PF, Kollidon ~17 PF, Kollidon~ 25, Kollidon~ 30, and Kollidon~ 90. Insoluble forms of polyvinylpyrrolidone include Polyplasdone XL~, Polyplasdone XL~10, Kollidon~CL, and Kollidon~ CL-M. See "Tableting With Plasdone~", GAF Technical Bulletin 2302-11081 (1986); "Polyplasdone XL~, Polyplasdone XL~ 10", GAF
Technical Bulletin 2302-099 R2 (1984); and "Kollidon~ Grades, Polyvinylpyrrolidone 5 for the Pharmaceutical Industry", BASF Technical Bulletin MEF 129e, Register 2, May 1986 (Bn).
The soluble forms of polyvinylpyrrolidone are preferred for use in the present invention. Preferred are soluble polyvinylpyrrolidones having a viscosity average molecular weight in the range from about 5000 to about 25,000; more preferred are those having a viscosity average molecular weight in the range from about 5000 to about 15,000; and most preferred are those having a viscosity average molecular weight from about 5,000 to about 10,000. 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 preferable from about 1% to about 15%, and most preferably from about 2% to about 10%.
Preferably, the ratio of the total amount of polyethylene glycol to polyvinylpyrrolidone should be at least about 2.5:1.
Propylene Glycol Propylene glycol, which is represented by the formula:
CH3CHOHCHzOH
is well known in the art for its solvent and/or humectant properties. A
colorless and viscous liquid, propylene glycol is miscible with water, alcohols and many organic solvents. Propylene glycol is described in Hawley's Condensed Chemical Dictionary pp. 970-971, (Revised by Richard J. Lewis, Sr.) (12th ed. 1993). Propylene glycol suitable for use in the present invention is obtainable from any number of suppliers, Dow Chemical being one.
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 activities 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 B
T'he 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 to about 55%.
Polvvin~pvrrolidone An essential component of the present compositions is polyvinylpyrrolidone ("PVP"), which is a polymei of N-vinyl-2-pyrrolidone having the following formula:
,s ~°
cH Ct~
L-Polyvinylpyrrolidones are described in.Lc Blecher et al: in Handbook of Water-Soluble Gums & Resins, R.L. Davidson, Ed. (McGraw-Hill, New York, 1980)pp.
21/21. 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 Plasdone~ and Polyplasdone~ trademarks, respectively, and from BASF
Aktiengesellschaft (Ludwigshafen, Germany) under the Kollidon~ trademark.
Soluble forms ofpolyvinylpyrrolidone include Plasdone~ K-25, Plasdone~ K-26/28, Plasdone~
K-29/32, Plasdone~ C-15, Plasdone~ C-30, Plasdone~ C-90, Kollidon~ 12 PF, Kollidon ~17 PF, Kollidon~ 25, Kollidon~ 30, and Kollidon~ 90. Insoluble forms of polyvinylpyrrolidone include Polyplasdone XL~, Polyplasdone XL~10, Kollidon~CL, and Kollidon~ CL-M. See "Tableting With Plasdone~", GAF Technical Bulletin 2302-11081 (1986); "Polyplasdone XL~, Polyplasdone XL~ 10", GAF
Technical Bulletin 2302-099 R2 (1984); and "Kollidon~ Grades, Polyvinylpyrrolidone 5 for the Pharmaceutical Industry", BASF Technical Bulletin MEF 129e, Register 2, May 1986 (Bn).
The soluble forms of polyvinylpyrrolidone are preferred for use in the present invention. Preferred are soluble polyvinylpyrrolidones having a viscosity average molecular weight in the range from about 5000 to about 25,000; more preferred are those having a viscosity average molecular weight in the range from about 5000 to about 15,000; and most preferred are those having a viscosity average molecular weight from about 5,000 to about 10,000. 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 preferable from about 1% to about 15%, and most preferably from about 2% to about 10%.
Preferably, the ratio of the total amount of polyethylene glycol to polyvinylpyrrolidone should be at least about 2.5:1.
Propylene Glycol Propylene glycol, which is represented by the formula:
CH3CHOHCHzOH
is well known in the art for its solvent and/or humectant properties. A
colorless and viscous liquid, propylene glycol is miscible with water, alcohols and many organic solvents. Propylene glycol is described in Hawley's Condensed Chemical Dictionary pp. 970-971, (Revised by Richard J. Lewis, Sr.) (12th ed. 1993). Propylene glycol suitable for use in the present invention is obtainable from any number of suppliers, Dow Chemical being one.
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 activities 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 B
channel blockers, beta-blockers, antibacterials, antidepressants.
antidiabetics, anti-emetics, antihistamines, cerebral stimulants, sedatives, anti-parasitics, expectorants, diuretics, decongestants, antitussives, muscle relaxants, anti-Parkinsonian agents, broncholdilators, 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 analgesic/nonsteroidal anti-inflammatory drugs are especially useful in the present invention. Examples such as drugs are disclosed in U.S. Patent No. 4,522,828, to Sunshine et al., issued June 1 l, 1985.
Examples of preferred difficultly soluble pharmaceutical actives 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 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 25% to about 35%.
Additional Pharmaceutical Actives The compositions of the instant invention can optionally contain one or more additional pharmaceutical actives having a solubility greater that 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. Such additional pharmaceutical actives may also be selected from among the pharmaceutical categories previously mentioned.
