SK96196A3 - Process for solubilizing difficultly soluble pharmaceutical actives - Google Patents

Abstract

A process for improving the solubility of difficultly soluble pharmaceutical actives in a mixture of polyethylene 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

Technical field

The present invention relates to a method of improving the solubility of poorly soluble pharmaceutical active ingredients in a mixture of polyethylene glycol, polyvinylpyrrolidone and propylene glycol.

BACKGROUND OF THE INVENTION

Liquid, and in particular concentrated liquid pharmaceutical compositions offer several advantages over solid pharmaceutical compositions. Liquid formulations are easier to swallow and provide an excellent system for uniform delivery of pharmaceutical active ingredients. In addition, the liquid compositions may enter directly into their own active therapeutic action, since their composition no longer requires their disintegration and dissolution in the gastrointestinal tract. Concentrated liquid compositions offer certain distinct advantages. These compositions are ideally suited for preparing easily swallowable, soft and flexible capsules. Encapsulation in this way allows accurate and uniform delivery of the dose of the pharmaceutical active, even if the amount of the pharmaceutical active is to be very small. Soft gelatin capsules are also aesthetically attractive (especially when filled with a transparent liquid) and can be produced in a wide range of sizes, shapes and colors.

Despite these advantages, it is often problematic to prepare such compositions from the desired pharmaceutical active ingredients used. Many pharmaceutical active ingredients are sparingly soluble and therefore require a relatively large volume of solvent, resulting in impractical, large doses. Also, encapsulation of such large volumes into easily swallowable gelatin capsules poses a problem. These disadvantages indicate the importance of introducing concentrated liquid formulations. The situation becomes more complicated when more pharmaceutical active substances are used, especially when a sparingly soluble substance is combined with a water-soluble substance (s).

The current approach to improving this problem is to increase the solubility in small volumes of solvent under the influence of heat. This method consists in dissolving the sparingly soluble pharmaceutical active in polyethylene glycol at elevated temperature and then adding another pharmaceutical active. As a separate additional mixture, polyvinylpyrrolidone is dissolved in an aqueous solution of propylene glycol. Finally, the polyvinyl pyrrolidone solution is added to the original mixture to complete the formulation. Since the resulting concentrated liquid is a supersaturated solution of sparingly soluble pharmaceutical active ingredients, it is much more difficult to increase the final concentration of sparingly soluble pharmaceutical active ingredients in the composition.

The present inventor describes a method which, by using polyvinylpyrrolidone with a specific viscous average molecular weight of 5000 to 25,000, provides the possibility of dissolving substantially higher amounts of sparingly soluble pharmaceutical active ingredients.

It is an object of the present invention to describe a method that improves the solubility of sparingly soluble pharmaceutical active ingredients. It is a further object of the present invention to increase the stability of the resulting composition and reduce the tendency of the sparingly soluble pharmaceutical active substances to precipitate out of solution. These and other objectives are described in the following discussion.

SUMMARY OF THE INVENTION

The present invention relates to a method for increasing the solubility of sparingly soluble pharmaceutical active substances by combining and mixing the compounds until 1% to 40% of at least one sparingly soluble pharmaceutical active substance is dissolved in a solution comprising:

(1) 20% to 70% polyethylene glycol;

(2) 4% to 20% of polyvinylpyrrolidone with a viscous average molecular weight of 5,000 to 25,000; and

3) 1% to 10% propylene glycol.

Preferably, the method further comprises combining and mixing, unless the above solution is dissolved with a separate additive mixture of 0.5% to 20% of the at least one sparingly soluble pharmaceutical active substance in the 1% to 50% aqueous phase.

All ratios are by weight and all measurements are made at 25 ° C unless otherwise stated.

DETAILED DESCRIPTION OF THE INVENTION

The term "sparingly soluble pharmaceutical active substance" refers to a substance having a solubility of less than or equal to 1% by weight in water at 25 ° C. The term also includes the descriptive terms "sparingly soluble", "sparingly soluble", "practically insoluble or insoluble * ^1" and their equivalents as defined in USP ΧΧΠ, p. 8 (1990).

