Gelatin Capsules Containing a Highly Concentrated

ii 1 1 mi ii mi i in i ii i ii i ii � European Patent Office

Office europeen des brevets (11) EP 0 713 390 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51 ) |nt. CI.6: A61 K 31 /1 65, A61 K 9/48 of the grant of the patent: 09.06.1999 Bulletin 1999/23 (86) International application number: PCT/US94/08790 (21) Application number: 94926475.8 (87) International publication number: (22) Date of filing: 04.08.1994 w0 95/04527 (16.02.1995 Gazette 1995/08)

(54) GELATIN CAPSULES CONTAINING A HIGHLY CONCENTRATED ACETAMINOPHEN SOLUTION GELATINEKAISELN DIE EINE HOCHDOSIERTE ACETAMINOPHENLOSUNG ENTHALTEN CAPSULES DE GELATINE CONTENANT UNE SOLUTION D'ACETAMINOPHENE FORTEMENT CONCENTREE

(84) Designated Contracting States: • WEI, Youching CH DE ES FR GB IT LI NL Clearwater, FL 34624 (US) • LINKING, Deborah (30) Priority: 05.08.1993 US 102464 Maderia Beach, FL 33708 (US) 22.06.1994 US 263630 (74) Representative: (43) Date of publication of application: Cockbain, Julian, Dr. 29.05.1996 Bulletin 1996/22 Frank B. Dehn & Co., European Patent Attorneys, (73) Proprietor: 1 79 Queen Victoria Street R.P. SCHERER CORPORATION London EC4V 4EL (GB) Troy, Michigan 48007-7060 (US) (56) References cited: (72) Inventors: EP-A- 0 243 930 • SHELLEY, Rickey S. Largo, FL 34640 (US)

Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).

