Technical field of invention
The present invention relates to a process for manufacturing pharmaceutical composition comprising poorly soluble pharmaceutical ingredient, particularly ibuprofen, encapsulated into a soft gelatin capsule. The solvent system of the present invention is useful in that it provides a highly concentrated clear aqueous solution of ibuprofen in a volume that is small enough to permit easy swallowing.
One of the most important aspect of the present invention is that clear solutions of ibuprofen can be prepared at a temperature not exceeding 45 °C.
Background of the invention
Ibuprofen is the most widely used analgesic and antipyretic and the most commonly used dosage form for the delivery of ibuprofen is a tablet. The absorption time of a tablet of ibuprofen is relatively long because of two significant factors. Ibuprofen being introduced as a solid needs to first dissolve before it can be absorbed by the body and further its absorption into the body is delayed because it is practically insoluble in water and in the acidic environment of the stomach.
Liquids and especially concentrated liquid pharmaceutical compositions offer many advantages over solid compositions. Liquids are easy to swallow and provide an excellent vehicle for the uniform delivery of pharmaceutical actives. These provide a rapid onset of pharmacological action, since the composition does not first have to disintegrate and dissolve in the gastrointestinal tract. Concentrated liquid compositions are ideally suited for encapsulation within a soft gelatin shell, to provide a portable and easy-to-swallow soft, flexible capsule.
Encapsulation permits accuracy and uniformity in delivering a unit dose of a pharmaceutical active. Additionally, soft gelatin capsules are aesthetically appealing (especially when filled with a transparent liquid) and can be manufactured in a wide variety of sizes, shapes, and colors. Furthermore, since the dosage form is generally swallowed, it is unnecessary to flavor or mask the unpleasant taste of the active pharmaceutical
ingredients. Finally unlike tablets, soft gelatin capsules do not chip or powder. A particularly good bioavailability of pharmaceutical active substance may be attained if the active is completely dissolved in a suitable solvent and the encapsulated solution is administered to the patient. Solutions provide the best liquid form to obtain optimal content uniformity. In addition a solution provides a faster and more uniform absorption. However, it is not always possible to prepare clear liquid compositions of the poorly soluble actives, to be filled into soft gelatin capsules due to constraints of solvent available.
Several processes have been developed in efforts to increase the solubility of ibuprofen. One approach has been to incorporate co-solvents and surfactants and another approach involves the use of heat to prepare clear solutions. The process of heating may result in clear solution but in some cases, there is a possibility of reprecipitation of the contents on reaching room temperature. Further, the heating process is disadvantageous since it demands long processing times and large amount of energy.
US patent No. 4,690,823, issued to Lohner et al, relates to the solubilization of ibuprofen in 70 to 85 parts of polyoxyethylene- polyoxypropylene polymer or in a mixture of 30 to 70 parts of polyethylene glycol and 7 to 40 parts of surfactant, at a temperature of 45-65°C. These soft gels exhibit very rapid and high bioavailability of the active ingredient.
US patent 6,387400, discloses a process for increasing the concentration of a pharmaceutically active ingredient relative to fill composition. It comprises of two-step process. In step one an initial suspension is made by combining first portion of a pharmaceutically active ingredient with polyethylene glycol having a molecular weight ranging from about 200 Daltons to about 100,000 Daltons and solublizing it subsequently with hydroxide ion. The second step involves adding a second portion of pharmaceutically active ingredient and of hydroxide ion source to the solution to form another suspension.
Gelatin-sheath-enclosed liquid soft gel formulations containing ibuprofen as the free acid are described in U.S. Pat. No. 6,251,426 assigned to Pharmacaps. The softgels are prepared by dissolving greater than 30% by weight of ibuprofen in polyethylene glycol and at least 10% of polyvinylpyrrolidone of an average molecular weight of about 2,000 to
54,000 Daltons. These formulations may also include a surfactant to increase the bioavailability of the ibuprofen.
Yu et al U. S. Pat. No. 5,071,643 describes the solvent system enhancing the bioavailability of the acidic pharmaceutical agent. Yu et al. invention consists of use of hydroxide ions to carry out the partial ionization of the acidic pharmaceutical agent and use of solvent system containing polyvinyl pyrollidone, and polyethylene glycol to enhance the bioavailability of acidic pharmaceutical agent.