Specific 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 doxylamine succinate;
phenindamine and its salts such as phenindamine hydrogen tartrate; pheniramine and its salts such as pheniramine maleate; chlorpheniramine and its salts such as chlorpheniramine maleate; ephedrine and its salts such as ephedrine sulfate;
triprolidine and its salts such as triprolidine hydrochloride; diphenhydramine and its salts such as diphenhydramine hydrochloride, diphenhydramine citrate, and diphenhydramine s 8-chlorotheophyllinate;phenyltoxylamine anditssalts;guaifenesin;phenylpropanolamine hydrochloride; and mixtures thereof. Preferred additional pharmaceutical actives are dextromethorphan hydrobromide, doxylamine succinate, pseudoephedrinehydrochloride, chlorpheniramine maleate, guaifenesin, triprolidine hydrochloride, diphenhydramine hydrochloride and mixtures thereof.
A further class of optional actives include those useful in promoting or maintaining healthy skin. Examples of such actives are disclosed in U.S.
Patent 5,073.371. to Turner et al. issued December 17, 1991.
The process for preparing the highly concentrated liquid compositions of the instant invention comprises adding one or more of these optionally additional pharmaceutical actives at a concentration of from about 0.5% to about 20%.
Coolants In addition, the present invention may optionally incorporate a cooling agent or a combination or cooling agents. Suitable cooling agents are those described in U.S.
Patent 4,136.163, January 23, 1979, to Watson et al., U.S. Patent 4.230,668, October 28, 1980, to Rowsell et al. and U.S. Patent 4,032,661, to Rowsell et al. A
particularly preferred cooling agent is N-ethyl-p-menthane-3-carboxamide (WS-3 supplied by Sterling Organics), taught by the above noted U.S. Patent 4.136.163. Another particularly preferred cooling agent is 3-1-menthoxypropane 1,2-diol (TK-10 supplied by Takasago Perfumery Co., Ltd., Tokyo, Japan). This material is described in detail in U.S. Patent 4,459,425, July 10, 1984 to Amano et al.
Other Optional Comaonents Optional components which can be incorporated into the compositions of the instant invention include coolants, colorings, flavourings, 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, propylene glycol and polyvinylpyrrolidone, are combined in the presence of heat and mixed until dissolved to form a homogeneous solution. Upon dissolution ofthe difficultly soluble pharmaceu-tical active, additional pharmaceutical actives may then be added to this batch solution or s 1 ~ 1 _?_ 41 PCT/US95/01018 dissolved separately in an aqueous phase. The process is completed once all additional pharmaceutical actives have been added, whether by direct addition to the original batch solution and/or by indirectly transferring the separately formed admixture to the original batch.
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 essentail, as well as optional, components.
Gelatin Gelatin is an essential component of the soft gelatin shells of the instant invention. The starting 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 fmm the Sigma Chemical Company, St. Louis, Mo. For a general description of gelatin and gelatin-based capsules, see Reminetons' 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.
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 SO% 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.
Plasticizes A plasticizes is another essential component of the soft gelatin shells of the instant invention. One or more plasticizers is incorporate~d~to produce soft gelatin shell.
The soft gelatin thus obtained has the required flexibility characteristics for use as a encapsulation agent. Useful plasicizers 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% plasticizes, preferably from about 10% to about 25%
plasticizes, and most preferably from about 10% to about 20% plasticizes. A preferred plasticizes useful in the present invention is glycerin.
z~ ~»4~
l!3 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 I S%
to about 50% water, more preferably from about 25% to about 40% water, and most 1o preferably from about 30% to about 40% water.
Other Optional Components Other optional components which can be incorporated into the soft gelatin shells in-clude 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 en-capsulated within any conventional soft gelatin shell that is capable of substantially containing the composition for a reasonable period of time. The soft gelatin shells of the instant invention can be prepared by combining appropriate amounts of gelatin, water, 2o 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", Drubs and the Pharmaceutical Sciences. 41 (Specialized Drua Delivery Systems), P. Tyle, Ed. (Marcel Dekker, Inc., New York, 1990) pp.409-449; F.S. Hom et al., "Capsules, Soft", Encyclopedia of Pharmaceutical Technoloav, vol. 2, J. Swarbrick and J.C. Boylan, eds. (Marcel Dekker, Inc., New York, 1990) pp. 269-284; M.S.. Pate) et al., "Advances in Softgel Formulation Technology", Manufacturing Chemist, vol. 60, no. 7, pp. 26-28 (July 1989); M.S. Pate) et al., "Softgel Technology", Manufacturins Chemist, vol. 60, no. 8, pp. 47-49 (August 1989);
R.F.
II
Jimerson, "Softgel (Soft Gelatin Capsule) Update", Drug Development and Industrial Pharmac (~rphex '86 Conference), vol. 12, no. 8 & 9, pp. 1133-I 144 (1986);
and W.R. Ebert, "Soft Elastic Gelatin Capsules: A Unique Dosage Form", Pharmaceutical Technolosv, vol. 1, no. 5, pp 44-50 (1977). Methods for tempering soft gelatin capsules are described in U.S. Patent 5,200,191 to Steele et al. 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.
EXAMPLES
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.
Solubilized Pharmaceutical Composition A highly concentrated solution containing acetaminophen in combination with other pharmaceutical actives is prepared from the following ingredients:
Ingredients Wei hght%
Acetaminophen 31.25 Pseudoephedrine HCI 2.88 Dextromethorphan HBr 1.44 Doxylamine Succinate 0.60 Polyethylene Glycol 600 24.38 Polyethylene Glycol 1000 22.14 Propylene Glycol 4.33 Polyvinylpyrollidone ' 8.17 Water Purified 4.81 ' Available as Kollidon K-17 PF from BASF Chem. Co. (Viscosity average molecular weight ~ 10,000) A solution of the polyethylene glycols, propylene glycol, and polyvinylpyrroli-done is prepared by mixing and warming these compositions to 70°C.
