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Nasally Administrable Compositions Containing Physiologically Active Peptides

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Europaisches Patentamt (19) European Patent Office Office europeen des brevets (11) EP 0 770 390 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) IntCI.6: A61K 31/70 02.05.1997 Bulletin 1997/18 (21) Application number: 96116490.2 (22) Date of filing: 15.10.1996 (84) Designated Contracting States: (72) Inventor: Yanagawa, Akira AT BE CH DE DK ES FR GB IT LI LU NL PT SE Yokohama-shi, Kanagawa 224 (JP) (30) Priority: 01.11.1995 JP 306406/95 (74) Representative: Weisert, Annekate, Dipl.-lng. Dr.- 17.01.1996 JP 22959/96 Ing. 28.05.1996 JP 154773/96 Patentanwalte Kraus Weisert & Partner (71) Applicant: DOTT RESEARCH LABORATORY Thomas-Wimmer-Ring 15 Yokohama-shi, Kanagawa 224 (JP) 80539 Munchen (DE) (54) Nasally administrable compositions containing physiologically active peptides (57) A nasally administrable composition having a physiologically active peptide dispersed homogene- ously in and adsorbed homogeneously onto a unique carrier. The composition contains an effective amount of physiologically active peptide dispersed homogene- ously in and adsorbed homogeneously onto a mucosa protecting and/or tissue repairing agent, e.g., gefarnate, aceglutamide aluminum, sucralfate, L-glutamine, sofal- cone, teprenone, plaunotol, rebamipide, aldioxa, cetrax- ate or troxipide. < O <7> CO o r»- o Q_ LU Printed by Rank Xerox (UK) Business Services 2.14.3/3.4 EP 0 770 390 A1 Description BACKGROUND OF THE INVENTION 5 1 . Field of the Invention The present invention relates to a nasally administrable composition containing a physiologically active peptide, and, more particularly, to a nasally administrable composition containing a physiologically active peptide such as pep- tide hormone, physiologically active protein, enzymatic protein and so on with a unique carrier, which is highly absorb- 10 able into the body via nasal route. 2. Description of the Prior Art Physiologically active peptides such as calcitonin, insulin, parathyroid hormone (PTH), human growth hormone 15 (HGH), gonadotropin-releasing hormone (GnRH) and derivatives thereof are polymers which are extensively employed in clinical practice for various medical usage owing to their specific physiological activity. The physiologically active peptides, however, can little be absorbed intact from the mucous membrane of the intes- tine because of either being likely to be decomposed with proteases existing in the digestive system or being high in molecular weight and polarity. Hence, the administration method has been limited to injection. However, injection can- 20 not be said to be preferable because it causes pain in patients. In particular, when injection is to be repeated at constant intervals, the patients have to suffer from the pain every time, which may often become too severe to endure. Under the circumstances, there has been strong demand for more simple and convenient means for administering physiologically active peptides, that is, administration via a non-injection route to enable patients to administer the drug by themselves. As one example of preparations for such non-injection administration, an aerosol in the form of a suspension has 25 been developed for nasal inhalation of calcitonin, in which a fluorinated hydrocarbon is used as a spouting agent. As another means for nasal administration, a spray has been proposed as a nasally administrable liquid preparation, which is a preparation in which calcitonin is formulated with a surface-active agent as an absorption promoter. Furthermore, recently, there have been proposed some nasally administrable powdery preparations with improved absorbability, which are prepared by adsorbing calcitonin onto a polysaccharide such as celluloses. These various techniques for 30 nasal administration, which have recently been actively developed, are said to be in principle superior as a means for administering such physiologically active peptides as unlikely to be administered orally. Since venous plexus develops at the lamina propria mucosae of the nasal cavity, physiologically active peptides, when administered nasally, can be absorbed through the mucous membrane of the nasal cavity into the circulatory system of the body; however, nasally administrable preparations so far proposed cannot be sufficient because of poor absorbability of physiologically active 35 peptides or local irritability, so that they are not commercially available yet. The inventor of the present invention has actively been studying about carriers for nasal administration of physio- logically active peptides such as insulin, calcitonin, parathyroid hormone (PTH), human growth hormone (HGH), gona- dotropin-releasing hormone (GnRH) and so on, and has proposed nasally administrable