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6162459 Methanol Concentration( 9, ) USOO6162459A United States Patent (19) 11 Patent Number: 6,162,459 Hu (45) Date of Patent: *Dec. 19, 2000 54 ACYCLOVIRTRANSDERMAL DELIVERY OTHER PUBLICATIONS SYSTEM The Merck Index, Susan Budavari, ed., 11th edition, 1989, 75 Inventor: Oliver Yoa-Pu Hu, Taipei, Taiwan p. 1079. Primary Examiner Thurman K. Page 73 ASSignee: National Science Council, Taipei, ASSistant Examiner T. Ware Taiwan Attorney, Agent, or Firm W. Wayne Liauh * Notice: This patent issued on a continued pros- 57 ABSTRACT ecution application filed under 37 CFR 1.53(d), and is subject to the twenty year A transdermal formulation for providing antiviral effect in patent term provisions of 35 U.S.C. dermis or epidermis, wherein comprising (a) 0.01 to 30 154(a)(2). weight percent of antiviral drug; (b) 0.05 to 20 weight percent of a Chinese medicine enhancer; and (c) a pharma 21 Ap1. No.: 08/801885 ceutical acceptable vehicles. The antiviral drug is Selected 21 Appl. No 1801, from the group consisting of ACV(Acyclovir), Carbovir, 22 Filed: Feb. 18, 1997 DDA(2',3'-Dideoxyadnosine), HPMPA(1-(3-Hydroxy-2- phosphonylmethoxylpropyl)-adenosine), DHPG Related U.S. Application Data (Ganciclovir), Desciclovir, IDC (5-Iodo-2'-deoxy-cytidine), - - - Vidarabine (Ara-A), DDI (2',3'-Dide oxy inosine), 62 Division of application No. 08/394,114, Feb. 24, 1995, Cordycepin, Cytarabine, Deoxyguanosine, d4T(2',3'- abandoned. Didehydro-3'-deoxythymidine), FIAC(2'-Fluoro-5- 51 Int. Cl." ............................. A61K 9/70; A61F 13/00; iodoaracytosine), AZT(ZDV, Zidovudine), Ara-T(1-?3-D- A61F 13/02; A61L 15/16 Ara-binofuranosylthymine), Deoxythymidine, Ribavirin, 52 U.S. Cl. ........................... 424/449; 424/447; 424/448 EDU(5-Ethyl-2'-deoxy-uridine), Enviroxime, Amantadine, 58 Field of Search ..................................... 424447,448, Arildone, HPMPC(9-(3-Hydroxy-2-phosphonyl-methoxyl 424/449 propyl)cytidine), Riboxamide, Rimantidine, Tromantadine, Foscamet sodium, Moroxydine, F3T(5-Trifluoro-methyl-2'- 56) References Cited deoxy-uridine), BVDU (Bromovinyldeoxyuridine). Preferably, the Chinese medicine enhancer is oleanolic acid, U.S. PATENT DOCUMENTS and the pharmaceutical acceptable vehicles is polyethylene 4,879,376 11/1989 Foresta et al. ......................... 536/181 glycols. 5,079.252 1/1992 Beauchamp ...... ... 514/262 5,733,572 3/1998 Unger et al. ............................ 424/450 2 Claims, 17 Drawing Sheets 35 Glycyrrhizin 2.5 18-B-Glycyrrhetinic acid Pinene : B-Myrcene O O 2O 3 O 4 O 5 O 6 O 7 O 8 O 9 O 1OO Methanol Concentration( 9, ) U.S. Patent Dec. 19, 2000 Sheet 1 of 17 6,162,459 FG 1 - 1 H - N - -N R. HN Nr. D 1 Acyclovil --(2-Hydroxyethoxy)methyl - R D 2 Ganciclovir (1,3-Dihydroxy-2-propoxy-methyl) D S Carbovir Carbocyclic 2',3'-didehydro-2',3'- dideoxy - - - D 9 DeoxyguanoSine R. D4 Vidarabine D-arabinofuranosyl --> D 6 2',3'-Dideoxyadnosine 2',3'-Dideoxy-9-beta ribofuranosyl D8 Cordycepin 9-cordycepOSido N1 Y-N -- -s-s ! - f R D 3 