Acetaminophen is then dissolved into this solution, stirring and heating the solution to 120°C in the presence of 21 ~ 1 ?_ 41 pCT~S95101018 WO 95!19759 a-nitrogen. Once the acetaminophen is dissolved the solution is removed from the heat.
In a separate container, pseudoephedrine an HBr and doxylamine HC1, dextromethorph succinate are dissolved in water at room temperature by stirring. Finally, this separate admixture is combined with the original batch solution and mixed until uniform.
Examples II-III are further examples of concentrated solutions containing acetaminophen in combination with other tives and are manufactured pharmaceutical ac in a manner substantially similar to Example I
EXAMPLE II
Solubilized Pharmaceutical Composition to Ingredients Weieht Acetaminophen 31.25 Pseudoephedrine HC1 2.88 Dextromethorphan HBr 1.44 Doxylamine Succinate 0.60 Polyethylene Glycol 600 24.38 Polyethylene Glycol 1000 22.14 Propylene Glycol 4.33 Polyvinylpyrollidonel 8.17 Water Purified 4.81 !Available as Kollidon K-12 PF from BASF (Viscosity average Chem.Co. molecular weight ~ 5,000) EXAMPLE III
Solubilized Pharmaceutical Composition Ingredients Weight Acetaminophen 31.25 Pseudoephedrine HCl 2.88 Dextromethorphan HBr I .44 Chlorpheniramine Maleate 0.19 Polyethylene Glycol 600 24.52 3o Polyethylene Glycol 1000 22.40 Propylene Glycol 4.33 Polyvinylpyrollidone 1 8.17 Water Purified 4.82 l Available as Kollidon K-17 PF from BASF(Viscosity average Chem.Co. molecular weight ~ 10,000) ?_181241 l3 EXAMPLE IV
Solubilized Pharmaceutical Composition A highly concentrated solution containing acetaminophen and guaifenesin in combination with other pharmaceutical actives is prepared from the following ingredients:
Ingredients Weight Acetaminophen 31.25 Pseudoephedrine HCI 2.88 Dextromethorphan HBr 0.96 Guaifenesin 9.62 to Polyethylene Glycol 600 21.12 Polyethylene Glycol 1000 19.26 Propylene Glycol 2.88 Polyvinylpyrollidone 1 8.17 Water Purified 3.86 1 Available as Kollidon K-17 PF from BASF Chem.Co. (Viscosity average molecular weight ~ 10,000) A solution of polyethylene glycols, propylene glycol, and polyvinylpyrrolidone is prepared by mixing and warming to 70°C. Acetaminophen is then dissolved into this solution, stirring and heating the solution to 120°C in the presence of nitrogen. Once the 2o acetaminophen is dissolved and the solution removed from heat, the guaifenesin is next added and dissolved. In a separate container, pseudoephedrine HCI, dextromethorphan HBr and doxylamine succinate are dissolved in water at room temperature by stirring.
Finally, this separate admixture is combined with the original batch solution and mixed until uniform.
EXAMPLE V
Solubilized Pharmaceutical Composition Example V is a further example of a concentrated solution containing aceta-minophen and guaifenesin in combination with other pharmaceutical actives and is manufactured in a manner substantially similar to Example IV.
- 3o tneredients Weight Acetaminophen 31.35 Pseudoephedrine HCI 2.88 Dextromethorphan HBr 0.96 Guaifenesin 9.62 Polyethylene Glycol 600 21.12 WO 95!19759 PCT/US95101018 21$1241 ~a Polyethylene Glycol 1000 19.26 Propylene Glycol 2.88 Polyvinylpyrollidone 1 8.17 Water Purified 3.86 !Available as Kollidon K-12 PF from BASF Chem.Co. (Viscosity average molecular weight ~ 5,000) EXAMPLE VI
Solubilized Pharmaceutical Composition A highly concentrated solution containing acetaminophen is prepared from the to following ingredients I redients Weight Acetaminophen 31.25 Polyethylene Glycol 600 26.96 Polyethylene Glycol 1000 24.48 Propylene Glycol 4.33 Polyvinylpyrrolidone 1 8.17 Water Purified 4.&l I Available as Kollidon K-30 from BASF Chem.Co. (Viscosity average molecular weight 38,000) 2o A solution of the polyethylene glycols, propylene glycol, and polyvinyipyrrolidone is prepared by mixing and warming these components to 70°C.
Acetaminophen is then dissolved into this solution, stirring and heating the solution to 120°C in the presence of nitrogen gas. Once the acetaminophen is dissolved, the solution is removed from the heat.
Finally, a measured quantity of the aqueous phase is combined with the original batch solution and mixed until uniform.
EXAMPLE VII
Solubilized Pharmaceutical Composition A highly concentrated solution containing acetaminophen and pseudoephedrine HCl is prepared from the following ingredients 3o Ineredients Weight Acetaminophen 31.25 Pseudoephedrine HCl 2.88 Polyethylene Glycol 600 . 25.45 Polyethylene Glycol 1000 23.1 1 Propylene Glycol 4.33 WO 95!19759 21 ~ 12 41 pCT~S95/01018 l~
Polyvinylpyrrolidone 1 8. I 7 Water Purified 4.81 1 Available as Kollidon K-30 from BASF Chem.Co. (Viscosity average molecular weight 38,000) A solution of the polyethylene glycols, propylene glycol, and polyvinylpyrrolidone is prepared by mixing and warming these components to 70°C.