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Description vent itself. The solvent must have sufficient solvating power to dissolve a large amount of the pharmaceutical [0001 ] The present invention relates to soft and hard agent to produce a highly concentrated solution, and yet shell gelatin capsules encapsulating a pharmaceutical^ not hydrolyze, dissolve, or tan the softgel capsule shell. acceptable fill containing acetaminophen. s [0008] In many cases, this problem would have been [0002] Soft gelatin capsules or softgels are predomi- solved by using the enhanced solubility system nantly used to contain liquids wherein the active ingredi- described in U.S. Patent No. 5,071 ,643. U.S. Patent No. ents are present in the dissolved or suspended state. 5,071,643 (Yu et al.) discloses, inter alia, soft gelatin Filled one-piece softgels have been widely known and capsules containing highly concentrated acetami- used for many years and for a variety of purposes. 10 nophen solutions comprising 25-40% by weight aceta- Because softgels have properties that are quite different minophen, 0.4-1.0 moles of hydroxide ion per mole of from telescoping two-piece, hard shell capsules, the acetaminophen (provided, for example, by potassium softgels are capable of retaining a liquid fill material. hydroxide), and 1-20% by weight water in a polyethyl- The fill material may vary from industrial adhesives to ene glycol base, such as PEG 600. A specific example bath oils. More commonly, however, the softgels are is of a 35% concentrated solution of acetaminophen is used to enclose consumable materials such as vitamins shown in Example VI of this patent. However, it has and pharmaceuticals in a liquid vehicle or carrier. been recently determined that the sodium hydroxide or [0003] A particularly good bioavailability of the phar- potassium hydroxide required to solubilize the acetami- macologically active substance is attained if the active nophen at very high concentrations increased the pH of substance is successfully dissolved in a suitable solvent 20 the polyethylene glycol solution to greater than 12. This and the encapsulated solution is administered to the resulted in the degradation of the acetaminophen and patient. The term "active substance" as used herein the dissolving of the softgel shell. describes any active substance that can be orally [0009] Thus, the problem of finding an appropriate sol- administered in capsule form. This term includes phar- vent system for a soft gelatin capsule fill still exists for maceuticals, dietary supplements and vitamins. 25 acetaminophen. It has been difficult to achieve a soft [0004] Solutions also provide the best liquid form to gelatin capsule of small enough size to be acceptable to obtain optimal "content uniformity" in softgel fill. In addi- patients, i.e. small enough to swallow, while still includ- tion, a solution provides a faster and more uniform ing in that capsule a sufficient amount of acetami- absorption of a pharmaceutical agent than a suspen- nophen in solution to provide an effective unit dose. sion. Because of these distinct technical advantages, 30 Thus, there is a need in the art for a soft gelatin capsule solutions are preferred over suspensions or other dis- containing a fill in which acetaminophen is dissolved in persions. a solvent system in a high enough concentration to pro- [0005] Producing a highly concentrated solution of vide an effective unit dose in a patient acceptable size any acidic, amphoteric or basic pharmaceutical agent is capsule while at the same time avoiding degradation of useful because it permits the encapsulation of a unit 35 the acetaminophen and the capsule shell. dose of the pharmaceutical agent in a softgel capsule [001 0] It is a primary object of the present invention to that is small enough to permit easy swallowing. Filling a provide a solvent system that is capable of producing unit dose in a small softgel capsule to permit easy swal- highly concentrated solutions of acetaminophen that lowing is useful because it increases patient accept- are suitable for filling into softgels. ance of the medication. Patient acceptance is especially 40 [001 1 ] Viewed from one aspect the invention thus pro- important in the case of medications, because patient vides a soft gelatin capsule for oral administration hav- acceptance of the medication is a substantial step ing a soft gelatin shell encapsulating a fill, characterised towards solving one of the major problems of drug ther- in that said fill comprises a pharmaceutical^ acceptable apy-patient noncompliance with the prescribed regi- highly concentrated solution of acetaminophen com- men. 45 prising acetaminophen, polyethylene glycol and from [0006] A further utility of highly concentrated solutions 0.6% to 25% by weight of an alkali metal acetate, the is enhancement of bioavailability of the dissolved phar- alkali metal acetate being present in an amount suffi- maceutical agent. Enhanced bioavailability occurs as a cient to increase the maximum solubility of the acetami- result of delivering the pharmaceutical agent already in nophen in the solution. solution at the site of absorption, permitting a faster and so [001 2] Viewed from a further aspect the invention pro- more uniform absorption to occur. vides a soft gelatin capsule for oral administration hav- [0007] However, a problem in the art is that an appro- ing a soft gelatin shell encapsulating a fill, characterised priate solution of the pharmaceutical agent cannot in that said fill comprises a pharmaceutical^ acceptable always be achieved. One constraint is size. Often, it is highly concentrated solution of acetaminophen com- not possible to dissolve the pharmaceutical agent in a 55 prising from 20% to 40% by weight acetaminophen, volume of solvent small enough to produce a softgel from 18% to 65% by weight polyethylene glycol, from that is appropriate from the standpoint of economics 0% to 15% by weight propylene glycol, from 0% to 15% and patient acceptance. Another constraint is the sol- by weight water, from 0% to 1 5% by weight polyvinylpyr-