Concentrated liquid pharmaceutical compositions

The highly concentrated liquid pharmaceutical compositions of the present invention contain the following necessary as well as other optional ingredients.

Polyetylénglvkol

An essential component of the present composition is polyethylene glycol. Polyethylene glycols are generally clear, viscous liquids or white solids that are soluble in water and many other organic solvents. These polymers correspond to the general formula:

H (OCH ₂ CH ₂ ) nOH where n is greater than or equal to 4. Polyethylene glycols are described in GM Powell, Handbook of Water-Soluble Gums & Resins, RL Davidson, Ed. (McGraw-Hill, New York, 1980), p. 18 / 1-18 / 31 December. Polyethylene glycols, also known as PEG or polyoxoethylenes, are referred to by their average molecular weight and the average n value according to the above formula. For example, polyethylene glycol 400, also known as CTFA, PEG-8, has an average molecular weight of 380-420 and an average n value ranging from 8.2 to 9.1. (CTFA Cosmetic Ingredient Dictionary, Third Edition (1982), pp. 201-203 and The Merck Index, Tenth Edition, entry 7441, p. 1092 (1983).

The polyethylene glycols used herein are mixtures that are liquid at room temperature or have only a slightly higher melting point. Preferred mixtures comprise polyethylene glycols having a molecular weight of 300 to 1000 and a n value of 6 to 20.

More preferred are polyethylene glycols having a molecular weight of 400 to 1000 and a n value of 8 to 20. Most preferred are polyethylene glycols with a molecular weight of 600 to 1000 and a value of n 12 to 20. Liquid and low melting polyethylene glycols are commercially available (Union Carbide (Danbury, CT) under by Carbowax (see " Carbowax Polyethylene Glycols, Union Carbide Technical Bulletin f-4772M-ICD 11 / 86-20M).

Polyethylene glycols with an average molecular weight of less than 300 are not required for use because of their tendency to diffuse, plasticity and, finally, the possibility of disrupting the soft gelatin shells that can be used to encapsulate the compositions herein.

The process for preparing the highly concentrated liquid compositions of the present invention comprises adding 20% to 70% polyethylene glycol, more preferably 30% to 60%, and most preferably 35% to 55%.

polyvinylpyrrolidone

An essential component of the present compositions is polyvinylpyrrolidone ("PVP"), which is a polymer of N-vinyl-2-pyrrolidone with the following general formula:

N

CH

Polyvinylpyrrolidones are described in L. Bletcheer et al., Handbook of Water-Soluble Gums & Resins, R.L. Davidson, Ed. (McGraw-Hill, New York, 1980) p. 21 / 1-21 / 21st

Polyvinylpyrrolidones have different solubilities according to their polymeric structure.

Long-chain polyvinylpyrrolidones, also known as povidones, are well soluble in water and other organic solvents. The branched polyvinylpyrrolidones are insoluble in all common solvents. Both types of polyvinylpyrrolidones, both soluble and insoluble, are commercially available (GAF Chemicals Company (Wayne, NJ) under the trademark Plasdone and Polyplasdone, BASF Aktiengesellschaft (Ludwigshagen, Germany) under the trademark Koididon). Soluble forms of polyvinylpyrrolidone are Plasdone K25, Plasdone K-26/28, Plasdone K-29/32, Plasdone C-15, Plasdone C-30, Plasdone C-90, Coidid 12 PF, Coidid 17 PF, Coidid 25, Coidid 30 and Coidid 90. The insoluble forms of polyvivylpyrrolidone are Polyplasdone XI, Polyplasdone XL10, Coidid CL and Coidid CL-M. (See "Tableting With Plasdone, GAF Technical Bulletin 2302-110R1 (1986)," Polyplasdone XL, Polyplasdone XL 10, GAF Technical BuUetin 2302-099R2 (1984), "KoUidon Grades, Polyvinylpyrrolidone for the Pharmaceutical Industry", BASF Technical BuUetin MEF 129e, register 2, May 1986).

