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United States Patent [191 [11] Patent Number: 5,397,771 Bechgaard Et Al

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United States Patent [191 [11] Patent Number: 5,397,771 Bechgaard Et Al USO05397771A United States Patent [191 [11] Patent Number: 5,397,771 Bechgaard et al. [45] Date of Patent: Mar. 14, 1995 [54] PHARMACEUTICAL PREPARATION Administration in Solution and by Suppository,” Acta [75] Inventors: Erik Bechgaard, Hellerup, Denmark; Paediatr Scand., 66 (1977) pp. 563-567. Sveinbjorn Gizurarson, Ke?avik, DeFlines, “Bereiding van een diazepam-clysma”, Phar Iceland; Rolf K. Hjortkjaer, maceutisch Weekblad, 114 (1979) p. 805. Humlebaer, Denmark Spiegelbert et al., “Ein Neues Injizierbares L'cisungsmit tel (Glycofurol)” 6 Jahrgang, $.75. [73] Assignee: Bechgaard International Research Moolenaar et al., “Biopharmaceutics of Rectal Admin and Development A/ S, Hellerup, istration of Drugs in Man IX . ”, International Journal Denmark of Pharmaceutics, 5 (1980) pp. 127-137. [21] Appl. No.: 118,683 (List continued on next page.) [22] Filed: Sep. 10, 1993 Primary Examiner-Lester L. Lee Related US. Application Data Assistant Examiner-A. M. Davenport Attorney, Agent, or Firm—Wegner, Cantor, Mueller & [63] Continuation of Ser. No. 791,651, Nov. 14, 1991, aban doned, which is a continuation-impart of Ser. No. Player . 696,564, May 8, 1991, abandoned. [30] Foreign Application Priority Data May 10, 1990 [DK] Denmark ........................... .. 1170/90 Aug. 30, 1990 [DK] Denmark ........................... .. 2075/90 [57] ABSTRACI‘ A pharmaceutical preparation for application of an [51] Int. (:1.6 ................... .. A01N 37/18; A61K 37/00; C07K 5/00; C07K 7/00 effective amount of one or more biologically active [52] US. Cl. ......................................... .. 514/2; 514/4; substance(s) to a mucosal membrane of a mammal com— 514/3; 530/303; 530/307; 530/311; 530/313 prising an n-glycofurol represented by the formula I: [58] Field of Search ................. .. 514/2, 3, 4; 530/303, 530/307, 311, 313 [56] References Cited U.S. PATENT DOCUMENTS 0 4,153,689 5/1979 Hirai et al. FOREIGN PATENT DOCUMENTS wherein n is 1 to 4 in an amount from: 01-30% prefera bly 01-20% most preferably l—15% in water, or in 95897 12/1983 European Pat. Off. 183527 6/ 1986 European Pat. OK. vegetable oil or n-ethylene glycol(s) represented by 278997 8/1988 European Pat. Off. formula II: 418642 3/1991 European Pat. Off. 430149 6/1991 European Pat. Off. mocnzcnppon 2528516 2/1976 Germany . OTHER PUBLICATIONS wherein p is 2 to 8, or in a mixture thereof. Nasal admin .Ieppsson et a1., “Anticonvulsant Activity in Mice of istration of the preparation produces a high plasma Diazepam in am Emulsion Formulation for Intravenous concentration of the pharmaceutically active substan Administration,” Acta Pharmacol. et TaxicoL, 36 (1975) ce(s) nearly as rapid as by i.v. administration. pp. 312-320. Knudsen, “Plasma-Diazepam in Infants After Rectal 29 Claims, 16 Drawing Sheets 5,397,771 Page 2 OTHER PUBLICATIONS PCT/EP89/01l86—WO 90/03796 (Schiapparelli). Kromann