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Pharmaceuticals Compositions Comprising Sulphonylurea-Class Insulin Secretagogue and Polyethylene Glycol Castor Oil

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Pharmaceuticals Compositions Comprising Sulphonylurea-Class Insulin Secretagogue and Polyethylene Glycol Castor Oil (19) & (11) EP 2 438 911 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 11.04.2012 Bulletin 2012/15 A61K 9/20 (2006.01) A61K 31/4439 (2006.01) A61K 31/64 (2006.01) A61K 9/16 (2006.01) (21) Application number: 10013440.2 (22) Date of filing: 08.10.2010 (84) Designated Contracting States: (72) Inventor: The designation of the inventor has not AL AT BE BG CH CY CZ DE DK EE ES FI FR GB yet been filed GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (74) Representative: Hodzar, Damjan et al Designated Extension States: Lek Pharmaceuticals d.d. BA ME Verovskova 57 1526 Ljubljana (SI) (71) Applicant: LEK Pharmaceuticals d.d. 1526 Ljubljana (SI) (54) Pharmaceuticals compositions comprising sulphonylurea-class insulin secretagogue and polyethylene glycol castor oil (57) The present invention relates to the field of a rea-class insulin secretagogue active pharmaceutical in- pharmaceutical technology. More specifically, the gredient and at the same time, when both formulated into present invention relates to a pharmaceutical composi- a pharmaceutical composition, ensures satisfying or ex- tion comprising sulphonylurea-class insulin secreta- ceeding other parameters like for example stability, hard- gogue and a surface active agent. Surface active agent ness, friability and handling of said pharmaceutical com- obtainable by reacting castor oil or hydrogenated castor position. oil with ethylene oxide, preferably hydrogenated castor oil, substantially improves dissolution of the sulphonylu- EP 2 438 911 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 438 911 A1 Description Field of the invention 5 [0001] The present invention relates to the field of a pharmaceutical technology. More specifically, the present invention relates to a pharmaceutical composition comprising sulphonylurea-class insulin secretagogue and a surface active agent. Further, the present invention provides for a process and use of said pharmaceutical composition. Background of the invention 10 [0002] Sulphonylurea-class insulin secretagogue have proved to be a class of potent drugs for treating diabetes. Sulphonylurea-class insulin secretagogue lowers blood glucose primarily by stimulating the secretion of insulin from functional pancreatic beta cells. In this way they exert a long- term effect of reducing the blood glucose levels. In addition, extrapancreatic effects may also play a role in the activity of sulfonylureas. An efficacious sulphonylurea-class insulin 15 secretagogue is glimepiride. This is supported by both preclinical and clinical studies demonstrating that glimepiride administration can lead to increased release of insulin by pancreatic beta cells. However, the characteristic low solubility of sulphonylurea-class active pharmaceutical ingredients poses great difficulty to providing pharmaceutical composition of suitable solubility or dissolution rate. In such case, when active pharmaceutical ingredient is not soluble or only sparingly soluble in neutral or acidic pH region, the dissolution is poor and a sufficient blood concentration of active 20 pharmaceutical ingredient can not be obtained. Specifically for the sulphonylurea-class insulin secretagogue pharma- ceutical ingredients the prior art describes various solutions to address the solubility problem. [0003] WO 2005/041962 A1 discloses a solid preparation comprising an insulin sensitizer, which can among others be pioglitazone; an insulin sectetagogue like for example glimepiride, and a polyoxyethylene sorbitan fatty acid ester. Polysorbate 80 is exemplified as a preferred polyoxyethylene sorbitan fatty acid ester. 25 [0004] In the US 2007/0264331 A1 immediate release of glimepiride was achieved by putting glimepiride in a film coating, wherein sodium lauryl sulphate was added. In addition, the glimepiride was micronized. [0005] It is indeed desired to provide a pharmaceutical composition comprising sulphonylurea-class insulin secreta- gogue as an active pharmaceutical ingredient that enables enhanced solubility and relatively fast dissolution of the otherwise insoluble or sparingly soluble active ingredient and thus allows the active ingredient to be better utilized when 30 such pharmaceutical composition is administered to a patient. In addition, adequate or even superior dissolution of the sulphonylurea-class insulin secretagogue is preferably ensured together with satisfying or exceeding other parameters of pharmaceutical formulation like for example stability, hardness, friability and handling properties. Summary of the invention 35 [0006] First aspect of the present invention is a pharmaceutical composition