Soluble forms of polyvinylpyrrolidone are suitable for use in the present invention. Preferably, soluble polyvinylpyrrolidones with a viscous average molecular weight of 5,000 to 25,000 may be used, more preferably they are of an average weight of 5,000 to 15,000, most preferably of an average weight of 5,000 to 10,000. Furthermore, a mixture of two or more polyvinylpyrrolides with different molecular weights may be used.

The process for preparing the highly concentrated liquid compositions of the present invention comprises adding 1% to 28% soluble polyvinylpyrrolidone, more preferably 1% to 15%, and most preferably 2% to 10%.

The ratio of the total amount of polyethylene glycol to polyvinylpyrrolidone should be at least 2.5: 1.

Propylénglvkol

Propylene glycol, which is described by the general formula:

CH 3 CHOHCH 2 OH is well known for its solvent properties. Propylene glycol is a colorless, viscous liquid that can be mixed with water, alcohol and many organic solvents. Propylene glycol is described in Hawley's Condensed Chemical Dictionary, p. 970 to 971.12. edition 1993.

Hardly soluble pharmaceutical active substances

The compositions of the present invention contain at least one sparingly soluble pharmaceutical active ingredient as an essential ingredient. In general, these sparingly soluble substances have a solubility of less than or equal to 1% by weight in water at 25 °. Pharmaceutically active agents that may become components of the compositions of the present invention include analgesics, anti-inflammatory agents, antipyretics, calcium channel blockers, antibacterial agents, antidepressants, antidiabetics, antihistamines, brain stimulants, sedatives, diuretics, expectorants, muscle relaxants , cardiotonics, antibiotics, antiviral substances, nutritional supplements (vitamins, minerals, fatty acids, etc.) and mixtures thereof. Poorly soluble pharmaceutical active substances selected from the group of non-narcotic analgesics and non-steroidal anti-inflammatory drugs are particularly suitable for use in the present invention. Examples of such substances are disclosed in U.S. Pat. Patent No. No. 4,522,828, Sunshine et al., June 11, 1985.

As sparingly soluble pharmaceutical active substances, for example, e.g. acetaminophen, acetylsalicylic acid, ibuprofen, fenprofen, fenoprofen, flurbiprofen, indomethacin, ketoprofen, naproxen, their pharmaceutically acceptable salts and mixtures thereof. Acetoaminophen is preferably used in the present invention.

The process for preparing the highly concentrated liquid compositions of the present invention comprises adding 1% to 40% sparingly soluble pharmaceutical active ingredient, more preferably 15% to 35%, and most preferably 25% to 35%.

Pharmaceutical active ingredients

The compositions of the present invention may contain one or more additional pharmaceutically active ingredients having a solubility greater than the sparingly soluble active ingredients described above. Generally, these additives have a solubility of greater than 1% by weight in water at 25 °. These additional pharmaceutically active substances may be selected from the groups of pharmaceutically active substances mentioned above.

Examples of specific pharmaceutical active ingredients include pseudoephedrine and its salts, such as e.g. pseudoephedrine hydrochloride, dextromethorphan and its salts, such as e.g. dextromethorphan hydrobromide, doxylamine and its salts, such as e.g. doxylamine succinate, phenindamine and salts thereof, e.g. phenindamine hydrogen tartrate pheniramine and its salts, such as e.g. pheniramine maleate, chlorpheniramine and salts thereof, e.g. chlorpheniramine maleate, ephedrine and its salts, such as e.g. ephedrine sulfate, triprolidine, and salts thereof, such as e.g. triprolidine hydrochloride, diphenhydramine and its salts, such as e.g. diphenhydramine hydrochloride, diphenhydramine citrate and diphenhydramine 8-chlorotheophylinate, phenyloxylamine and its salts, guaifenesin, phenylpropanolamine hydrochloride and mixtures thereof. Preferred additives are dextromethorphan hydrobromide, doxylamine succinate, pseudoephedrine hydrochloride, chlorpheniramine maleate, triprolidine hydrochloride, diphenyramine hydrochloride, and mixtures thereof.