The US patent 5,141,961 discloses a process for solubilizing difficulty soluble pharmaceutical actives. It uses polyethylene glycol, polyvinyl pyrolidine and monohydric alcohols. The ratio of polyethylene glycol to polyvinyl pyrolidine is about 2.5 to 1. It does not involve either use of heat or surfactants. However, nowhere it is mentioned that clear solutions are prepared.
US patent No. 6,221,391 discloses a self-emulsifying, clear highly concentrated ibuprofen formulation to be filled into soft gel capsules, comprising active ingredient, non-ionic surfactant (polyoxyethylene derivative of castor oil) and a complexing agent, polyvinyl pyrrolidone used as solubilizer. The process steps involve heating of the mixture to a temperature of 50 to 70°C.
PCT application No. WO 03/013481, filed by Cadila discloses a process for solublizing poorly soluble active pharmaceutical ingredient, of a mixture of two or more by using 40 to 60 % of a mixture of two or more polyethylene glycols of different molecular weights along with 4-8% of dispersing agent like polyvinyl pyrrolidone, wherein solubilization is aided by heating the contents at a temperature not exceeding 90°C.
All the prior art processes include the step of heating (45-90°C) to aid the mixing of all the ingredients that results in a clear solution. The inventors have developed a process for preparing clear aqueous solutions of ibuprofen, which is carried out at a temperature not exceeding 45°C.
Summary of the Invention
The invention provides clear aqueous solutions comprising ibuprofen and a solvent system for filling into soft gelatin capsules.
It is one of the aspects to provide a process for obtaining clear aqueous solutions of ibuprofen wherein the process is carried out at a temperature not exceeding 45°C.
It is another aspect to provide clear aqueous solutions comprising ibuprofen and a solvent system, wherein the solvent system comprises:
(a) from about 15 to 50% by weight of polyethylene glycol,
(b) from about 1 to 20% by weight of surfactant,
(c) from about 1 to 10% by weight of alkalizing agent,
(d) from about 2 to 10% of the solubilizer,
(e) from about 2 to 10% of water.
and wherein, solubilization of ibuprofen is carried out at a temperature not exceeding 45°C.
It is yet another aspect to provide soft gelatin capsules filled with clear aqueous solutions comprising ibuprofen and a solvent system, wherein the solvent system comprises:
(a) from about 15 to 50% by weight of polyethylene glycol,
(b) from about 1 to 20% by weight of surfactant,
(c) from about 1 to 10% by weight of alkalizing agent,
(d) from about 2 to 10% of the solubilizer,
(e) from about 2 to 10% of water
and wherein, solubilization of ibuprofen is carried out at a temperature not exceeding 45"'C.
It is still another aspect to provide a process of preparing soft gelatin capsules filled with a clear solution of ibuprofen, comprising the steps of:
(a) preparing a solution of polyethylene glycol and the surfactant,
(b) mixing the solution with an aqueous solution of alkalizing agent,
(c) dispersing solubilizer in the solution of step (b),
(d) adding ibuprofen to the dispersion of step (c) and stirring at a temperature not exceeding 45°C to obtain a clear solution, and
(e) encapsulating the solution in a soft gelatin capsule.
In another general aspect, there are provided methods of treating an inflammatory conditions and for relieving pain in mammals in need of treatment, which include administering pharmaceutical compositions comprising soft gelatin capsules filled with clear ibuprofen solution, wherein solubilization of ibuprofen is carried out at a temperature not exceeding 45°C.
The pharmaceutical composition may further include one or more of glucosamine, pseudoephedrine, codeine, paracetamol, econazole, COX-2 inhibitor, alprazolam, dextromethorphan and chlorpheniramine.
The details of one or more embodiments are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description and claims.
Detailed Description of the Invention
The present invention is not limited to particular process steps and materials disclosed herein, but is extended to equivalents thereof as would be recognized by those ordinarily skilled in the relevant arts. It should also be understood that terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting.
When used in the following description, "ibuprofen" will be understood to mean ibuprofen in its free acid form. Ibuprofen constitutes from about 15% to about 40% of the solution by weight.
The term 'clear solutions', as used herein, describes liquid pharmaceutical compositions, which are transparent and free from turbidity or cloudiness or any other foreign particulate matter.