2 3 EP 0 713 390 B1 4 rolidone and from 0.6% to 25% by weight of an alkali ethylene glycol solution, which in turn increases the metal acetate, the alkali metal acetate being present in solubility of the weak acid acetaminophen. an amount sufficient to increase the maximum solubility [0017] Without using the solubility system of the of the acetaminophen in the solution. present invention, the maximum amount of acetami- [0013] The solvent system of the present invention is 5 nophen that could be dissolved in a polyethylene glycol, useful in that it provides for the encapsulation of a phar- propylene glycol, water, and polyvinylpyrrolidone mix- maceutical agent, acetaminophen, in a volume of solu- ture was 27% by weight. In the present invention, an tion that is small enough to permit easy swallowing. It alkali metal acetate is used in the solvent system in the further provides for the preparation of highly concen- absence of the strong base taught in Yu et al (supra). By trated solutions of the pharmaceutical agent to obtain w the addition of the potassium acetate or sodium acetate, for a higher dosage the same size softgel capsule as is the solubility of acetaminophen could be increased to presently commercially available for a lower dose soft- 32% or greater to achieve the same size softgel for a gel product. larger dose of acetaminophen without substantial deg- [0014] The present invention also relates generally to radation of the drug or the capsule shell caused by a a pharmaceutical carrier system or "solvent system" for 15 strong base. enhancing the solubility of acetaminophen alone or in [0018] Presently, acetaminophen is commercially sol- combination with other pharmaceutical agents, such as ubilized by addition to a mixture of polyethylene glycol, antihistamines, antitussives, decongestants, and propylene glycol, water and polyvinylpyrrolidone. But, expectorants, to form a clear solution for encapsulation as stated previously, this method will allow only 27% of into a softgel. The inventive solution comprises in its 20 the acetaminophen to be solubilized. The solubility sys- simplest form a mixture of 20-40% by weight acetami- tem of the Yu et al. disclosure was tried but was unsat- nophen, 18-65% by weight polyethylene glycol, 0-15% isfactory because of the resultant high pH of the by weight propylene glycol, 0-15% by weight water, 0- solution. The addition of the potassium (sodium) ace- 15% by weight polyvinylpyrrolidone, and 0.6-25% by tate, as set forth in the present invention, allows the weight alkali metal acetate, such as potassium or 25 acetaminophen solubility to be increased to 32% or sodium acetate. This solution may additionally be used greater. with hard shell gelatin capsules and this forms a further [001 9] The preferred alkali metal acetates are sodium aspect of the invention. Viewed from this further aspect acetate and potassium acetate. In preferred embodi- the invention provides a hard shell gelatin capsule for ments, the polyethylene glycol that forms a portion of oral administration having a hard gelatin shell encapsu- 30 the solvent system has an average molecular weight lating a semi-solid or solid fill, characterised in that said ranging between 200 and 800. However in the case of fill comprises a pharmaceutical^ acceptable highly con- the hard shell gelatin capsules of the invention the poly- centrated solution of acetaminophen comprising from ethylene glycol preferably has an average molecular 20 to 40% by weight acetaminophen, from 1 8 to 65% by weight of between 600 and 100000. weight polyethylene glycol, from 0 to 1 5% by weight pro- 35 [0020] In preferred embodiments, the alkali metal ace- pylene glycol, from 0 to 15% water by weight, from 0 to tate is present in amounts from 3 to 20% by weight of 1 5% by weight polyvinylpyrrolidone and from 0.6 to 25% the solution. by weight of an alkali metal acetate, the alkali metal [0021] The invention encompasses highly concen- acetate being present in an amount sufficient to trated solutions of acetaminophen wherein the prepared increase the maximum solubility of the acetaminophen 40 solutions are particularly suitable for softgel filling. In in the solution. Again acetaminophen may be present addition to the acetaminophen, other known active as the sole pharmaceutical agent or in combination with agents are suitable for use with the solvent system of a second pharmaceutical agent such as an antihista- this invention and may be either acidic, basic, ampho- mine, antitussive, decongestant or expectorant. teric or neutral compounds. [0015] In additional embodiments of the present 45 [0022] This invention may be used to manufacture invention, the inventive solutions comprise (a) from 30 softgels containing 325 mg acetaminophen alone or in to 65% by weight polyethylene glycol and from 1 to 25% combination with the other types of ingredients by weight of alkali metal acetate or (b) from 1 8 to 52% described above as a clear solution. These softgels by weight polyethylene glycol, 0 to 12% by weight pro- would then be of the approximate size of the present pylene glycol, 0 to 12% by weight water, 0 to 12% by so 250 mg acetaminophen product. weight polyvinylpyrrolidone and from 0.6 to 20% by [0023] The soft gelatin capsules that are useful with weight of alkali metal acetate. the present invention include conventional soft gelatin [001 6] In addition, the present invention increases the shells. Capsules useful in the present invention may be solubility of the acetaminophen to obtain the same size made by the conventional rotary die process. softgel for a 325 mg dose as is presently available for a 55 [0024] In its most basic form, the inventive fill for soft 250 mg dose softgel product. This is believed to be gelatin capsules include acetaminophen, polyethylene achieved by using a solubilizing agent such as potas- glycol and an alkali metal acetate. Using the present sium or sodium acetate to increase the pH of the poly- invention, concentrations of acetaminophen in the

