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()Acial-On O 4,153,689 5/1979 Hirai Et Al USOO5397771A United States Patent 19 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, Keflavik, 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 Lösungsmit tel (Glycofurol)” 6 Jahrgang, s.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 U.S. Application Data Assistant Examiner-A. M. Davenport 63 Continuation of Ser. No. 791,651, Nov. 14, 1991, aban Attorney, Agent, or Firm-Wegner, Cantor, Mueller & doned, which is a continuation-in-part 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 ............................. 2O75/90 57 ABSTRACT 51) Int. Cl. ..................... A01N 37/18: A61K 37/00; A pharmaceutical preparation for application of an C07K 5/00; CO7K 7/00 effective amount of one or more biologically active 52 U.S.C. ........................................... 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, i 530/307, 311, 313 56) References Cited U.S. PATENT DOCUMENTS ()acial-on O 4,153,689 5/1979 Hirai et al. FOREIGN PATENT DOCUMENTS wherein n is 1 to 4 in an amount from: 0.1-30% prefera 95897 12/1983 European Pat. Off.. bly 0.1-20% most preferably 1-15% in water, or in 183527 6/1986 European Pat. Off. vegetable oil or n-ethylene glycol(s) represented by 278997 8/1988 European Pat. Off. formula II: 418642 3/1991 European Pat. Off. 4301.49 6/1991 European Pat. Off. HOCH2CH2OH 2528516 2/1976 Germany . OTHER PUBLICATIONS wherein p is 2 to 8, or in a mixture thereof. Nasal admin Jeppsson et al., “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 Toxicol, 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/EP89/01186-WO 90/03796 (Schiapparelli). Kromann et al., "Diazepam in an Oil Emulsion', Letters PCT/US89/05260-WO 90/06136 (Schering). to the Editor, 61, No. 6 (1982) p. 544. Vromans et al., "Effect of Solvents on Rectal Absorp Moolenaar et al., “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 al., "Rectal Versus Oral Absorption of and Zoxazolamine by Glycofurol,” Biochemical Phar Diflunisal 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 Archiv for Pharmaci og 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. Moolenaazr 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. U.S. Patent Mar. 14, 1995 Sheet 1 of 16 5,397.771 LA) M O M CN g 2 CD 3. s Lo re m O Vm D O O O O O O 3 O O Q CN (VNSWild u/6u) WZVNOO U.S. Patent Mar. 14, 1995 Sheet 2 of 16 5,397,771 SNs S.ur Ne ur N CN s S.M Ns SNs Q N CN Ne O O OO N uo i? rh. No Cn O your (SLnNIN) 3SNOdS32 OL3NLL NV3 U.S. Patent Mar. 14, 1995 Sheet 3 of 16 5,397.771 3 S. & 24 - N?' 9 isLL NS O C us C 2 O S 5s 4. S23O O O O O O O O Oc + () Sp O) OO N O f) q MINI IO 2. SW WS00?) U.S. Patent Mar. 14, 1995 Sheet 4 of 16 5,397,771 240 2 O O 160 120 80 TIME (MINUTES) FIG.4 U.S. Patent Mar. 14, 1995 Sheet 5 of 16 5,397,771 gsg S 2 S 9 O O f O f O O N CN CN vur ve : (WNSWild u/bu) WZVNOIO U.S. Patent Mar. 14, 1995 Sheet 6 of 16 5,397,771 2s 53 S. s S. S Sp O O O CN vo wn (WNSWild u/bu) WW ZWO U.S. Patent Mar. 14, 1995 Sheet 7 of 16 5,397.771 S. Sg Z N 3. CD 2 EL l R Lll C9s L1 SS O + -- its ill CDse 1 E Cin st- on + + O L?) O f C L? O O O rt N. N. CN CN v- via (u/bu) NOLIVILN3ON00 WNSYld U.S. Patent Mar. 14, 1995 Sheet 8 of 16 5,397,771 O N O O O L) S 43 EZ OOO 5 Co N1 m. Lu l O 2 N) O CN S2 O O O O O O O O q M CN quo (WNSYld u/bu) W3ZWLNN U.S. Patent Mar. 14, 1995 Sheet 9 of 16 5,397,771 O N O CO O L O u -N E.(V) O. 2 O S 3 CD 2 us O GN S2 O O O O O O O O O O O O O OO CO Q ON Quo (WNSYld u/Bu) WZVOIN U.S. Patent Mar. 14, 1995 Sheet 11 of 16 5,397.771 s a s S. ve an 2 5 CD - S R2 - O CN O vum O O O O S2 O O O OO o N qm NOWNON00 WNSW (3 U.S. Patent Mar. 14, 1995 Sheet 12 of 16 5,397.771 s CN is cdus - O L?) S. 2 3. s S R S Se u- GN O CO O q- CN O vo ve v NOWN ONOO WNSW, 9 U.S. Patent Mar. 14, 1995 Sheet 13 of 16 5,397,771 NN~ Ñ ZZZZZZZZZZZ• O FYZZZZZZZZZZZZ-o ZZZZZZZZ-$2 % Glycofurol in tetraethyleneglycolºº!” Test . Hind legs to One side. NNN Test 2. ind legs stretched out backwards. Test3. The robbit is loying in O Supine position. ------ Mox. tes period is 10 minutes. FIG.13 U.S. Patent Mar. 14, 1995 Sheet 14 of 16 5,397,771 NYY Y NYS N N N SN N N N N N N N N N N N N N. NNNN SS SN N N N N N N SN N N N N N N N ŠNN NS SNNNNNN NY YSYNYN NYNYN NYNYNN O re O) o N to O W No Q - O (Uu) 00UOdsay O. eu UD9W U.S. Patent Mar. 14, 1995 Sheet 15 of 16 5,397.771 NYNY Y NYS NY NY NNNNNNNNNN NYSYNY Y Yo Y NYS N NYNYNY YYYYYY NYNNNNNNNN NY. NYS NYNY Y N N-2 NYS N. Y. Ya Ya NYS NY-st NNNNYS NY NY NY NNY ( u) e3UOdsel O. eu, UDeW U.S. Patent Mar. 14, 1995 Sheet 16 of 16 5,397.771 NYNY YYYYYYY NY. NNNNNNNN NYNY YYYYQ YNYNYN NYS NYS NYNY YYY NY N N N N N N N N NNN N N N N N N N NYNY YNNYNY NYYYYYYYYQYN SNNNNNNN NS NYSYNYNYSYNY YNY Y S3 NNNNNNNNN N is N N N N N N N N N > SNNNNNNNNN SYYYYYYY Ya N to NYSYNY YYYYYYQ- to SNNNNNNN st SNNNNNNN ro SNNNN N N N (n SN N N N N N N - O) o N to to St. No C - C (Uu)00UOdsel O. eul, UD9W 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, filed 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 pull. A larger No. 07/696,564, filed 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.
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