The major constituent of the solvent system is a carrier in which the pharmaceutically active agent to be delivered is dissolved or dispersed. One class of carrier that has been used widely in the filling is liquid polyethylene glycols (PEG). Polyethylene glycols having an average molecular weight from about 200-800 Daltons, particularly from about 400-700 Daltons, and more particularly about 400 Daltons, are liquids at room temperature or have a melting point slightly above room temperature. Mixtures of two or more polyethylene glycols of different average molecular weight range may be employed. Polyethylene glycols can be added in a concentration of about 15 to 50% by weight of the formulation.
According to one of the embodiments, polyethylene glycols having an average molecular weight of about 400 Daltons are used as carrier.
Apart from polyethylene glycols, the solvent system comprises at least one surfactant to effectuate uniform dispersion of the drug in water or gastric juices without increasing the volume of the solvent system. Suitable surfactants may include hydrophilic surfactants, which may be anionic, cationic, zwitterionic or non-ionic, although non-ionic hydrophilic surfactants are particularly used. These non-ionic hydrophilic surfactants generally have HLB values greater than about 10. Mixtures of hydrophilic surfactants may also be employed.
Suitable non-ionic hydrophilic surfactants are selected from the group consisting of polyoxyethylene alkyl ethers; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof. Suitable examples of these are polyethylene glycol-20 laurate, polyethylene glycol-20 oleate, polyethylene glycol-35 castor oil, polyethylene glycol-40 palm kernel oil,
polyethylene glycol-40 hydrogenated castor oil, polyethylene glycol-60 corn oil, polyethylene glycol-25 glyceryl trioleate, polyglyceryl-10 laurate, polyethylene glycol-6 caprate/caprylate glycerides, polyethylene glycol-8 caprate/caprylate glycerides, polyethylene glycol-30 cholesterol, polysorbate 20, polysorbate 80, polyoxyethylene-9 lauryl ether, polyoxyethylene-23 lauryl ether, polyoxyethylene-10 oleyl ether, polyethylene glycol-24 cholesterol, sucrose monostearate, sucrose monolaurate and poloxamers. The surfactants may constitute from about 1 to 20%, by weight of the formulation.
In one of the embodiments, the surfactant comprises polyoxyethylene sorbitan fatty acid esters. Particularly, polysorbate 80.
To prevent the repreciptation or recrystallization of ibuprofen from the solution and to stabilize the preparation, suitable solubilizers are added. Suitable solubilizers may be selected from amongst triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly polyvinyl pyrrolidone is added. Polyvinyl pyrrolidone is a polymeric compound formulated to specific molecular weights, which can range from approximately 2000 to 1,500,000 Daltons. Polyvinyl pyrrolidone has the capacity or property of forming water-soluble complexes with water insoluble drug substances such as ibuprofen. Typically, higher molecular weight polyvinyl pyrrolidones are used as thickeners while low molecular weight polyvinyl pyrrolidones are typically used as solubilizers or crystallization inhibitors. Polyvinyl pyrrolidone K-12 (molecular weight approximately 2000-3000 Daltons), Polyvinyl pyrrolidone K-17 (molecular weight approximately 7000-11,000 Daltons), and Polyvinyl pyrrolidone K-30 molecular weight approximately 30,000 Daltons) are utilized as solubilizers. The solubilizers constitute about 2 to 10% by weight of the formulation.
An alkalizing agent may also be added to the composition to improve the solubility of the ibuprofen during the formulation of the composition. The alkalizing agents may be selected from amongst organic amines and bases. Suitable organic amines include colamine (ethanolamine), lysine, triethanolamine, N- methylglucamine (meglumine), ethylene diamine, trimethylamine, and triisopantolamine. Suitable bases, which are salts of
pharmaceutically acceptable acids include ammonium bicarbonate, sodium bicarbonate, calcium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, calcium carbonate, ammonium hydroxide, sodium hydroxide, calcium hydroxide, ammonium hydroxide or mixture thereof. The alkalizing agent constitutes from about 1 to 10 % by weight of the formulation.
In order to prepare a solution of alkalizing agent, water may be added in approximately about 2 to 10% by weight of the solution.