Another class of suitable additives are skin maintenance agents. Examples of such substances are disclosed in U.S. Pat. No. 5,073,371, Tumer et all., December 17,1991.

The process for preparing the highly concentrated liquid compositions of the present invention comprises adding one or more additional pharmaceutically active agents at a concentration of 0.5% to 20%.

Coolants

The compositions of the present invention may further comprise a coolant or a combination of a plurality of coolants. Suitable coolants are described in U.S. Pat. U.S. Patent 4,136,163, January 23, 1979 to Watson et al. U.S. Patent 4,230,668, Rev. 28, 1980 to Rowsell et al., U.S. Pat. U.S. Patent 4,032,661 to Rowsell et al. A highly suitable refrigerant is N-ethyl-menthane-3-carboxamide (WS-3, Sterling Organics) (U.S. Patent 4,136,163). Another suitable substance is 3-1-menthoxypropane 1,2-diol (TK-10, Takasago Perfumery Co., Ltd., Tokyo, Japan) (U.S. Patent 4,459,425).

Other optional additives

Optional ingredients that may be included in the compositions of the present invention are coolants, colorants, lubricants, preservatives, fillers, antioxidants, essences, and other suitable substances.

Method for dissolving sparingly soluble pharmaceutical active substances

Highly concentrated liquid pharmaceutical compositions are prepared according to the methods described above by mixing the individual components and selecting a suitable mixing device. The sparingly soluble pharmaceutical active, polyethylene glycol, propylene glycol, and polyvinylpyrrolidone are combined under heat and mixed until a homogeneous mixture is formed. After dissolution of the sparingly soluble substance, additional pharmaceutical active ingredients may be added or may be dissolved separately in the aqueous phase. The preparation process is complete when all the additional components, whether dissolved in the original mixture or separately, are added.

Soft gelatin capsules

The selected amount of the highly concentrated liquid pharmaceutical composition of the present invention may be encapsulated into soft gelatin shells. The gelatin shells may also be transparent, thereby enhancing the aesthetic qualities of the capsule itself. Soft gelatin shells contain the following necessary and additional optional components.

gelatin

Gelatin is an essential part of the soft gelatin shells of the present invention. The original gelatin material used in the manufacture of soft capsules was obtained by partial hydrolysis of collagen materials (e.g., skin, connective tissue, bone). The gelatinous material can be divided into Type A, which is obtained by acid hydrolysis from pork skin and has an isoelectric point between pH 7 and pH 9, and Type B, which is obtained by alkaline hydrolysis of bones and skin (especially bovine) and has an isoelectric point between pH 4.7 and pH 5.2. By a suitable ratio of the mixture of gelatin types A and B it is possible to obtain gelatin with the desired viscosity and other suitable properties for the production of capsules. Gelatin suitable for the manufacture of capsules is commercially available (Sigma Chemical Company, St. Luis, Mo.). Gelatin and gelatin capsules are generally described in Remingtons' Pharmaceutical Sdences, 16th ed., Mack Publishing Company, Easton, Pa., 1980, p. 1245 and p. 1576-1582, and U.S. Pat. U.S. Patent 4,935,243 to Borkan et al., June 19,1990.

The soft gelatin capsules of the present invention comprise 20% to 60% gelatin, more preferably 25% to 50% gelatin, and most preferably 40% to 50% gelatin. The gelatin may be type A, type B or a mixture thereof.

I A plasticity relief

Plasticity agents are another essential component of the soft gelatin capsules of the present invention. Upon addition of these materials, soft gelatin acquires the necessary flexibility to use it as an encapsulating agent. The plasticity enhancers of the present invention include glycerin, sorbitan, sorbitol or the like low molecular weight polyols or mixtures thereof.