Acetaminophen is then dissolved into this solution, stirring and heating the solution to 120°C in the presence of nitrogen gas. Once the acetaminophen is dissolved, the solution is removed from the heat.
In a separate container, pseudoephedrine HCl is dissolved in water at room temperature to by stirring. Finally, this separate admixture is combined with the orivinal batch solution and mixed until uniform.
EXAMPLE VIII
Softeel Capsule Containing a Solub'~I'zed Pharmaceutical Composition A soft gelatin capsule is first prepared form the~following ingredients:
Insredients Wei h~ t Gelatin 47.00 Glycerin l 5.00 Water Purified qs 100 The above ingredients are combined in a suitable vessel and heated with mixing at 2o about 65°C to form a uniform solution. Using standard encapsulation methodology, the resulting solution is used to prepare soft gelatin capsules containing approximately 1040 mg. of the compositions of Examples I-VII. The resulting soft gelatin capsules are suitable for oral administration.
l.-,, .~ .
antidiabetics, anti-emetics, antihistamines, cerebral stimulants, sedatives, anti-parasitics, expectorants, diuretics, decongestants, antitussives, muscle relaxants, anti-Parkinsonian agents, broncholdilators, 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 analgesic/nonsteroidal anti-inflammatory drugs are especially useful in the present invention. Examples such as drugs are disclosed in U.S. Patent No. 4,522,828, to Sunshine et al., issued June 1 l, 1985.
Examples of preferred difficultly soluble pharmaceutical actives 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 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 25% to about 35%.
Additional Pharmaceutical Actives The compositions of the instant invention can optionally contain one or more additional pharmaceutical actives having a solubility greater that 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. Such additional pharmaceutical actives may also be selected from among the pharmaceutical categories previously mentioned.
Specific 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 doxylamine succinate;
phenindamine and its salts such as phenindamine hydrogen tartrate; pheniramine and its salts such as pheniramine maleate; chlorpheniramine and its salts such as chlorpheniramine maleate; ephedrine and its salts such as ephedrine sulfate;
triprolidine and its salts such as triprolidine hydrochloride; diphenhydramine and its salts such as diphenhydramine hydrochloride, diphenhydramine citrate, and diphenhydramine s 8-chlorotheophyllinate;phenyltoxylamine anditssalts;guaifenesin;phenylpropanolamine hydrochloride; and mixtures thereof. Preferred additional pharmaceutical actives are dextromethorphan hydrobromide, doxylamine succinate, pseudoephedrinehydrochloride, chlorpheniramine maleate, guaifenesin, triprolidine hydrochloride, diphenhydramine hydrochloride and mixtures thereof.
A further class of optional actives include those useful in promoting or maintaining healthy skin. Examples of such actives are disclosed in U.S.
Patent 5,073.371. to Turner et al. issued December 17, 1991.
The process for preparing the highly concentrated liquid compositions of the instant invention comprises adding one or more of these optionally additional pharmaceutical actives at a concentration of from about 0.5% to about 20%.
Coolants In addition, the present invention may optionally incorporate a cooling agent or a combination or cooling agents. Suitable cooling agents are those described in U.S.
Patent 4,136.163, January 23, 1979, to Watson et al., U.S. Patent 4.230,668, October 28, 1980, to Rowsell et al. and U.S. Patent 4,032,661, to Rowsell et al. A
particularly preferred cooling agent is N-ethyl-p-menthane-3-carboxamide (WS-3 supplied by Sterling Organics), taught by the above noted U.S. Patent 4.136.163. Another particularly preferred cooling agent is 3-1-menthoxypropane 1,2-diol (TK-10 supplied by Takasago Perfumery Co., Ltd., Tokyo, Japan). This material is described in detail in U.S. Patent 4,459,425, July 10, 1984 to Amano et al.
Other Optional Comaonents Optional components which can be incorporated into the compositions of the instant invention include coolants, colorings, flavourings, 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, propylene glycol and polyvinylpyrrolidone, are combined in the presence of heat and mixed until dissolved to form a homogeneous solution. Upon dissolution ofthe difficultly soluble pharmaceu-tical active, additional pharmaceutical actives may then be added to this batch solution or s 1 ~ 1 _?_ 41 PCT/US95/01018 dissolved separately in an aqueous phase. The process is completed once all additional pharmaceutical actives have been added, whether by direct addition to the original batch solution and/or by indirectly transferring the separately formed admixture to the original batch.
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 essentail, as well as optional, components.
Gelatin Gelatin is an essential component of the soft gelatin shells of the instant invention. The starting 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 fmm the Sigma Chemical Company, St. Louis, Mo. For a general description of gelatin and gelatin-based capsules, see Reminetons' 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.
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 SO% 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.
Plasticizes A plasticizes is another essential component of the soft gelatin shells of the instant invention. One or more plasticizers is incorporate~d~to produce soft gelatin shell.
The soft gelatin thus obtained has the required flexibility characteristics for use as a encapsulation agent. Useful plasicizers 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% plasticizes, preferably from about 10% to about 25%
plasticizes, and most preferably from about 10% to about 20% plasticizes. A preferred plasticizes useful in the present invention is glycerin.
z~ ~»4~
l!3 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 I S%
to about 50% water, more preferably from about 25% to about 40% water, and most 1o preferably from about 30% to about 40% water.
