(19) & (11) EP 2 168 579 A1 (12) EUROPEAN PATENT APPLICATION published in accordance with Art. 153(4) EPC (43) Date of publication: (51) Int Cl.: 31.03.2010 Bulletin 2010/13 A61K 31/485 (2006.01) A61K 9/14 (2006.01) A61K 9/20 (2006.01) A61K 9/48 (2006.01) (2006.01) (2006.01) (21) Application number: 08752992.1 A61K 47/12 A61K 47/16 A61P 1/14 (2006.01) A61P 13/02 (2006.01) (2006.01) (2006.01) (22) Date of filing: 20.05.2008 A61P 17/04 A61P 25/04 C07D 489/02 (2006.01) (86) International application number: PCT/JP2008/059196 (87) International publication number: WO 2008/143240 (27.11.2008 Gazette 2008/48) (84) Designated Contracting States: • MINAKAMI, Satoshi AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Kamakura-shi HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT Kanagawa 248-8555 (JP) RO SE SI SK TR • TOKUMITSU, Hiroyuki Designated Extension States: Kamakura-shi AL BA MK RS Kanagawa 248-8555 (JP) (30) Priority: 21.05.2007 JP 2007133854 (74) Representative: Webster, Jeremy Mark et al Mewburn Ellis LLP (71) Applicant: Toray Industries, Inc. 33 Gutter Lane Tokyo 103-8666 (JP) GB-London EC2V 8AS (GB) (72) Inventors: • OHTA, Kotoe Kamakura-shi Kanagawa 248-8555 (JP) (54) ORAL PREPARATION COMPRISING SPECIFIC ORGANIC ACID, AND METHOD FOR IMPROVEMENT IN ELUTION PROPERTY AND CHEMICAL STABILITY OF ORAL PREPARATION (57) A chemically stable oral preparation with an ex- cellent dissolution property comprising as an effective ingredient a specific morphinan derivative or a pharma- ceutically acceptable acid addition salt thereof is dis- closed. The oral preparation according to the present in- vention comprises a specific morphinan derivative or a pharmaceutically acceptable acid addition salt thereof as an effective ingredient and an organic acid, wherein 1 g of said organic acid requires not less than 30 mL of water to dissolve in at 20°C. The method for improving disso- lution property and chemical stability of an oral prepara- tion according to the present invention comprises incor- porating an organic acid in the oral preparation compris- ing as an effective ingredient a specific morphinan deriv- ative or a pharmaceutically acceptable acid addition salt thereof, wherein 1 g of said organic acid requires not less than 30 mL of water to dissolve in at 20°C. EP 2 168 579 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 168 579 A1 Description Technical Field 5 [0001] The present invention relates to chemically stable oral preparations having high dissolution property, comprising a specific organic acid and as an effective ingredient a morphinan derivative having a nitrogen-containing heterocyclic group or a pharmaceutically acceptable acid addition salt thereof. Background Art 10 [0002] It is disclosed that specific morphinan derivatives having a nitrogen-containing cyclic group or pharmaceutically acceptable acid addition salts thereof, which have a remarkable therapeutic or prophylactic effect against pollakiuria or urinary incontinence, antipruritic effect, analgesic effect, and therapeutic or prophylactic effect against functional bowel disorder, are useful as a therapeutic agent for pollakiuria, antipruritic, analgesic and therapeutic or prophylactic agent 15 for functional bowel disorder (see, e.g., Patent Literatures 1, 2, 3 and 10). However, morphinan derivatives are known to be chemically unstable to light, heat or oxygen (see, e.g., Patent Literature 4), and actually it was confirmed that morphinan derivatives described in Patent Literatures 1 to 3 are also unstable. Therefore, it has been required to develop remedies with a good stability to ensure quality. In addition, the specific morphinan derivatives mentioned above are much slightly soluble in water, and have a problem in the dissolution property particularly in the neutral region. Thus, it 20 has been required to develop remedies with an improved dissolution property in the neutral region as well as a good chemical stability to ensure stable absorption. [0003] As a method for improving the dissolution property of various morphinan derivatives including morphine, a method in which the active ingredient is dissolved in oil or a solubilizer such as polyethylene glycol or surfactant (e.g., Patent Literature 5), and a method in which a remedy is prepared as a composition comprising a nonionic solubilizer, 25 lipophilic antioxidant and aqueous solvent (e.g., Patent Literature 6) have been reported. However, although Patent Literature 5 demonstrates that the active ingredients show a good dissolution property even after 6-month storage, it does not describe the data of chemical stability such as a change in the amount of decomposition products and the like. In Patent Literature 6, although it describes the effect of antioxidants on solubility and stability, the