The capsules of the present invention comprise 10% to 35% of plasticite-providing agents, more preferably 10% to 25% and most preferably 10% to 20%. Glycerol is preferably used in the present invention.

Water

The soft gelatin capsules of the present invention also contain water as an essential ingredient. Water is considered important in the process of dissolving or breaking the gelatin capsule upon contact with the gastrointestinal juices.

The capsules of the present invention contain 15% to 50% water, more preferably 25% to 40% water, and most preferably 30% to 40% water.

Other optional components

Dyes, flavoring agents, preservatives, antioxidants, and other suitable agents can be used as additional optional ingredients incorporated into gelatin capsules.

Preparation of soft gelatin shells and encapsulation

The dissolved pharmaceutical compositions of the present invention may be encapsulated into conventional soft gelatin capsules capable of retaining the composition for a period of time. The soft gelatin capsules of the present invention are prepared by combining an appropriate amount of gelatin, water, plasticizer and other optional ingredients in a suitable container with shaking or stirring at a temperature of up to 65 ° C until a homogeneous solution is obtained. This preparation is suitable for encapsulating the required amount of solubilized composition by standard methods by which individual, hermetically sealed soft gelatin capsules can be prepared. Gelatin capsules are formed into desirable shapes and sizes suitable for easy swallowing. The soft gelatin capsules of the present invention are of a suitable size for easy swallowing and usually contain 100 mg to 2000 mg of the dissolved pharmaceutical composition. Soft gelatin capsules and the encapsulation process are described in P.K. Wilkinson et al., &Quot; Softgels: Manufactoring Considerations ", Drugs and the Pharmaceutical Sciences, 41 (Specialized Drug Derilvery Systems). P. Tyle, Ed. (Marcel Dekker, Inc., New York, 1990) p. 409-449; F. S. Hom et al., &Quot; Capsules, Soft ", Encyclopedia of Pharmaceutical Technology, vol. 2, J. Swabrik and J.C. Boylan, eds. (Marcel Dekker, Inc., New York, 1990) p. 269-284; M.S. Patel et al., &Quot; Advanced in Softgel Formulation Technology ", Manufacturing Chemist, vol. 60, no. 7, 26-28 (July 1989); M.S. Patel et al., &Quot; Softgel Technology ", Manufacturing Chemist, vol. 60, no. 8.4749 (August 1989); R.F. Jimerson, "Softgel (Soft Gelatin Capsule) Update," Drug

Developmenr and Industrial Pharmacy (Interphex '86 Conference), vol. 12, no. 8 & 9, 1133-1144 (1986); W.R. Ebert,: Soft Elastic Gelatin Capsules: A Unique Dosage Form, Pharmaceceutical Technology, vol. 1, no. 5: 44-50 (1977). Methods for preparing soft gelatin capsules are disclosed in U.S. Pat. U.S. Patent 5,200,191 to Steele et al. Upon swallowing of the capsule, the capsule rapidly dissolves or ruptures within the gastrointestinal tract, thereby bringing the pharmaceutical composition into the physiological system.

Examples of use

The following examples further describe and demonstrate the scope of the present invention. The examples are given to indicate a possible use and are therefore not a limitation on its use with respect to other possible variants.

Example I

Dissolved pharmaceutical composition

A highly concentrated solution containing acetaminophen in combination with other pharmaceutical active ingredients is prepared from the following ingredients:

ingredients acetaminophen % by weight 31,25 Pseudoephedrine HCl 2.88 dextromethorphan 1.44 Doxylamine succinate Polyethylene glycol 600 Polyethylene glycol 1000 Propylene glycol Polyvinylpyrrolidone ¹ Purified water 0.60 24.38 22.14 4.33 8.17 4.81

available as Kollidon K-17 (BASF Chem. Co.), viscous average molecular weight 10000

A solution of polyethylene glycol and polyvinylpyrrolidone is prepared by mixing and heating the mixture to 70 ° C. Acetaminophen is dissolved in this solution with stirring and heating to 120 ° C in the presence of nitrogen. Once the acetoaminophen has dissolved, heating is stopped. Pseudoephedrine HCL, dextromethorphan, is dissolved in another vessel

HBr and doxylamine succinate in water at room temperature. Finally, this solution is combined with the original solution and mixed until the composition is homogeneous.