Desciclovir methoxy ethanol NH. R. r D 1 1 Cytarabine 1-beta-D-arabinofuranosyl -- - - 1 N- D2 2',3'-Dideoxy- 2',3'-Dideoxy-4-amino-1- cytidine beta-D-ribofuranosyl R ) 7 2'-Flor()-5- 2'-Fluoro-5-iodo-4-amino-i- iodoaracytosine beta-D-arabinofuranosyl D 8 S-Odo-2'- 2'-Deoxy-5-iodo-4-amino-1- deoxycytidine beta-D-ribofuranosyl U.S. Patent Dec. 19, 2000 Sheet 2 of 17 6,162,459 FIG 1-2 O n -N R. N-SN-SN1 D Acyclovir (2-Hydroxyethoxy)methyl--L-- - - - - - - - - - . - - - - - - - - R D 2 Ganciclovir (1,3-Dihydroxy-2-propoxy-methyl) D 5 Carbovir Carbocyclic 2',3'-didehydro-2',3'- dideoxy - -, ---- -- D 9 Deoxyguanosine R l H. D 4 Vidarabine D-arabinofuranosyl D 6 2',3'-Dideoxyadnosine 2',3'-Dideoxy-9-beta N ribofuranosyl D8 Cordycepin 9-cordvceposido N21 N his R R. D 3 Desciclovir methoxy ethanol NH R. Dll Cytarabine 1-beta-D-arabinofuranosyl o D12 2',3'-Dideoxy- 2',3'-Dideoxy-4-amino-1- cytidine beta-D-ribofuranosyl R D17 2'-Fluoro-5- 2'-Fluoro-5-iodo-4-amin ()-- iodoaracytosine beta-D-arabinofuranosyl Dl 8 5-IOdo-2'- 2'-Deoxy-5-iodo-4-amino-1- deoxycytidine beta-D-ribofuranosyl U.S. Patent Dec. 19, 2000 Sheet 3 of 17 6,162,459 FIG. 1-3 O R D13 Zidovudine 1-(3-Azido-2,3-dideoxy-3- ". D-erythro-pentofuranosyl) orn D 4 2',3'-Didehydro-2',3'- 1-(2,3-didehydro-3-deoxy-3- R deoxythymidine D-erythro-pentofurano IDS Deoxythymidine D 6 Bromovinyl- 5-(2-Bromovinyl)-2'-deoxy deoxyuridine - D 9 Deoxyuridine 1-(2-deoxy-beta-D-erythro pentofuranosyl D2 () 5-Trifluoromethyl-2'- deoxyuridine R. D25 Amantidine amine D26 Rimantidine methyl-methanamine D27 Tromantadine 2-(dimethylamino)ethoxy acetamide HO O R R. D23 Ribavirin 124-triazole-3- OH OH carboxamide D24 thiazolcaboxamide Riboxamide U.S. Patent Dec. 19, 2000 Sheet 4 of 17 6,162,459 FIG - 4 ID28 Arildone 4-6-(2-Chloro-4-methoxyphenoxy)hexyl D29 Moroxydine N-(Aminoiminomethyl)-4-morpholine . carbOXimid-Bloxine D3 () EnviroXime 6-(Hydroxyimino)phenylmethyl-1-( -- - - - - - - - - - - - I-methylethyl) Sulfonyl-(1H)-benzimidazol-2-amine D3 Foscarnet Sodium Dihydroxyphosphinecarboxylic acid ---. ---------- Xide triSodium U.S. Patent Dec. 19, 2000 Sheet 6 of 17 6,162,459 5 r 9 -o- No.39 st 4 - O - No.38 3 E < 9 2 3 2 N () () O 20 30 Time(hr) FIG. 3 U.S. Patent Dec. 19, 2000 Sheet 7 of 17 6,162,459 50 -- No.5 (Nude Mices skin) O -o- No.5*(80 Day Pigskin, SD N. 40 -o- No.5*(25 Day Pigskin) 5O 30 s 20 E 10 S Si 0 () 20 40 60 8O Time(hr) FIG. 4 U.S. Patent Dec. 19, 2000 Sheet 8 of 17 6,162,459 4 O -o- NO. 5 ... 3 O N O 20 O O 20 40 60 80 Time(hr) FIG. 5 U.S. Patent Dec. 19, 2000 Sheet 9 of 17 6,162,459 Time(hr) FIG. 6 U.S. Patent Dec. 19, 2000 Sheet 10 of 17 6,162,459 8 O O 6 O O 24 OOOO U.S. Patent Dec. 19, 2000 Sheet 11 of 17 6,162,459 3000 2 O O O 1000 Time(hr) FIG. 8 U.S. Patent Dec. 19, 2000 Sheet 12 of 17 6,162,459 3500 3000 2500 2000 1500 1000 500 Time(hr) FIG. 9 U.S. Patent Dec. 19, 2000 Sheet 13 of 17 6,162,459 3500 3000 2500 2000 1500 1000 500 Time(hr) FIG. 10 U.S. Patent Dec. 19, 2000 Sheet 14 of 17 6,162,459 × fº“D(Z-FONVOAOV(?onuos)(c.1-u)^0(eNOWO O O O08 CO OOZ (uo/57)) unouv U.S. Patent Dec. 19, 2000 Sheet 15 of 17 6,162,459 08 U.S. Patent Dec. 19, 2000 Sheet 16 0f 17 6,162,459 as a : N. N:A x S2 * - N. O) A - St. S2 * St 5 gst as Oe ed Cr exa s SE (5 2 Qe- S Sl- g S. Qi 2 fig2 - : : E ŽCD il C Sz ZS is GgZ is na s2 2s > 3 2 9 5. N--f, its - , N ,- M N/ N S1 a Q is ra < < < 9 :8 i if * NS: It 22C 22C e-a, S.