3 5 EP 0 713 390 B1 6

resulting solution may be up to 40% by weight of the more preferably from 1 to 25% or 0.6 to 20%, especially solution. However, the present invention also contem- 3 to 20%. The alkali metal acetate selected is also plates encapsulation of lower concentrations of aceta- present in an amount sufficient to increase the maxi- minophen ranging down to 20% by weight of the mum solubility of the acetaminophen in the solution. In solution. The use of pharmaceutical grade acetami- 5 other words, the acetate should be present in an nophen USP is preferred. amount that results in an acetaminophen solution hav- [0025] Various polyethylene glycols may be used in ing a greater concentration of acetaminophen than the the present invention having average molecular weights concentration of acetaminophen in the identical solution between 200 and 800, most preferably between about without the acetate. This is referred to as an enhanced 400 and about 600. A single molecular weight polyethyl- 10 solubility amount of alkali metal acetate. ene glycol may be used or mixtures of various molecu- [0030] The person of ordinary skill in the art can, lar weight polyethylene glycols may be used. In the case through easy and routine experimentation, determine of mixtures, small proportions of polyethylene glycols the amount of the selected acetate that will result in the outside of the preferred average molecular weight acetaminophen fill solution of maximum concentration. ranges cited above may be used in admixture with poly- 15 For this purpose, a series of solutions of a particular sol- ethylene glycols within the preferred ranges. The molec- vent base with varying amounts of the acetate may be ular weights of the polyethylene glycols used in the prepared. To each solution, acetaminophen is added present invention should be selected such that the until no more dissolves and the concentration of aceta- resulting solution has viscosity compatible with the fill- minophen in each resulting saturated solution is then ing equipment contemplated for production of the soft 20 determined. These data points will establish a curve of gelatin capsules. The solution most preferably will con- acetaminophen concentration versus acetate concen- tain from 30 to 65% or 1 8 to 52% by weight polyethylene tration that will allow a person of ordinary skill in the art glycol. to determine the best particular level of acetate to be [0026] By altering the polyethylene glycol used, the used with a particular solvent base. present invention may be easily adapted for use with 25 [0031 ] Three optional adjuvants may be added to the hard shell gelatin capsules. By raising the average inventive fill solution: propylene glycol, water and/or pol- molecular weight of the polyethylene glycol used, a yvinylpyrrolidone. Propylene glycol may be present in semi-solid or solid solution of acetaminophen may be amounts from 0 to 1 5% by weight of the solution, partic- prepared that can suitably filled into conventional hard ularly 0 to 12%, more preferably from 3 to 10% or 12%. shell gelatin capsules according to known methods. In 30 Water may be present in amounts ranging from 0 to such cases, polyethylene glycols having an average 15% by weight of the solution, particularly 0 to 12%, molecular weight from 600 to about 10,000, preferably more preferably from 3 to 10% or 12%. Finally, polyvi- from 2,000 to about 8,000, can be used to prepare a nylpyrrolidone may be present in amounts from 0 to hard shell gelatin capsule fill solution that is semi-solid. 15% by weight of the solution, particularly 0 to 12%, Suitable fills for use in hard shell gelatin capsules would 35 more preferably between 3 and 10% or 12%. Polyvi- preferably have viscosities of about 20,000 to about nylpyrrolidone useful in the present invention may have 40,000 centipoise and up at 38°C. average molecular weights ranging between about [0027] Polyethyleneglycols having an average molec- 15,000 and 120,000, more preferably between about ular weight between about 10,000 and 100,000, prefer- 24,000 and 32,000. ably about 15,000 to about 60,000, can be used to 40 [0032] Because a strong base need not be used to produce a hard shell gelatin fill solution that is solid. The enhance the solubility of the acetaminophen in the polyethylene glycol in these instances would be used in present invention, the acetaminophen in the inventive the same amounts with respect to the total weight of the solution is typically not present in its salt form. Thus, the solution as in the case of soft gelatin capsule fills. Also, acetaminophen that is dissolved in high concentrations mixtures of various polyethylene glycols can be used to 45 in the inventive solution can conform to the U.S.P mon- achieve suitable semi-solid and solid fill solutions. ograph for acetaminophen as confirmed by nmr analy- [0028] The inventive fills also include at least one sis. alkali metal acetate, though mixtures of alkali metal ace- [0033] The following Examples are given by way of tates are contemplated to fall within the scope of the illustration. present invention. The two most preferred alkali metal so acetates are sodium acetate and potassium acetate. EXAMPLE 1 These two are preferred because of their general avail- ability and cost relative to the other alkali metal ace- [0034] A mixture of polyethylene glycol (1 8 to 65% by tates. It is contemplated, however, that the alkali metal weight), propylene glycol (0 to 15% by weight), and acetates known to the art may be used, such as sodium 55 water (from 0 to 1 5% by weight) is prepared and mixed acetate trihydrate. until homogeneous. Polyvinylpyrrolidone (or Povidone) [0029] The alkali metal acetate(s) selected is used in (from 0 to 1 5% by weight) is added to the above mixture an amount from 0.6 to 25% by weight of the solution, slowly while stirring. This mixture is stirred until dis-