oral administration form is restricted to solutions or gels, and solid formulations such as tablets and capsules are not described. Moreover, 30 the two literatures do not disclose that the dissolution property can be improved by addition of a specific organic acid according to the present invention. [0004] As a method for improving the dissolution property of basic remedies, a method in which acidic compounds such as organic acids are added thereto, a method in which the dissolution rate is increased by pulverizing active substances with a grinder to increase the surface area, or the solid dispersion method in which the active substances 35 are dispersed in a polymer molecule such as polyethylene glycol or polyvinylpyrrolidone is generally used. However, it is known that pulverization not merely increases surface area of particles, but strongly affects on reactivity and stability of the solid, and the problem that destabilization occurs concurrently with improvement of the dissolution property has been pointed out. It has been also reported that, in the solid dispersion method, many amorphous particles of solid dispersions are often generated and that destabilization occurs due to the high surface energy of the amorphous particles 40 (e.g., Patent Literature 1). Thus, it is a very difficult problem to provide a chemically stable preparation with a high dissolution property containing a poorly soluble, unstable compound. [0005] On the other hand, as a method for stabilizing various morphinan derivatives including morphine, a method in which a basic component is added to morphine (e.g., Patent Literature 7), a method in which naloxone is combined with an antioxidant such as sodium thiosulfate or tocopherol (e.g., Patent Literature 8), and a method in which an antioxidant 45 such as sodium thiosulfate or propyl gallate is added to morphinan derivatives to stabilize the preparation (e.g., Patent Literature 4) have been disclosed. [0006] With respect to the effect of addition of organic acids on the chemical stability of morphinan derivatives, stabilized oral preparations comprising naloxone in combination with ascorbic acid and the like (e.g., Patent Literature 8), stabili- zation by adding an organic acid to naltrexone hydrochloride (e.g., Patent Literature 9), and stabilization by adding 50 ascorbic acid, erythorbic acid or citric acid to morphinan derivatives (e.g., Patent Literature 4) have been reported. However, none of these publications describes the solubility and the stabilizing effect of the organic acids to be added. In fact, it has been reported that stability is decreased when citric acid and tartaric acid are added to morphine (e.g., Patent Literature 7). [0007] Thus, these known techniques do not give the slightest suggestion of adding a specific organic acid to the 55 above-mentioned specific morphinan derivatives having a nitrogen-containing heterocyclic group or a pharmaceutically acceptable acid addition salt thereof in order to provide remedies with an excellent dissolution property and chemical stability. [0008] 2 EP 2 168 579 A1 Non-patent Literature 1: Mitsuru HASHIDA eds., "Designing and Evaluation of Oral Preparations", 1st Edition, Jihou Co., Ltd., February 10, 1995, p.167-179 Patent Literature 1: WO 2004/033457 Patent Literature 2: WO 2005/094826 5 Patent Literature 3: WO 2006/049248 Patent Literature 4: WO 99/02158 Patent Literature 5: JP 2960169 B Patent Literature 6: WO 2004/026231 Patent Literature 7: JP 2-160719 A 10 Patent Literature 8: WO 98/35679 Patent Literature 9: JP 2005-531515 A Patent Literature 10: WO 2007/055184 Disclosure of the Invention 15 Problems Which the Invention Tries to Solve [0009] An objection of the present invention is to provide a chemically stable oral preparation with an excellent disso- lution property comprising as an effective ingredient a specific morphinan derivative or a pharmaceutically acceptable 20 acid addition salt thereof. Means for Solving the Problem [0010] Since a preliminary experiment revealed that morphinan derivatives having a nitrogen-containing heterocyclic 25 group represented by the Formula (I) below are chemically unstable to light, heat and oxygen, the present inventors tried preparing various formulations selecting compatible additives and production methods based on the prior art infor- mation. However, it was proved that such common techniques are not effective enough to ensure stability and dissolution property. On the other hand, the dissolution property could be improved to some extent by adding an organic acid to the basic compound morphinan derivatives having a nitrogen- containing heterocyclic group represented by the Formula 30 (I). However, the effective ingredient was severely decomposed and destabilized depending on the type of