compositions using a polyvalence metal compound such as hydroxyapatite and calcium carbonate as the carrier, finding that water-insoluble 40 substances which are soluble under acidic condition, other than high molecular weight compounds such as polysaccha- ride celluloses so far studied, can be an desirable carrier for use in nasally administrable physiologically active peptide compositions. SUMMARY OF THE INVENTION 45 The present invention has the object to provide a nasally administrable composition that can nasally administer such a physiologically active peptide as unlikely to be administered orally, with higher bioavailability and less irritability than the preparations so far proposed. Through extensive studies and researches, the inventor of the present invention found that mucosa protecting so and/or tissue repairing agents, which had never been used as a carrier for nasally administrable compositions, would be useful as the carrier to administer physiologically active peptides nasally. For example, gastric mucosa protecting and/or tissue repairing agents are soluble under acidic condition, and can promote mucus secretion and alkali secre- tion, enhance mucous glycoproteins and glycolipids, increase mucous bloodstream and prostaglandin, promote mucous tissular respiration and metabolism, thereby activating the tissues. Also, since these agents are highly adhe- 55 sive to the mucosa and persist there for a long time, they can provide a long-lasting absorption characteristic. Accord- ingly, these agents, when administered nasally, are expected to activate the venous plexus of the lamina propria mucosae of the nasal cavity, and therefore, physiologically active peptides, dispersed homogeneously onto the agents as the carrier, are expected to be highly absorbable into the circulatory system of the body through the mucous mem- brane of the nasal cavity. 2 EP 0 770 390 A1 The inventor of the present invention actually prepared nasally administrable compositions using a mucosa protect- ing and/or tissue repairing agent, e.g., a gastric mucosa protecting and/or tissue repairing agent as the carrier, wherein the physiologically active peptide is dispersed homogeneously in and adsorbed homogeneously onto the carrier, and found that the compositions would be highly useful for clinical treatment of patients. 5 In more detail, the present inventor found that a nasally administrable composition having a physiologically active peptide such as calcitonin, insulin, parathyroid hormone (PTH), human growth hormone (HGH) and gonadotropin- releasing hormone (GnRH) dispersed homogeneously in and adsorbed homogeneously onto the unique carrier, i.e., a mucosa protecting and/or tissue repairing agent, can attain equal or higher bioavailability as compared with that attained by injection. 10 Furthermore, the present inventor found that the mucosa protecting and/or tissue repairing agent, e.g., a gastric mucosa protecting and/or tissue repairing agent, as the carrier for the nasally administrable composition mentioned above, is also useful for stabilizing the active ingredient of the composition, i.e., a physiologically active peptide. The present invention has been completed on the basis of these findings. Accordingly, the present invention provides a nasally administrable composition wherein an effective amount of a 15 physiologically active peptide is dispersed homogeneously in and adsorbed homogeneously onto a mucosa protecting and/or tissue repairing agent, preferably a gastric mucosa protecting and/or tissue repairing agent, as the carrier. DETAILED DESCRIPTION OF THE INVENTION 20 It should be noted herein that mucosa protecting and/or tissue repairing agents had never been expected to be a carrier for a nasally administrable composition, and the present inventor is the first to have discovered the applicability. In the present invention, gastric mucosa protecting and/or tissue repairing agents are most preferable as the car- rier. Such agents include gefarnate (trade name: Gefanil), aceglutamide aluminum (trade name: Glumal), sucralfate (trade name: Ulcerlmin), L-glutamine (trade name: Glumin), sofalcone (trade name: Solon), teprenone (trade name: 25 Selbex), plaunotol (trade name: Kelnac), rebamipide (trade name: Mucosta), aldioxa (trade name: Altanta, Isalon, Ascomp, etc.), cetraxate (trade name: Neuer), and troxipide (trade name: Aplace). The present inventor prepared nasally administrable compositions by homogeneously dispersing physiologically active peptides onto the above-men- tioned agents and found that the compositions thereby prepared were highly absorbable into the body through nasal mucous membrane. 30 Phygiologically active peptides to be used as the active ingredient of the composition according to the present invention may be peptide hormones, physiologically active
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