Other Optional Components Other optional components which can be incorporated into the soft gelatin shells in-clude 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 en-capsulated within any conventional soft gelatin shell that is capable of substantially containing the composition for a reasonable period of time. The soft gelatin shells of the instant invention can be prepared by combining appropriate amounts of gelatin, water, 2o 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", Drubs and the Pharmaceutical Sciences. 41 (Specialized Drua Delivery Systems), P. Tyle, Ed. (Marcel Dekker, Inc., New York, 1990) pp.409-449; F.S. Hom et al., "Capsules, Soft", Encyclopedia of Pharmaceutical Technoloav, vol. 2, J. Swarbrick and J.C. Boylan, eds. (Marcel Dekker, Inc., New York, 1990) pp. 269-284; M.S.. Pate) et al., "Advances in Softgel Formulation Technology", Manufacturing Chemist, vol. 60, no. 7, pp. 26-28 (July 1989); M.S. Pate) et al., "Softgel Technology", Manufacturins Chemist, vol. 60, no. 8, pp. 47-49 (August 1989);
R.F.
II
Jimerson, "Softgel (Soft Gelatin Capsule) Update", Drug Development and Industrial Pharmac (~rphex '86 Conference), vol. 12, no. 8 & 9, pp. 1133-I 144 (1986);
and W.R. Ebert, "Soft Elastic Gelatin Capsules: A Unique Dosage Form", Pharmaceutical Technolosv, vol. 1, no. 5, pp 44-50 (1977). Methods for tempering soft gelatin capsules are described in U.S. Patent 5,200,191 to Steele et al. 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.
EXAMPLES
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.
Solubilized Pharmaceutical Composition A highly concentrated solution containing acetaminophen in combination with other pharmaceutical actives is prepared from the following ingredients:
Ingredients Wei hght%
Acetaminophen 31.25 Pseudoephedrine HCI 2.88 Dextromethorphan HBr 1.44 Doxylamine Succinate 0.60 Polyethylene Glycol 600 24.38 Polyethylene Glycol 1000 22.14 Propylene Glycol 4.33 Polyvinylpyrollidone ' 8.17 Water Purified 4.81 ' Available as Kollidon K-17 PF from BASF Chem. Co. (Viscosity average molecular weight ~ 10,000) A solution of the polyethylene glycols, propylene glycol, and polyvinylpyrroli-done is prepared by mixing and warming these compositions to 70°C.
Acetaminophen is then dissolved into this solution, stirring and heating the solution to 120°C in the presence of 21 ~ 1 ?_ 41 pCT~S95101018 WO 95!19759 a-nitrogen. Once the acetaminophen is dissolved the solution is removed from the heat.
In a separate container, pseudoephedrine an HBr and doxylamine HC1, dextromethorph succinate are dissolved in water at room temperature by stirring. Finally, this separate admixture is combined with the original batch solution and mixed until uniform.
Examples II-III are further examples of concentrated solutions containing acetaminophen in combination with other tives and are manufactured pharmaceutical ac in a manner substantially similar to Example I
EXAMPLE II
Solubilized Pharmaceutical Composition to Ingredients Weieht Acetaminophen 31.25 Pseudoephedrine HC1 2.88 Dextromethorphan HBr 1.44 Doxylamine Succinate 0.60 Polyethylene Glycol 600 24.38 Polyethylene Glycol 1000 22.14 Propylene Glycol 4.33 Polyvinylpyrollidonel 8.17 Water Purified 4.81 !Available as Kollidon K-12 PF from BASF (Viscosity average Chem.Co. molecular weight ~ 5,000) EXAMPLE III
Solubilized Pharmaceutical Composition Ingredients Weight Acetaminophen 31.25 Pseudoephedrine HCl 2.88 Dextromethorphan HBr I .44 Chlorpheniramine Maleate 0.19 Polyethylene Glycol 600 24.52 3o Polyethylene Glycol 1000 22.40 Propylene Glycol 4.33 Polyvinylpyrollidone 1 8.17 Water Purified 4.82 l Available as Kollidon K-17 PF from BASF(Viscosity average Chem.Co. molecular weight ~ 10,000) ?_181241 l3 EXAMPLE IV
Solubilized Pharmaceutical Composition A highly concentrated solution containing acetaminophen and guaifenesin in combination with other pharmaceutical actives is prepared from the following ingredients:
Ingredients Weight Acetaminophen 31.25 Pseudoephedrine HCI 2.88 Dextromethorphan HBr 0.96 Guaifenesin 9.62 to Polyethylene Glycol 600 21.12 Polyethylene Glycol 1000 19.26 Propylene Glycol 2.88 Polyvinylpyrollidone 1 8.17 Water Purified 3.86 1 Available as Kollidon K-17 PF from BASF Chem.Co. (Viscosity average molecular weight ~ 10,000) A solution of polyethylene glycols, propylene glycol, and polyvinylpyrrolidone is prepared by mixing and warming to 70°C. Acetaminophen is then dissolved into this solution, stirring and heating the solution to 120°C in the presence of nitrogen. Once the 2o acetaminophen is dissolved and the solution removed from heat, the guaifenesin is next added and dissolved. In a separate container, pseudoephedrine HCI, dextromethorphan HBr and doxylamine succinate are dissolved in water at room temperature by stirring.
Finally, this separate admixture is combined with the original batch solution and mixed until uniform.