-era NEO : N - SO (u?e 7d.) Jo (3/37)) unouw U.S. Patent Dec. 19, 2000 Sheet 17 of 17 6,162,459 01 G0#79O8O/O6O0 O O C. £0 2O X so 6,162,459 1 2 ACYCLOVIRTRANSIDERMAL DELIVERY PEG as the base gave the least flux, while the fluxes from the SYSTEM other two with modification aqueous cream and DMSO as the bases were 8 and 10 times higher, respectively. This This application is a Division of Ser. No. 08/394,114 demonstrates that the use of different vehicles does make a filed Feb. 24, 1995 now abandoned. difference. Recently, Greg, E. et al. (J. Invest. Dermatol. 98:856–63, 1992) found in a clinic study that the effect of TECHNICAL FIELD OF THE INVENTION ACV in the treatment of HSV 1 is actually better with oral administration than with local application. The drug con The present invention relates to a topical formulation, centration in the skin after local application is 2-3 times especially to shown highly antiviral effect in dermis or lower than after given orally. However, it is still considered epidermis. safer to give the drug locally Since ACV cannot be effective unless it can penetrate the epidermis into deeper layers, it is BACKGROUND OF THE INVENTION highly desirable to find an efficient penetration enhancer for Viruses have caused a great Stir in this century. Disease it's local application. The present invention is a formulation attributed to them such as HSV-1, hepatitis, HIV and AIDS 15 that contains Such enhancer notably from Chinese medicine are incurable. Antiviral drug that are in current use could be herbs and was found to Significantly improve the transder classified as antipurines, antipyrimidines, antibiotics, natural mal delivery of a number of antiviral drugs. alkaloids, and enzymes which include Acyclovir (ACV, D1), A transdermal delivery System is a drug delivery System 9-(1,3-Dihydroxy-2-propoxymethyl) guanine(Ganciclovir, that releases it's drug slowly and continuously at a con D2, DHPG), Desciclovir(D3), 9-3-D-arabinofuranosyl-9H trolled rate to the skin upon application. Once released, the purin-6-amine (Vidarabine, Ara-A, D4), 2',3'- drug penetrates the epidermis and enters the micro Dideoxyadnosine (2',3'-Dideoxy-9-f-ribofuranosyl-9H circulation, which carries it to the target Site for an effect. purine-6-amine, DDA, D6), Carbovir (D5),2',3'- The advantages of Such Systems are the ease of use, being Dide oxy inosine (DDI, D7), 1-(3-Hydroxy-2- relatively Safe, and affording the interruption of the medi phosphonylmethoxylpropyl) -adenosine (HPMPA, D10), 25 cation by Simply peeling off or removing from the skin Cordycepin(D8), Deoxyguanosine(D9), Cytarabine(D11), whenever an overdosing is Suspected.
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