The solution may further contain other pharmaceutically acceptable additives, such as antioxidants, buffering agents, antifoaming agents, detackifiers, preservatives, chelating agents, viscosity modifiers, tonicifiers, flavorants, colorants, odorants, opacifiers, stabilizing agents, fillers, plasticizing agents, or mixtures thereof.
Soft gelatin capsules containing clear aqueous solutions can be prepared using conventional and known encapsulation techniques. In general, the solution is deposited between two opposing ribbons of a gel composition. The composition of the ribbons may include gelatin, modified starches, gums, carrageenans and mixtures thereof. The opposing ribbons are then run between two die rollers having die pockets thereon the surface of which corresponds to the configuration of the desired soft capsule. The composition is sealed within the fused casing.
According to one of the embodiments, a clear aqueous solutions of ibuprofen can be prepared by following steps: preparing a solution of polyethylene glycol and the surfactant, mixing the solution with an aqueous solution of alkalizing agent, dispersing solubilizer in it, adding ibuprofen to the dispersion and stirring at a temperature not exceeding 45°C to obtain a clear solution.
In another embodiment, a clear aqueous solutions of ibuprofen can be prepared by following steps: preparing a solution of polyethylene glycol 400 and polysorbate 80, mixing the solution with an aqueous solution of N-methylglucamine, dispersing polyvinyl pyrrolidone in it, adding ibuprofen to the dispersion and stirring the solution at a temperature not exceeding 45°C to obtain a clear solution.
According to yet another embodiment, soft gelatin capsules of ibuprofen may comprise clear aqueous solutions comprising from about 15 to 40% by weight of ibuprofen, from about 15 to 50% by weight of polyethylene glycol, from about 1 to 20% by weight of surfactant, from about 1 to 10% by weight of alkalizing agent, from about 2 to 10% of the solubilizer, from about 2 to 10% of water.
According to yet another embodiment, soft gelatin capsules of ibuprofen may comprise from about 15 to 40% by weight of ibuprofen, from about 15 to 50% by weight of polyethylene glycol 400, from about 1 to 20% by weight of polysorbate-80, from about 1 to 10% by weight of N-methylglucamine, from about 2 to 10% of the polyvinyl pyrrolidone, from about 2 to 10% of water.
The invention is illustrated in more detail by means of the following Examples. This is for illustration only and should not be construed as limiting scope of the invention.
Example 1: Preparation of soft gelatin capsules of ibuprofen:
(TABLE REMOVED)
Process:
1. N-methylglucamine was dissolved in purified water.
2. Polyethylene glycol and Polysorbate 80 were mixed separately, to obtain a clear solution.
3. The solution of Step 1 was mixed with that of Step 2 and polyvinyl pyrrolidone was dispersed in it,
4. Ibuprofen was added slowly to the dispersion and stirred continuously till clear solution was obtained,
5. The solution of Step 4 was allowed to deaerate, and
6. The deareated solution was finally encapsulated in a soft gelatin shell.
While several particular forms of the invention have been illustrated and described, it will be apparent that various modifications and combinations of the invention detailed in the text can be made without departing from the spirit and scope of the invention. For example, the alkalizing agent used in the pharmaceutical compositions does not necessarily need to include only N-methyl glucamine but instead can be made up of any other alkalizing agent or mixture of different alkalizing agents, e.g., potassium carbonate. Further aspects of this invention, together with additional features contributing thereto and advantages accruing therefrom will be apparent from the following hypothetical example.
Example 2: Preparation of soft gelatin capsules of ibuprofen:
(TABLE REMOVED)
Process:
1. Dissolve potassium carbonate in purified water.
2. Separately mix polyethylene glycol and Polysorbate 80, to obtain a clear solution.
3. Mix the solution of Step 1 with that of Step 2 and disperse polyvinyl pyrrolidone in it.
4. Add ibuprofen slowly to the dispersion and stir continuously to obtain clear solution,
5. Allow the solution of step 4 to deaerate, and
6. Encapsulate the deareated solution in a soft gelatin shell.

WE CLAIM:
1. A clear aqueous solution comprising ibuprofen and a solvent system, wherein the solvent system comprises:
(a) from about 15 to 50% by weight of polyethylene glycol,
(b) from about 1 to 20% by weight of surfactant,
(c) from about 1 to 10% by weight of alkalizing agent,
(d) from about 2 to 10% of the solubilizer,
(e) from about 2 to 10% of water.
wherein, solubilization of ibuprofen is carried out at a temperature not exceeding 45°C.