Examples Π and ΠΙ are further examples of concentrated solutions containing acetoaminophen in combination with other pharmaceutically active substances and are prepared in a manner similar to Example I.

example

Dissolved pharmaceutical composition

ingredients

Acetoaminophen Pseudoephedrine HCl Dextromethorphan HBr Doxylamine succinate Polyethylene glycol 600 Polyethylene glycol 1000 Propylene glycol Polyvinyl pyrrolidone ¹ Purified water% by weight

31,25

2.88

1.44

0.60

24.38

22.14

4.33

8.17

4.81 ‘Available as Kollidon K-12 (BASF Chem. Co.), viscous average molecular weight

5000

Example m

Dissolved pharmaceutical composition

Components Acetaminophen Pseudoephedrine HCl Dextromethorphan HBr Chlorpheniramine Maleate Polyethylene Glycol 600 Polyethylene Glycol 1000 Propylene Glycol Polyvinylpyrrolidone ¹ Purified water% by weight

31,25

2.88

1.44

0.19

24.52

22.40

4.33

8.17

4.82 ^l Available as Kollidon K-17 (BASF Chem. Co.), viscous average molecular weight

10000

Example IV

Dissolved pharmaceutical composition

A highly concentrated solution containing acetaminophen and guaifenesin in combination with other pharmaceutical active ingredients is prepared from the following ingredients:

Components Acetaminophen Pseudoephedrine HCl Dextromethorphan HBr Guaifenesin Polyethylene glycol 600 Polyethylene glycol 1000 Propylene glycol Polyvinylpyrrolidone ¹ Purified water% by weight

31.25

2.88

0.96

9.62

21.12

19:26

2.88

8.17

3.86 available as Kollidon K-17 PF (BASF Chem. Co.), viscous average molecular weight 10000

A solution of polyethylene glycols, propylene glycol and polyvinylpyrrolidone is prepared by stirring and heating to 70 ° C. Acetaminophen is then dissolved in this solution by stirring and heating to 120 ° C in the presence of nitrogen. Once acetaminophen is dissolved, heating is stopped and guaifenesin is added and dissolved. In another vessel, pseudoephedrine HCl, dextromethorphan HBr, and doxylamine succinate are dissolved in water at room temperature by stirring. This solution is finally combined with the original mixture and mixed until the solution is homogeneous.

Example V

Dissolved pharmaceutical composition

Example V is another example of a concentrated solution comprising acetaminophen and guaifenesin in combination with other pharmaceutically active agents and is prepared in a manner similar to Example IV.

Components Acetaminophen Pseudoephedrine HCl Dextromethorane HBr Guaifenesin Polyethylene glycol 600 Polyethylene glycol 1000 Propylene glycol Polyvinylpyrrolidone ¹ Purified water% by weight

31.25

2.88

0.96

9.62

21.12

19:26

2.88

8.17

3.86 ‘Available as Kollidon K-12 PF (BASF Chem. Co.), viscosity average molecular weight 5000

Example VI

Dissolved pharmaceutical composition

A highly concentrated acetaminophen-containing solution is prepared from the following ingredients:

Components Acetaminophen Polyethylene glycol 600 Polyethylene glycol 1000 Propylene glycol Polyvinylpyrrolidone ¹ Purified water% by weight

31,25

26.96

24.48

4.33

8.17

4.81 ‘Available as Kollidon K-30 (BASF Chem. Co.), viscous average molecular weight

38000

A solution of polyethylene glycols, propylene glycol and polyvinylpyrrolidone is prepared by stirring and heating to 70 ° C. Acetaminophen is then dissolved in this solution by stirring and heating the solution to 120 ° C in the presence of nitrogen gas. Once the acetaminophen is dissolved, heating is stopped. Finally, this solution is combined with a given amount of water and mixed until the composition of the solution is homogeneous.