4 7 EP 0 713 390 B1 8 solved. Acetaminophen (from 20 to 40% by weight) is added slowly, along with other optional ingredients, while stirring. This mixture is stirred until homogeneous. Potassium and/or sodium acetate (from 0.6 to 25% by c. % weight) is added. While mixing, the mixture is heated 5 PEG 600 39.39 and a temperature between 48.9 and 65.6°C (120° to 150°F) is maintained. The mixture is stirred until dis- Propylene Glycol 5.0 solved and a clear solution is formed. The mixture is Povidone 7.0 cooled and deaerated. The mixture is then encapsulated in conventional soft gelatin capsules using a con- w Dextromethorphan HBr 1 .47 ventional die The finished rotary process. dry softgels Pseudophedrine HCI 2.94 are dried to an appropriate hardness and fill moisture. Doxylamine Succinate 0.61 EXAMPLE 2 Acetaminophen 31.86 15 Potassium Acetate 3.83 [0035] The following formulations A through H were prepared according to the present invention in accord- Water 8.0 with the of 1 ance procedures Example . TOTAL 100.0

A. % PEG 400 38.5 Propylene Glycol 5.0 D. % Povidone 5.0 PEG 400 41.5 Acetaminophen 32.0 Propylene Glycol 3.0 Sodium Acetate Trihydrate Solution 19.5 Povidone 2.35 TOTAL 100.0 Dextromethorphan HBr 1 .47 • Dissolve 15gm Sodium Acetate Trihydrate in 5g Pseudophedrine HCI 2.94 water with heat Doxylamine Succinate 0.61 Acetaminophen 31.86 Potassium Acetate 8.27 Water 8.0 TOTAL 100.0 B. % PEG 400 39.4 Propylene Glycol 5.0 Povidone 5.0 Acetaminophen 32.0 E. % Potassium Acetate 10.6 PEG 400 43.91 Water 8.0 Povidone 5.0 TOTAL 100.0 Dextromethorphan HBr 1 .47 Pseudophedrine HCI 2.94 Doxylamine Succinate 0.61

55 Acetaminophen 31.86 Potassium Acetate 6.21 Water 8.0

5 9 EP 0 713 390 B1 10

(continued) a soft gelatin shell encapsulating a fill, characterised in that said fill E. % comprises a pharmaceutical^ acceptable highly concentrated solution of acetami- TOTAL 100.0 nophen comprising acetaminophen, polyethylene 5 glycol and from 0.6% to 25% by weight of an alkali metal acetate, the alkali metal acetate being present in an amount sufficient to increase the maximum solubility of the acetaminophen in the solution. F. % 2. A capsule as claimed in claim 1 wherein said solu- PEG 400 39.92 tion comprises from 20% to 40% by weight aceta- Propylene Glycol 3.0 minophen, from 18% to 65% by weight Povidone 5.0 polyethylene glycol, from 0% to 15% by weight propylene glycol, from 0% to 15% by weight water, Acetaminophen 35.0 from 0% to 1 5% by weight polyvinylpyrrolidone and Potassium Acetate 9.08 from 0.6% to 25% by weight of an alkali metal acetate. Water 8.0 TOTAL 100.0 3. A capsule as claimed in claim 1 or claim 2 wherein said solution comprises from 30 to 65% by weight polyethylene glycol and from 1 to 25% by weight of said alkali metal acetate.

4. A capsule as claimed in claim 1 or claim 2 wherein said solution comprises from 18 to 52% by weight G. % polyethylene glycol, 0 to 12% by weight propylene glycol, 0 to 12% by weight water, 0 to 12% by PEG 400 34.48 weight polyvinylpyrrolidone and from 0.6 to 20% by Propylene Glycol 2.58 weight of said alkali metal acetate. Povidone 4.30 5. A capsule as claimed in any one of claims 1 to 4 Acetaminophen 37.42 wherein said polyethylene glycol has an average Potassium Acetate 12.14 molecular weight of between 200 and 800.

