Specification
WO 2005/112937 PCT/TJS2005/017815
ACYCLOVIR FORMULATIONS
[1] This application claims the benefit of U.S. Provisional Application No. 60/573,003, filed May 19, 2004, which is hereby incorporated by reference.
FIELD OF THE INVENTION
[2] The present invention relates to an acyclovir formulation having improved bioavailability resulting in improved efficacy and/or requiring less frequent administration.
BACKGROUND OF THE INVENTION
[3] Acyclovir (9<(2-hydroxyethoxy)methyl)guanine) is an antiviral which inhibits human herpes viruses, including herpes simplex types 1 (HSV-1) and 2 (HSV-2), varicella zoster, Epstein-Barr virus (EBV) and cytomegalovirus (CMV). The inhibitory activity of acyclovir is highly selective for these viruses. O'Brien and Campoli-Richards, Drugs, 37:233-309 (1989). The chemical composition of acyclovir is reported in Shaffer, et al. {X Med. Chem. 14:367 (1971)), U.S. PatentNo. 4,199,574, and UK Patent Specification No. 1,523,865, all of which are hereby incorporated by reference.
[4] Acyclovir has been demonstrated to be a potent antiviral agent, particularly against herpes viruses. Shaffer, et al. Nature 272:583-585 (1978). Acyclovir has also been demonstrated to effectively suppress reactivated or newly acquired viral diseases such as genital herpes simplex, shingles, and varicella-zoster, as well as acute varicella-zoster infections. Balfour, J. Med. Virology, SI :74-8l ( 1993). Morbidity and mortality from viral disease have been reduced by pre- and postoperative prophylaxis with long-term (> 6 months) oral acyclovir therapy. Prentice et al., Lancet 343:749-753 (1994). Concurrent acyclovir and AZT (azidothymidine) therapy has extended the survival of AIDS patients by one year when acyclovir therapy was begun at time of diagnosis. Stein, et al., Ann. Intern. Med. 121:100-108(1994). Additionally, acyclovir therapy for acute varicella-zoster disease reduces fever, chronic pain, and the progression of rash and accelerates cutaneous healing.
WO 2005/112937 PCT/US2005/037815
[5] Other uses include, but are not limited to, mucocutaneous, ocular, and systemic herpes simplex infections (HSV), including in human immunodeficiency virus (HIV)-infected individuals. It is also useful to treat HSV encephalitis, neonatal HSV infections, and genital herpes (first episode, recurrent and suppressive therapy for recurrent infections). Further, acyclovir is effective therapy for varicella-zoster infections, herpes zoster (shingles, zoster), cytomegalovirus infections, infections and disorders associated with Epstein-Barr virus, and the Center for Disease Control states that oral acyclovir may be used in pregnant women. These and other uses are found in AHFSDrug Information, American Society of Health System Pharmacists, Bethesda, MD, 2005, which is incorporated by reference herein.
[6] Acyclovir, is currently marketed as capsules, tablets and suspension for oral administration. Orally administered acyclovir is slowly and erratically absorbed with 15-30% bioavailabiliry. Barnhart (ed.), Physicians' Desk Reference, Oradell, N.J.: Medical Economics Data (1994). Over half the dose of the currently marketed formulation is recovered in the feces. Schaeffer et al, Nature, 272:583-585 (1978). Failure to respond to acyclovir therapy may arise from an inadequate dose (frequency of dose or total daily dose); patient noncompliance; malabsorption in the intestine; or, resistant viral strains. Mindel, J. Med. Virology, SI :39-44 (1993). The need for readily absorbed oral antiviral agents has been identified as imperative for treatment of viral diseases to both patient populations since long term IV treatment is restrictive and compliance with currently available oral acyclovir formulations is difficult. Katlama, J. Med. Virology Sl:128-133 (1993). An acyclovir preparation for oral delivery which permitted lower dosing and less frequent administration would facilitate compliance.
[7] Previous attempts have been made to improve the oral delivery of acyclovir. U.S. Patent No. 5,629,016, which is hereby incorporated by reference, discloses water dispersible tablets containing acyclovir which facilitates the ingestion of large doses (i.e. up to 800 rag) of acyclovir. The tablets, however, do not improve the bioavailabiliry of the acyclovir.