EXAMPLE V
Solubilized Pharmaceutical Composition Example V is a further example of a concentrated solution containing aceta-minophen and guaifenesin in combination with other pharmaceutical actives and is manufactured in a manner substantially similar to Example IV.
- 3o tneredients Weight Acetaminophen 31.35 Pseudoephedrine HCI 2.88 Dextromethorphan HBr 0.96 Guaifenesin 9.62 Polyethylene Glycol 600 21.12 WO 95!19759 PCT/US95101018 21$1241 ~a Polyethylene Glycol 1000 19.26 Propylene Glycol 2.88 Polyvinylpyrollidone 1 8.17 Water Purified 3.86 !Available as Kollidon K-12 PF from BASF Chem.Co. (Viscosity average molecular weight ~ 5,000) EXAMPLE VI
Solubilized Pharmaceutical Composition A highly concentrated solution containing acetaminophen is prepared from the to following ingredients I redients Weight Acetaminophen 31.25 Polyethylene Glycol 600 26.96 Polyethylene Glycol 1000 24.48 Propylene Glycol 4.33 Polyvinylpyrrolidone 1 8.17 Water Purified 4.&l I Available as Kollidon K-30 from BASF Chem.Co. (Viscosity average molecular weight 38,000) 2o A solution of the polyethylene glycols, propylene glycol, and polyvinyipyrrolidone is prepared by mixing and warming these components to 70°C.
Acetaminophen is then dissolved into this solution, stirring and heating the solution to 120°C in the presence of nitrogen gas. Once the acetaminophen is dissolved, the solution is removed from the heat.
Finally, a measured quantity of the aqueous phase is combined with the original batch solution and mixed until uniform.
EXAMPLE VII
Solubilized Pharmaceutical Composition A highly concentrated solution containing acetaminophen and pseudoephedrine HCl is prepared from the following ingredients 3o Ineredients Weight Acetaminophen 31.25 Pseudoephedrine HCl 2.88 Polyethylene Glycol 600 . 25.45 Polyethylene Glycol 1000 23.1 1 Propylene Glycol 4.33 WO 95!19759 21 ~ 12 41 pCT~S95/01018 l~
Polyvinylpyrrolidone 1 8. I 7 Water Purified 4.81 1 Available as Kollidon K-30 from BASF Chem.Co. (Viscosity average molecular weight 38,000) A solution of the polyethylene glycols, propylene glycol, and polyvinylpyrrolidone is prepared by mixing and warming these components to 70°C.
Acetaminophen is then dissolved into this solution, stirring and heating the solution to 120°C in the presence of nitrogen gas. Once the acetaminophen is dissolved, the solution is removed from the heat.
In a separate container, pseudoephedrine HCl is dissolved in water at room temperature to by stirring. Finally, this separate admixture is combined with the orivinal batch solution and mixed until uniform.
EXAMPLE VIII
Softeel Capsule Containing a Solub'~I'zed Pharmaceutical Composition A soft gelatin capsule is first prepared form the~following ingredients:
Insredients Wei h~ t Gelatin 47.00 Glycerin l 5.00 Water Purified qs 100 The above ingredients are combined in a suitable vessel and heated with mixing at 2o about 65°C to form a uniform solution. Using standard encapsulation methodology, the resulting solution is used to prepare soft gelatin capsules containing approximately 1040 mg. of the compositions of Examples I-VII. The resulting soft gelatin capsules are suitable for oral administration.
l.-,, .~ .
Claims (18)
1. A process to enhance solubility of difficultly soluble pharmaceutical actives by combining and mixing in the presence of heat until dissolved from about 1%
to about 40% by weight of at least one difficultly soluble pharmaceutical active in a solution comprising:
i) from about 20% to about 70% by weight of a polyethylene glycol;
ii) from about 4% to about 20% by weight of a polyvinylpyrrolidone having a viscosity average molecular weight from about 5,000 to about 25,000; and iii) from about 1% to about 10% by weight of a propylene glycol.
to about 40% by weight of at least one difficultly soluble pharmaceutical active in a solution comprising:
i) from about 20% to about 70% by weight of a polyethylene glycol;
ii) from about 4% to about 20% by weight of a polyvinylpyrrolidone having a viscosity average molecular weight from about 5,000 to about 25,000; and iii) from about 1% to about 10% by weight of a propylene glycol.
2. A process according to claim 1 wherein the viscosity average molecular weight of said polyvinylpyrrolidone is from about 5,000 to about 15,000.
3. A process according to claim 1 wherein the viscosity average molecular weight of said polyvinylpyrrolidone is from about 5,000 to about 10,000.
4. A process according to claim 1 further comprising the step of combining and mixing until dissolved the composition of claim 1 with from about 1% to about 50% by weight of an aqueous phase.
5. A process according to claim 4 wherein said aqueous phase is water.
6. A process according to claim 5 wherein the weight ratio of polyethylene glycol to said difficultly soluble pharmaceutical active and said polyvinylpyrrolidone is from about 1:0.3 to about 1:0.9 and from about 1:0.09 to about 1:0.3 respectively.
7. A process according to claim 6 wherein said difficultly soluble pharmaceutical active is added in an amount from about 20% to about 40% by weight.
8. A process according to claim 7 wherein said difficultly soluble pharmaceutical active is added in an amount from about 25% to about 35% by weight.
9. A process according to claim 8 wherein said difficultly soluble pharmaceutical active is selected from the group consisting of acetaminophen, acetylsalicylic acid, ibuprofen, fenbuprofen, fenoprofen, flubiprofen, indomethacin, naproxen, and mixtures thereof.