Example VI

A highly concentrated solution containing acetaminophen and pseudoephedrine HCl is prepared from the following ingredients:

ingredients

Acetaminophen Pseudoephedrine HCl Polyethylene glycol 600 Polyethylene glycol 1000 Propylene glycol Polyvinylpyrrolidone ¹ Purified water% by weight

31,25

2.88

25.45

23,11

4.33

8.17

4.81 ‘Available as Kollidon K-30 (BASF Chem. Co.), viscous average molecular weight

38000

A solution of polyethylene glycols, propylene glycol and polyvinylpyrrolidone is prepared by stirring and heating to 70 ° C. Acetaminophen is then dissolved in this solution by stirring and heating to 120 ° C in the presence of nitrogen gas. Once the acetaminophen is dissolved, heating is stopped. In another vessel, the pseudoephedrine HCl is dissolved in water at room temperature by stirring. Finally, this solution is combined with the original mixture and mixed until the composition of the solution is homogeneous.

Example Vm

Soft gelatin capsules containing a dissolved pharmaceutical composition

The soft gelatin capsule is prepared from the following ingredients:

% By weight

Gelatine 47

Glycerin 1 5.00

Purified water qs 100

The above ingredients are combined in a suitable container and heated to 65 ° C to form a homogeneous solution. Using standard encapsulation methods, soft gelatin capsules containing about 1040 mg of the compositions of Examples I to VII are prepared. The resulting gelatin capsules are suitable for oral administration.

Industrial usability

The method of the present invention serves to improve the solubility of poorly soluble pharmaceutical active ingredients which are then suitable for the preparation of soft, flexible and readily swallowable gelatin capsules. The encapsulation in this way ensures an accurate and uniform delivery of the dose of the pharmaceutical active substance.

Claims (7)

A method of increasing the solubility of sparingly soluble pharmaceutical active compounds by combining and mixing them until 1% to 40%, preferably 20% to 40%, and more preferably 25% to 35%, of at least one sparingly soluble pharmaceutical active substance is dissolved in a solution characterized by characterized in that it contains: I) 20% to 70%, preferably 30% to 65%, more preferably 40% to 60% polyethylene glycol, Π) 4% to 20% polyvinylpyrrolidone with a viscous average molecular weight of 5000 to 25000, preferably 5000 to 15000, more preferably 5000 to 10000 and %Π) 1% to 10% propylene glycol. Method according to claim 1, characterized in that the composition according to claim 1 is further combined and mixed with 1% to 50% of the aqueous phase, preferably with water. The process according to any one of claims 1 to 2, wherein the ratio of polyethylene glycol to sparingly soluble pharmaceutical active ingredient and polyvinylpyrrolidine is 1: 0.3 to 1: 0.9 and 1: 0.09 to 1: 0.3. Method according to any one of claims 1 to 3, characterized in that the sparingly soluble pharmaceutical active substance is selected from the group consisting of acetaminophen, acetylsalicylic acid, ibuprofen, fenbuprofen, phenoprofen, flubiprofen, indomethacin, naproxen and mixtures thereof, preferably acetaminophen. The method according to any one of claims 1 to 4, wherein the 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. Method according to any one of claims 1 to 6, characterized in that the polyethylene glycol is a mixture of PEG-12 and PEG-20, preferably in a ratio of 1: 1. A method according to any one of claims 1 to 6, characterized in that one or more additional pharmaceutical active ingredients are added to the aforementioned aqueous phase and the additives are selected from the group of pharmaceutical active ingredients comprising dextromethorphan HBr, doxylamine succinate, pseudoephedrine HCl , chlorpheniramine maleate, guaifenesin, triprolidine HCl, diphenhydramine HCl and mixtures thereof.