Water 9.08 6. A hard shell gelatin capsule for oral administration TOTAL 100.0 having a hard gelatin shell encapsulating a semi- solid or solid fill, characterised in that said fill comprises a pharmaceutical^ acceptable highly concentrated solution of acetaminophen comprising from 20 to 40% by weight acetaminophen, from 18 to 65% by weight polyethylene glycol, from 0 to 15% by weight propylene glycol, from 0 to 15% H. % water by weight, from 0 to 15% by weight polyvinylpyrrolidone and from 0.6 to 25% by weight of an PEG 400 33.42 alkali metal acetate, the alkali metal acetate being Propylene Glycol 3.0 present in an amount sufficient to increase the maximum of the in the solu- Acetaminophen 40.0 solubility acetaminophen tion. Potassium Acetate 1 5.58 Water 8.0 7. A capsule as claimed in claim 6 wherein said polyethylene glycol has an average molecular weight of TOTAL 100.0 between 600 and 100,000.

55 8. A capsule as claimed in any one of claims 1 to 7 Claims wherein said alkali metal acetate is selected from the group consisting of potassium acetate and 1 . A soft gelatin capsule for oral administration having sodium acetate.

6 11 EP 0 713 390 B1 12

9. A capsule as claimed in any one of claims 1 to 8 Loslichkeit des Acetaminophens in der Losung zu wherein said alkali metal acetate is present in said erhohen. solution in an amount of from 3 to 20% by weight. 7. Kapsel gemaB Anspruch 6, worin das Polyethylen- 10. A capsule as claimed in any one of claims 1 to 9 5 glykol ein durchschnittliches Molekulargewicht zwi- wherein said fill additionally comprises a second schen 600 und 100.000 aufweist. pharmaceutical agent in addition to acetaminophen, said second pharmaceutical agent being 8. Kapsel gemaB einem der Anspriiche 1 bis 7, worin selected from the group consisting of antihista- das Alkalimetallacetat unter Kaliumacetat und mines, antitussives, decongestants and expecto- 10 Natriumacetat ausgewahlt ist. rants. 9. Kapsel gemaB einem der Anspriiche 1 bis 8, worin Patentanspruche das Alkalimetallacetat in besagter Losung in einer Menge von 3 bis 20 Gew.% vorliegt. 1. Weichgelatine-Kapsel fur die orale Verabreichung 15 mit einer eine Fullung einkapselnden weichen 10. Kapsel gemaB einem der Anspriiche 1 bis 9, worin Gelatinehulle, dadurch gekennzeichnet, daB diese besagte Fullung auBerdem ein zweites pharmazeu- Fullung eine pharmazeutisch annehmbare hoch- tisches Mitt el zusatzlich zu dem Acetaminophen konzentrierte Losung von Acetaminophen umfaBt, umfaBt, wobei dieses zweite pharmazeutische Mit- die Acetaminophen, Polyethylenglykol und 0,6 bis 20 tel unter Antihistaminen, Antitussiva, Congestio 25 Gew.% eines Alkalimetallacetats umfaBt, wobei abbauenden Mitteln und Expektoranzien ausge- das Alkalimetallacetat in einer ausreichenden wahlt ist. Menge vorliegt, urn die maximale Loslichkeit des Acetaminophens in der Losung zu erhohen. Revendications 25 2. Kapsel gemaB Anspruch 1 , worin besagte Losung 1 . Capsule a base de gelatine souple pour une admi- 20 bis 40 Gew.% Acetaminophen, 18 bis 65 Gew.% nistration orale ayant une enveloppe de gelatine Polyethylenglykol, 0 bis 15 Gew.% Propylenglykol, souple encapsulant une charge, caracterisee en ce 0 bis 15 Gew.% Wasser, 0 bis 15 Gew.% Polyvinyl- que ladite charge comprend une solution d'aceta- pyrrolidon und 0,6 bis 25 Gew.% eines Alkalimetall- 30 minophene pharmaceutiquement acceptable, hau- acetats umfaBt. tement concentree, comprenant de I'acetaminophene, du polyethylene glycol et de 3. Kapsel gemaB Anspruch 1 oder 2, worin besagte 0,6% a 25% en poids d'un acetate d'un metal alca- Losung 30 bis 65 Gew.% Polyethylenglykol und 1 lin, I'acetate de metal alcalin etant present en une bis 25 Gew.% besagten Alkalimetallacetats umfaBt. 35 quantite suffisante pour augmenter la solubilite maximale de I'acetaminophene dans la solution. 4. Kapsel nach Anspruch 1 oder 2, worin die besagte Losung 18 bis 52 Gew.% Polyethylenglykol, 0 bis 2. Capsule selon la revendication 1, dans laquelle 12 Gew.% Propylenglykol, 0 bis 12 Gew.% Wasser, ladite solution comprend de 20% a 40% en poids 0 bis 12 Gew.% Polyvinylpyrrolidon und 0,6 bis 20 40 d'acetaminophene, de 18% a 65% en poids de Gew.% besagten Alkalimetallacetats umfaBt. polyethylene glycol, de 0% a 15% en poids de propylene glycol, de 0% a 15% en poids d'eau, de 0% 5. Kapsel gemaB einem der Anspriiche 1 bis 4, worin a 15% en poids de polyvinylpyrrolidone et de 0,6% das Polyethylenglykol ein durchschnittliches Mole- a 25% en poids d'un acetate de metal alcalin. kulargewicht zwischen 200 und 800 aufweist. 45 3. Capsule selon la revendication 1 ou la revendica- 6. Gelatinekapsel mit harter Hulle fur die orale Verab- tion 2, dans laquelle ladite solution comprend de 30 reichung, die eine eine halbfeste oder teste Fullung a 65% en poids de polyethylene glycol et de 1 a einkapselnde Hulle aus harter Gelatine aufweist, 25% en poids dudit acetate de metal alcalin. dadurch gekennzeichnet, daB die Fullung eine 50 pharmazeutisch annehmbare hochkonzentrierte 4. Capsule selon la revendication 1 ou la revendica- Losung von Acetaminophen umfaBt, die 20 bis 40 tion 2, dans laquelle ladite solution comprend de 18 Gew.% Acetaminophen, 18 bis 65 Gew.% Polyethy- a 52% en poids de polyethylene glycol, de 0 a 12% lenglykol, 0 bis 15 Gew.% Propylenglykol, 0 bis 15 en poids de propylene glycol, de 0 a 12% en poids Gew.% Wasser, 0 bis 15 Gew.% Polyvinylpyrrolidon 55 d'eau, de 0 a 1 2% en poids de polyvinylpyrrolidone und 0,6 bis 25 Gew.% eines Alkalimetallacetats et de 0,6 a 20% en poids dudit acetate de metal umfaBt, wobei das Alkalimetallacetat in einer aus- alcalin. reichenden Menge vorhanden ist, urn die maximale