et al., “Diazepam in an Oil Emulsion”, Letters PCT/US89/O5260--WO 90/06136 (Schering). to the Editor, 61, No. 6 (1982) p. 544. Vromans et al., “Effect of Solvents on Rectal Absorp Moolenaar et a1., “Rectale Irritatie van Vehiculae . ”, tion Rate of Paracetamol in Man: an in vitro Ap Pharmaceutisch Weekblad, 116 (1981) pp. 33-34. proach”, International Journal of Pharmaceutics, 26 Yasaka et al., “Mechanisms in the Potentiation and (1985) pp. 5-13. Inhibition of Pharmacological Actions of Hexobarbital Moolenaar et a1., “Rectal Versus Oral Absorption of and Zoxazolamine by Glycofurol,” Biochemical Phar Di?unisal in Man”, International Journal of Pharmaceu macology, 27 (1978) pp. 2851-2858). tics, 19 (1984) pp. 161-167. Illum, “Drug Delivery Systems for Nasal Application”, Moolenaar et al., “Rectal Absorption of Methadone Archivfor Pharmaci 0g Chemi, 94 (1987) pp. 127-135. from Dissolution-Promoting Vehicles”, International Morimoto et al., “Nasal Absorption of Nifedipine from Journal of Pharmaceutics, 33 (1986) pp. 249-252. Gel Preparations in Rats”, Chem Pharm. Bull, 35/7, Lashmar et al., “Topical Application of Penetration (1987) pp. 3041-3044. Enhancers to the Skin of Nude Mice: a Histopathologi Lau et al., “Absorption of Diazepam and Lorazepam cal Study,” Journal of Pharmaceutics, 41 (1988) pp. Following Intranasal Administration”, International 118-121. Journal of Pharmaceutics, 54 (1989) pp. 171-174. Moolenaa‘zr et al., “Manipulation of Rectal Absorption PCT/US89/03897—WO 90/02737 (Goldberg). Rate of Phenytoin in Man,” Pharmaceutisch Weekblad PCT/AT87/00015-WO 87/05210 (Burghart). Scientific Edition, 3 (1981) pp. 175-180. US. Patent Mar. 14, 1995 Sheet 1 of 16 5,397,771 _.o_.._ @523Mi:S25E51? g;-+ O o o 8 8 (D N (vwsvu lw/bu) “Emma 5,397,771 4 > 100 > 70 2/4 x\\\\\\ 20.30 4EGm736FIN 10 l I I I I l I I l l o m w N Q m + n N Po (sammw) asuodsaa 01 am uvzm US. Patent Mar. 14, 1995 Sheet 3 of 16 5,397,771 a8.82.oa. @522NE mdESE28.0. 28558.a"aE;if 'MJJNI JO 2 SV ‘El/G1 HSOOITIS US. Patent Mar. 14, 1995 Sheet 4 of 16 5,397,771 240 m. 0 m $830ma: lhm?u _Jrll In!w,2 0 i (ill‘lllllll lull-“sh M Im “ll)llw \llulll-m 6 0 US. Patent Mar. 14, 1995 Sheet-5 of 16 5,397,771 5% ‘8. S: t‘?- 2 ‘n o vIIsvI lw/?u) wvdazvumo US. Patent Mar. 14, 1995 Sheet 6 of 16 5,397,771 on @525“.5: pmCW0.»,oweo wdEN3363:2:IT all.5.25z_Non “6IT CD O 0 o If) O LO N , US. Patent Mar. 14, 1995 Sheet 8 of 16 5,397,771 (MINUTES)TIME 1'0 INTRAVENOUS+—- INTRANASAL-0- I | | O :2 a é 5% a 2 => (vwsvw Iw/BU) nvdazvaunnu U.S. Patent Mar. 14, 1995 Sheet 9 of 16 5,397,771 @523ms: ad: I | O O o o O o o Q’ N q US. Patent Mar. 14, 1995 Sheet 10 0f 16 5,397,771 lzmom 22.5: 62 :NnwOLO‘ONOQPPFNFF-PF 8pmp“%a.a“PN28. Dom._.<5.202wzc5r?>mu>oowmR 3.0; o S “a65:5 lllllHHU3InQ205% E?8an: .533an: 55:; 3In9285a 3In92$2; 5de2“.52 3In92252 E2N;9% 3618252% R392055 53HE: 3Ine22%: 5655e+" Q2.Nzum5n2"+ Q2.52NIa:u RadNEE:2+u 5.3<.Nzwm2+n “6%. to“B“6%+ US. Patent Mar. 14, 1995 Sheet 11 of 16 5,397,771 F|G.11 (MIN)TIME US. Patent Mar. 14, 1995 Sheet 12 0f 16 5,397,771 I I I N O . , NOLLVHLNEIONOO VWSV'Id l3 US. Patent Mar. 14, 1995 Sheet 13 of 16 5,397,771 13 12 H g 1Q---- '""""“"" ‘ 3v "'“Q'Z "" “3'7; ______ ‘ E 9- a f 4 2 / / g 8- ¢ / ¢ ? a ¢ 4 ¢ / E 6 / 1 / / ? za 5 ?