2. The solution according to claim 1, wherein ibuprofen constitutes from about 15 to 40% of the solution by weight.
3. The solution according to claim 1, wherein polyethylene glycol Is has an average molecular weight of about 200-800 Daltons.
4. The solution according to claim 3, wherein polyethylene glycol is has an average molecular weight of about 400-700 Daltons.
5. The solution according to claim 4, wherein polyethylene glycol is has an average molecular weight of about 400 Daltons.
6. The solution according to claim 1, wherein the surfactant is selected from amongst hydrophilic non-ionic surfactants having an HLB value equal to or greater than 10.
7. The solution according to claim 6, wherein the hydrophilic surfactant Is a non-ionic surfactant selected from amongst polyoxyethylene alkyl ethers; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the
group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof.
8. The solution according to claim 7, wherein the hydrophilic non- ionic surfactant is polyoxyetheylene sorbitan fatty acid ester.
9. The solution according to claim 1, wherein the alkalizing agent is selected from amongst organic amines and bases.

10. The solution according to claim 9, wherein the organic amine is selected from the group consisting of ethanolamine, lysine, triethanolamine, and N-methylglucamine.
11. The solution according to claim 10, wherein the organic amine is N- methylglucamine.
12. The solution according to claim 9, wherein the bases are selected from amongst ammonium bicarbonate, sodium bicarbonate, calcium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, calcium carbonate, ammonium hydroxide, sodium hydroxide, calcium hydroxide, ammonium hydroxide or mixture thereof.
13. The solution according to claim 1, wherein the solubilizer is polyvinyl pyrrolidone.
14. The solution according to claim 1, wherein the solution is filled into soft gelatin capsule.
15. The solution according to claim 1, further comprising pharmaceutically acceptable additives selected from the group comprising antioxidants, buffering agents, antifoaming agents, detackifiers, preservatives, chelating agents, viscosity modifiers, tonicifiers, flavorants, colorants, odorants, opacifiers, stabilizing agents, fillers, plasticizing agents, or mixtures thereof.
16. A process for preparing a clear aqueous solution of ibuprofen comprising the steps of:

(a) preparing a solution of polyethylene glycol and the surfactant,
(b) mixing the solution with an aqueous solution of alkalizing agent,
(c) dispersing solubilizer in the solution of step (b),
(d) adding ibuprofen to the dispersion of step (c) and stirring at a temperature not exceeding 45°C to obtain a clear solution, and
(e) encapsulating the solution in a soft gelatin capsule.

17. The process according to claim 16, wherein ibuprofen constitutes from about 15 to 40% of the solution by weight.
18. The process according to claim 16, wherein polyethylene glycol has an average molecular weight of about 200-800 Daltons.
19. The process according to claim 18, wherein polyethylene glycol has an average molecular weight of about 400-700 Daltons.
20. The process according to claim 19, wherein polyethylene glycol has an average molecular weight of about 400 Daltons.
21. The process according to claim 16, wherein polyethylene glycol constitutes from about 15 to 50% of the solution by weight.
22. The process according to claim 16, wherein the surfactant is selected from amongst hydrophilic non-ionic surfactants having an HLB value equal to or greater than 10.
23. The process according to claim 22, wherein the hydrophilic surfactant is a non-ionic surfactant selected from amongst polyoxyethylene alkyl ethers; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof.
24. The process according to claim 23, wherein the hydrophilic non- ionic surfactant is polyoxyetheylene sorbitan fatty acid ester.
25. The process according to claim 16, wherein the non- ionic hydrophilic surfactant constitutes from about 1 to 20% of the solution by weight.
26. The process according to claim 16, wherein the alkalizing agent is selected from amongst organic amines and bases.
27. The process according to claim 16, wherein the alkalizing agent constitutes from about 1 to 10% of the solution by weight.
28. The process according to claim 26, wherein the organic amine is selected from the group consisting of ethanolamine, lysine, triethanolamine, and N-methylglucamine.