10. A process according to claim 9 wherein said difficultly soluble pharmaceutical active is acetaminophen.
11. A process according to claim 10 wherein said polyethylene glycol is added in an amount from about 30% to about 65% by weight.
12. A process according to claim 11 wherein said polyethylene glycol is added in an amount from about 40% to about 60% by weight.
13. A process according to claim 12 wherein said polyethylene glycol is selected from a group consisting of PEG-6, PEG-8, PEG-9, PEG-10, PEG-12, PEG-14, PEG-16, PEG-18, PEG-20, and mixtures thereof.
14. A process according to claim 13 wherein said polyethylene glycol is a mixture of PEG-12 and PEG-20.
15. A process according to claim 14 wherein said PEG-12 and PEG-20 are in a weight ratio of about 1:1.
16. A process according to claim 15 wherein one or more additional pharmaceutical actives are added to said aqueous phase and wherein said active is selected from the group of pharmaceutical actives consisting of dextromethorphan HBr, doxylamine succinate, pseudoephedrine HCI, chlorpheniramine maleate, guaifenesin, triprolidine HCI, diphenhydramine HCI, and mixtures thereof.
17. A process according to claim 16 wherein the said additional pharmaceutical actives are doxylamine succinate, dextromethorphan HBr, and pseudoephedrine HCI.
18. A process according to claim 16 wherein the said additional pharmaceutical actives are dextromethorphan HBr, guaifenesin, and pseudoephedrine HCI.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US18557694A | 1994-01-24 | 1994-01-24 | |
| US185,576 | 1994-01-24 | ||
| PCT/US1995/001018 WO1995019759A1 (en) | 1994-01-24 | 1995-01-24 | Process for solubilizing difficultly soluble pharmaceutical actives |
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| Publication Number | Publication Date |
|---|---|
| CA2181241A1 CA2181241A1 (en) | 1995-07-27 |
| CA2181241C true CA2181241C (en) | 2000-04-25 |
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| CA002181241A Expired - Fee Related CA2181241C (en) | 1994-01-24 | 1995-01-24 | Process for solubilizing difficultly soluble pharmaceutical actives |
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| Country | Link |
|---|---|
| EP (1) | EP0741560A1 (en) |
| JP (1) | JPH09508128A (en) |
| CN (1) | CN1138827A (en) |
| AU (1) | AU706890B2 (en) |
| BR (1) | BR9506564A (en) |
| CA (1) | CA2181241C (en) |
| CZ (1) | CZ210496A3 (en) |
| FI (1) | FI962948A (en) |
| MX (1) | MX9602955A (en) |
| NO (1) | NO963052L (en) |
| NZ (1) | NZ279443A (en) |
| PL (1) | PL315635A1 (en) |
| SK (1) | SK96196A3 (en) |
| WO (1) | WO1995019759A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998058637A1 (en) * | 1996-06-20 | 1998-12-30 | Mcneil-Ppc | Acetaminophen and diphenhydramine analgesics |
| ZA975444B (en) * | 1996-06-20 | 1998-12-21 | Mcneil Ppc Inc | Acetaminophen and meclizine hydrochloride analgesics |
| FR2751875B1 (en) * | 1996-08-05 | 1998-12-24 | Scr Newpharm | NOVEL STABLE LIQUID FORMULATIONS BASED ON PARACETAMOL AND THEIR METHOD OF PREPARATION |
| US5763449A (en) * | 1996-08-07 | 1998-06-09 | Ascent Pediatrics, Inc. | Pleasant-tasting aqueous liquid composition of a bitter-tasting drug |
| US6365180B1 (en) * | 1998-01-20 | 2002-04-02 | Glenn A. Meyer | Oral liquid compositions |
| EP1049459B1 (en) * | 1998-01-20 | 2009-04-22 | Applied Analytical Industries, Inc. | Oral liquid compositions |
| US20020082307A1 (en) * | 1999-01-11 | 2002-06-27 | Dobrozsi Douglas Joseph | Compositions having improved stability |
| US6846495B2 (en) | 1999-01-11 | 2005-01-25 | The Procter & Gamble Company | Compositions having improved delivery of actives |
| US20020086878A1 (en) * | 1999-01-11 | 2002-07-04 | Douglas Joseph Dobrozsi | Compositions having improved stability |
| US6211246B1 (en) | 1999-06-10 | 2001-04-03 | Mcneil-Ppc, Inc. | Rapidly absorbed liquid compositions |
| FR2796843B1 (en) * | 1999-07-29 | 2003-05-09 | So Ge Val Sa | CONCENTRATED AND STABILIZED ANTIPYRETIC COMPOSITION FOR VETERINARY USE INTENDED TO BE INCORPORATED IN ANIMAL FEEDING AS WELL AS A METHOD OF INCORPORATING THIS COMPOSITION INTO ANIMAL BEVERAGE WATER |
| US6251426B1 (en) | 1999-09-02 | 2001-06-26 | Banner Pharmacaps, Inc. | Ibuprofen-containing softgels |
| DE10011032A1 (en) * | 2000-03-07 | 2001-09-13 | Bayer Ag | Stable solutions of acetylsalicylic acid in mixture of organic solvent and water, useful for topical treatment of pain, especially pain associated with herpes zoster |