7 13 EP 0 713 390 B1 14

5. Capsule selon I'une quelconque des revendications 1 a 4, dans laquelle ledit polyethylene glycol a un poids moleculaire moyen compris entre 200 et 800.

6. Capsule a base de gelatine a enveloppe dure pour s administration orale, ayant une enveloppe de gelatine dure encapsulant une charge semi-solide ou solide, caracterisee en ce que ladite charge comprend une solution d'acetaminophene pharmaceutiquement acceptable, hautement concentree, 10 comprenant de 20 a 40% en poids d'acetaminophene, de 18 a 65% en poids de polyethylene glycol, de 0 a 15% en poids de propylene glycol, de 0 a 1 5% en poids d'eau, de 0 a 1 5% en poids de polyvinylpyrrolidone et de 0,6 a 25% en poids d'un ace- 15 tatede metal alcalin, I'acetate de metal alcalin etant present en une quantite suffisante pour augmenter la solubilite maximale de I'acetaminophene dans la solution. 20 7. Capsule selon la revendication 6, dans laquelle ledit polyethylene glycol a un poids moleculaire moyen compris entre 600 et 100.000.

8. Capsule selon I'une quelconque des revendications 25 1 a 7, dans laquelle ledit acetate de metal alcalin est choisi parmi le groupe constitue de I'acetate de potassium et de I'acetate de sodium.

9. Capsule selon I'une quelconque des revendications 30 1 a 8, dans laquelle ledit acetate de metal alcalin est present dans ladite solution en une quantite de 3 a 20% en poids.

10. Capsule selon I'une quelconque des revendications 35 1 a 9, dans laquelle ladite charge comprend en outre un second agent pharmaceutique en plus de I'acetaminophene, le second agent pharmaceutique etant choisi dans le groupe constitue des anti- histaminiques, des antitussifs, des 40 decongestionnants et des expectorants.