29. The process according to claim 28, wherein the organic amine is N- methylglucamine.
30. The process according to claim 26, wherein the bases are selected from amongst ammonium bicarbonate, sodium bicarbonate, calcium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, calcium carbonate, ammonium hydroxide, sodium hydroxide, calcium hydroxide, ammonium hydroxide or mixture thereof.
31. The process according to claim 16, wherein the solubilizer is polyvinyl pyrrolidone.
32. The process according to claim 16, wherein the solubilizer constitutes from about 2 to10% of the solution by weight.
33. The process according to claim 16, further comprising pharmaceutically acceptable additives selected from the group comprising antioxidants, buffering agents, antifoaming agents, detackifiers, preservatives, chelating agents, viscosity modifiers, tonicifiers, flavorants, colorants, odorants, opacifiers, stabilizing agents, binders, fillers, plasticizing agents, lubricants, and mixtures thereof.
34. A soft gelatin capsule filled with clear aqueous solution, comprising ibuprofen and a
solvent system, wherein the solvent system comprises:
(a) from about 15 to 50% by weight of polyethylene glycol,
(b) from about 1 to 20% by weight of surfactant,
(c) from about 1 to 10% by weight of alkalizing agent,
(d) from about 2 to 10% of the solubilizer,
(e) from about 2 to 10% of water.
wherein, solubilization of ibuprofen is carried out at a temperature not exceeding 45°C.
35. A soft gelatin capsule according to claim 34, wherein ibuprofen constitutes from about 15 to 40% of the solution by weight.
36. A soft gelatin capsule according to claim 34, wherein polyethylene glycol is has an average molecular weight of about 200-800 Daltons.
37. A soft gelatin capsule according to claim 36, wherein polyethylene glycol is has an average molecular weight of about 400-700 Daltons.
38. A soft gelatin capsule according to claim 37, wherein polyethylene glycol is has an average molecular weight of about 400 Daltons.
39. A soft gelatin capsule according to claim 34, wherein the surfactant is selected from amongst hydrophilic non-ionic surfactants having an HLB value equal to or greater than 10.
40. A soft gelatin capsule according to claim 39, wherein the hydrophilic surfactant is a non-ionic surfactant selected from amongst polyoxyethylene alkyl ethers; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethyiene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof.
41. A soft gelatin capsule according to claim 40, wherein the hydrophilic non- ionic surfactant is polyoxyetheylene sorbitan fatty acid ester.
42. A soft gelatin capsule according to claim 34, wherein the alkalizing agent is selected from amongst organic amines and bases.
43. A soft gelatin capsule according to claim 42, wherein the organic amine is selected from the group consisting of ethanolamine, lysine, triethanolamine, and N-methylglucamine.
44. A soft gelatin capsule according to claim 43, wherein the organic amine is N-methylglucamine.
45. A soft gelatin capsule according to claim 42, wherein the bases are selected from amongst ammonium bicarbonate, sodium bicarbonate, calcium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, calcium carbonate, ammonium hydroxide, sodium hydroxide, calcium hydroxide, ammonium hydroxide or mixture thereof.
46. A soft gelatin capsule according to claim 34, wherein the solubilizer is polyvinyl pyrrolidone.
47. A soft gelatin capsule according to claim 34, further comprising pharmaceutically acceptable additives selected from the group comprising antioxidants, buffering agents, antifoaming agents, detackifiers, preservatives, chelating agents, viscosity modifiers, tonicifiers, flavorants, colorants, odorants, opacifiers, stabilizing agents, fillers, plasticizing agents, or mixtures thereof.
48. A method of treating inflammatory condition in mammals in need of such treatment
comprising administering to said mammal a clear aqueous solution, comprising ibuprofen
and a solvent system, wherein the solvent system comprises:
(a) from about 15 to 50% by weight of polyethylene glycol,
(b) from about 1 to 20% by weight of surfactant,
(c) from about 1 to 10% by weight of alkalizing agent,
(d) from about 2 to 10% of the solubilizer,
(e) from about 2 to 10% of water.
wherein, solubilization of ibuprofen is carried out at a temperature not exceeding 45°C.
49. A process for preparing ibuprofen soft gelatin capsules comprising a clear aqueous solution of ibuprofen as described and illustrated in the examples herein.