/ / ?/ / 2 4 y 4 / f 3 / / / / 2 / / / / g e¢ 4¢ 4,¢ 4? 6 2'0 3'0 7'0 % Glycofurol in tetraethylenegiycol - Testi. Hind legs to one side. E333 Test 2. Hind legs stretched out backwards 222.1 Test3. The rabbit is laying in a supine position. ---- —- Max. test period is 10 mmufes US. Patent Mar. 14, 1995 Sheet 15 of 16 5,397,771 mfoE m? .0; Z O) Q N (0 in q‘ H‘) N ‘ O hmnemmv ('ugw) GOUOdSQJ 0; sum, unaw US. Patent Mar. 14, 1995 Sheet 16 of 16 5,397,771 222m 505m; owmvmvtovnv32$:9mmNnwv mmncom rows-Q 5,397,771 1 2 very often it is not possible to dissolve a clinically rele PHARMACEUTICAL PREPARATION vant amount in the relatively small volume which may be applied for intranasal administration. This application is a continuation of United States For liquid compositions it is essential that an effective application Ser. No. 07/791,651, ?led Nov. 14, 1991, amount of the biologically active substance(s) can be now abandoned; which is a continuation-in-part of Ser. dissolved in a volume of less than about 300 al. A larger No. 07/696,564, ?led May 8, 1991, now abandoned. ' volume can be disagreeable to the patient and will evi The present invention relates to pharmaceutical com dently drain out anteriorly through the nostrils or poste positions for administration of a biologically active riorly toward the pharynx. The result is that a part of substance to a mammal via a mucosal membrane. the active substance is lost from the absorption site and The administration by injection (intravenous, intra that in practice it will be impossible reproducibly to muscular and subcutaneous) of biologically active sub administer a correct dose. The volume for human adults stances is normally regarded as the most convenient is preferably from about 1 ul to about 1000 p.l and more way of administration when the purpose is to achieve a preferably from about 50 pl to about 150 pl per nostril. rapid and strong systemic effect, e.g. within 3-5 min 15 The mucosal epithelium in the nasal cavity is covered utes, and when the active substance is not absorbed or is with many hair-like cilia being an important defense inactivated in the gastrointestinal tract or by ?rst-pass mechanism for the mammal body against inhaled dust, hepatic metabolism. However, the administration by allergens and microorganisms. The normal half-time for injection presents a range of disadvantages. Thus it non-absorbed substances administered to the nasal cav requires the use of sterile syringes and may cause pains 20 ity is about 15 minutes due to the mucociliary clearance and irritations, particularly in the case of repeated injec removing foreign particles and excess mucus toward tions, including the risk of infection. Besides, injections the pharynx. For this reason it is preferred that the cannot be administered by untrained persons. absorption occurs rapidly and preferably within 1 to 20 Intranasal administration is currently receiving spe minutes.
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