comprising a sulphonylurea- class insulin secretagogue and a surface active agent, wherein the surface active agent is obtainable by reacting castor oil or hydro- genated castor oil with ethylene oxide. [0007] Second aspect of the present invention is a process for preparing a pharmaceutical composition comprising a 40 sulphonylurea-class insulin secretagogue and a surface active agent, wherein the surface active agent is obtainable by reacting castor oil with ethylene oxide, wherein the process comprises dissolving the surface active agent in a solvent, dispersing therein the sulphonylurea-class insulin secretagogue by mixing and removing the solvent. [0008] Third aspect of the present invention is a pharmaceutical composition according to the first aspect for use as a medicine. 45 [0009] Yet another aspect of the present invention is a use of a surface active agent as defined in the first aspect for enhancing dissolution of a sulphonylurea-class insulin secretagogue, preferably glimepiride. Preferred embodiments of the invention and advantageous combinations thereof 50 [0010] The aspects, advantageous features and preferred embodiments of the present invention summarized in the following items, respectively alone or in combination, further contribute to solving the object of the invention: (1) A pharmaceutical composition comprising a sulphonylurea-class insulin secretagogue and a surface active agent, wherein the surface active agent is obtainable by reacting castor oil or hydrogenated castor oil with ethylene oxide, 55 preferably hydrogenated castor oil. (2) The pharmaceutical composition according to item (1), wherein the surface active agent is obtainable by reacting 30 to 100 moles of ethylene oxide with 1 mole of castor oil, preferably 30 to 60 moles of ethylene oxide with 1 mole of castor oil, more preferably 40 to 45 moles of ethylene oxide with 1 mole of castor oil. 2 EP 2 438 911 A1 (3) The pharmaceutical composition according to item (1) or (2), wherein the surface active agent is polyoxyl 40 hydrogenated castor oil (Cremophor RH 40). (4) The pharmaceutical composition according to any one of the items (1) to (3), wherein at least 50%, preferably at least 70%, more preferably at least 90%, particularly substantially all of the sulphonylurea- class insulin secreta- 5 gogue in the composition is in contact with the surface active agent. (5) The pharmaceutical composition according to any one of preceding items, wherein the weight ratio of the surface active agent to the sulphonylurea-class insulin secretagogue is from 1:20 to 10: 1, preferably from 1:10 to 5:1, more preferably from 1:8 to 2:1, even more preferably from 1:4 to 1:1, most preferably from 1:2 to 1:1. (6) The pharmaceutical composition according to any one of preceding items, further comprising a polymer selected 10 from a group containing cellulose derivative, polyethylene glycol, polyvinylpyrrolidone, polyvinylacetate, polyvinyla- lcohol, polyester, polyamide, polyanhydride, polyorthoester, polycarbonate, (phosphoester),poly poly(phosp- hazene), poly(iminocarbonate), mixtures and copolymers thereof, preferably is selected from the group consisting of cellulose derivative, polyethylene glycol, polyvinylpyrrolidone, polyvinylacetate, polyvinylalcohol, mixtures and copolymers thereof, more preferably is selected from hydroxypropylcellulose and hydroxypropylmethylcellulose, 15 wherein the polymer is in contact with the sulphonylurea-class insulin secretagogue and the surface active agent. (7) The pharmaceutical composition according to any one of preceding items, further comprising a disintegrant and optionally other excipients, wherein said other excipients are water soluble. (8) The pharmaceutical composition according to item (7), wherein the water soluble excipient is a hydrophilic diluent. (9) The pharmaceutical composition according to item (8), wherein the hydrophilic diluent is any modified or un- 20 modified monosaccharide, straight or branched oligosaccharide, straight or branched polysaccharide, or mixtures thereof, wherein the monosaccharide, oligosaccharide or polysaccharide are optionally additionally substituted; preferably the hydrophilic diluent is selected from the group consisting of lactose, starch, sucrose, mannitol, sorbitol and cellulose derivatives, more preferably the hydrophilic diluent is lactose. (10) The pharmaceutical composition according any one of items (7) to (9), wherein the disintegrant is selected from 25 the group consisting of sodium croscarmellose, sodium starch glycolate, crospovidone, starch, modified starch, low substituted hydroxypropyl cellulose, microcrystallilne celllouse, preferably the disintegrant is sodium croscarmellose. (11) The pharmaceutical composition according to any one of the preceding items, wherein the sulphonylurea- class insulin secretagogue is glimepiride, tolbutaminde, glibenclamide, gliclazide, glycopyraminde,
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