| KR20020069387A (en) * | 2001-02-26 | 2002-09-04 | 진양제약주식회사 | Mixing method of composition containing doxylamine succinate and soft capsule preparation containing the composition |
| NZ530889A (en) * | 2001-07-31 | 2005-03-24 | Wyeth Corp | Use of sucralose as a sweetening agent combined with pH modulation of chemical formulations generates enhanced taste-masking effects |
| US7101572B2 (en) * | 2001-12-07 | 2006-09-05 | Unilab Pharmatech, Ltd. | Taste masked aqueous liquid pharmaceutical composition |
| CN100379406C (en) * | 2003-09-22 | 2008-04-09 | 北京德众万全药物技术开发有限公司 | Method for preparing tiny pellets of difficult soluble drugs and formulation containing the pellets |
| US8333989B2 (en) * | 2005-10-26 | 2012-12-18 | Banner Pharmacaps, Inc. | Hydrophilic vehicle-based dual controlled release matrix system |
| DE102005053066A1 (en) | 2005-11-04 | 2007-05-10 | Basf Ag | Use of copolymers as solubilizers for sparingly water-soluble compounds |
| WO2007065846A2 (en) * | 2005-12-09 | 2007-06-14 | Basf Se | Use of polyvinyl lactam-polyoxyalkylene block copolymers as solubilisers for poorly water-soluble compounds |
| US8637076B2 (en) | 2006-06-01 | 2014-01-28 | Cima Labs Inc. | Prednisolone salt formulations |
| JP2008184430A (en) * | 2007-01-30 | 2008-08-14 | Ss Pharmaceut Co Ltd | Soft capsule |
| CA2690488C (en) * | 2010-01-19 | 2013-06-11 | Accucaps Industries Limited | Pharmaceutical formulations of naproxen for soft gel encapsulation and combinations thereof |
| CA2690490C (en) * | 2010-01-19 | 2012-06-26 | Accucaps Industries Limited | Pharmaceutical formulations of loratadine for encapsulation and combinations thereof |
| LT2528602T (en) | 2010-01-28 | 2017-02-27 | Eagle Pharmaceuticals, Inc. | Formulations of bendamustine |
| EP2827862B1 (en) | 2012-03-20 | 2023-12-27 | Eagle Pharmaceuticals, Inc. | Formulations of bendamustine |
| PT3533447T (en) | 2012-03-20 | 2023-05-17 | Eagle Pharmaceuticals Inc | Bendamustine liquid compositions for use in method of treating bendamustine-responsive conditions in patients requiring reduced volumes for administration |
| PL2961377T3 (en) | 2013-02-28 | 2020-11-02 | Pf Consumer Healthcare 1 Llc | Enhanced stability of novel liquid compositions |
| GB201506755D0 (en) * | 2015-04-21 | 2015-06-03 | Reckitt Benckiser Llc | Novel pharmaceutical formulation |
| TWI586379B (en) * | 2015-06-29 | 2017-06-11 | 永信藥品工業股份有限公司 | Method of preparing very slightly soluble drug with solid dosage form |
| WO2017062997A1 (en) | 2015-10-09 | 2017-04-13 | Reckitt Benckiser Llc | Pharmaceutical formulation |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5141961A (en) * | 1991-06-27 | 1992-08-25 | Richrdson-Vicks Inc. | Process for solubilizing difficulty soluble pharmaceutical actives |
-
1995
- 1995-01-24 SK SK961-96A patent/SK96196A3/en unknown
- 1995-01-24 JP JP7519747A patent/JPH09508128A/en active Pending
- 1995-01-24 EP EP95908124A patent/EP0741560A1/en not_active Withdrawn
- 1995-01-24 CZ CZ962104A patent/CZ210496A3/en unknown
- 1995-01-24 CA CA002181241A patent/CA2181241C/en not_active Expired - Fee Related
- 1995-01-24 MX MX9602955A patent/MX9602955A/en unknown
- 1995-01-24 AU AU16075/95A patent/AU706890B2/en not_active Ceased
- 1995-01-24 WO PCT/US1995/001018 patent/WO1995019759A1/en not_active Application Discontinuation
- 1995-01-24 CN CN95191303.4A patent/CN1138827A/en active Pending
- 1995-01-24 NZ NZ279443A patent/NZ279443A/en unknown
- 1995-01-24 BR BR9506564A patent/BR9506564A/en not_active Application Discontinuation
- 1995-01-24 PL PL95315635A patent/PL315635A1/en unknown
-
1996
- 1996-07-22 NO NO963052A patent/NO963052L/en not_active Application Discontinuation
- 1996-07-23 FI FI962948A patent/FI962948A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU1607595A (en) | 1995-08-08 |
| FI962948A0 (en) | 1996-07-23 |
| CA2181241A1 (en) | 1995-07-27 |
| NO963052L (en) | 1996-09-24 |
| SK96196A3 (en) | 1997-03-05 |
| MX9602955A (en) | 1997-06-28 |
| CZ210496A3 (en) | 1996-12-11 |
| BR9506564A (en) | 1997-09-02 |
| WO1995019759A1 (en) | 1995-07-27 |
| NO963052D0 (en) | 1996-07-22 |
| PL315635A1 (en) | 1996-11-25 |
| AU706890B2 (en) | 1999-07-01 |
| NZ279443A (en) | 1998-04-27 |
| FI962948A (en) | 1996-07-23 |
| EP0741560A1 (en) | 1996-11-13 |
| CN1138827A (en) | 1996-12-25 |
| JPH09508128A (en) | 1997-08-19 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| MKLA | Lapsed |