[8] U.S. Patent No. 5,883,103 discloses a microemulsion system for the oral delivery of acyclovir. The system includes a water-in-oil emulsion with acyclovir dispersed in aqueous phase droplets. The droplets have an average droplet size of 20-40 nanometers and are uniformly dispersed in the continuous oil phase.
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[9] Although, previous attempts have been made to improve the delivery and bioavailability of aeyelavir, ifaese attempts have had limited success. Therefore, there is a need for oral acyelovir formulations having increased bioavailability.
SUMMARY OF THE INVENTION
[10] The present invention provides a composition (e.g., a pharmaceutical composition) comprising (a) at least one delivery agent compound and (b) acyelovir or a salt, ester, or prodrag thereof. Preferably, the composition includes a iherapetttically effective amount of aeyclovir and the delivery agent compound. The composition of flie present invention facilitates the delivery of acyelovir and increases its bioavailability compared to administration without the delivery agent compound. The composition is particularly well suited for oral administration. Preferably, the composition provides bioavailability (i.e., AUC) substantially equivalent to the current acyelovir formulations marketed, as Zovirax® (U.S. FDANTDANo. 18828,19909, or 20089) when:
(1) 200,400, or 800 mg of acyelovir is administered every 4 hours 5 times
daily,
(2) 400 mg of acyelovir is administered 2 times daily,
(3) 200 mg of acyelovir is administered 3 times daily,
(4) 200 mg of acyelovir is administered 4 times daily, or
(5) 200 mg of acyelovir is administered 5 times daily.
[11] Preferred delivery agent compounds include, but are not limited to, N-(8-[2-hydroxybajzoyl]amino)caprylic acid,lM-(10-[2-liydroxyi)enzoyl]ainino)decanoic acid, 4-[{4~ cMoro-2~hydroxy-benzoyl)ammo]butaiioic acid (also known as 4~[(2-hydroxy-4-chlorobenzoyi)amiijo]l)«tanoate), S-CN^-hydroxy-S-cMorobenzoy^amiiiocaprylic acid, 8-(N-2-hydroxy-4-methoxybenzoyl)-aniino-caprylic acid, and salts (e.g., pharmaceutically acceptable salts) thereof, and solvates and hydrates thereof. The salt can be, for example, a sodium salt, such as a monosodium or disodium salt.
[12] In ono embodiment, the composition comprises acyelovir or a salt, ester, or prodrug thereof and at least one delivery agent of the following structure or a salt (e.g., a
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WO 2005/112937 PCT/US2005/017815
Ar is phenyl or naphthyl;
Ar is optionally substituted with one or more of-OH, halogen, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkoxy or C1-C4 haloalkoxy;
R7is C4-C2o alkyl, C4-C20 alkenyl.. phenyl, naphthyl (Ci-Cu, alkyl) phenyl, (Ci-Ci0 alkenyl)phenyl, (Ci~Ci0 alkyl) naphthyl, (Q-C10 alkenyl) naphthyl, phenyl(Ci-Ci0 alkyl), phenyl(C1-C10 alkenyl), naphthyl(Ci-C1o alkyl), or naphthyl(C1-Cl0 alkenyl);
R8 1s hydrogen, C1 to C4 alkyl, C2 to C4 alkenyl, Cx to C4 alkoxy, or C1-C4 haloalkoxy;
R7 1s opt1onally subst1tuted w1th Cj to C4 alkyl, C2 to C4 alkenyl, C1 to G4 alkoxy, C1-C4 haloalkoxy, -OH, -SH, -CO2R9, or any comb1nat1on thereof;
R9 1s hydrogen, C1 to C4 alkyl, or C2 to C4 alkenyl; and
R7 1s opt1onally 1nterrupted by oxygen, n1trogen, sulfur or any comb1nat1on thereof. Accord1ng to one embod1ment, the compounds are not subst1tuted w1th an atn1no group 1n the pos1t1on alpha to the ac1d group.
[13] 1n another embod1ment, the compos1t1on compr1ses acyclov1r or a salt, ester, or prodrug thereof and at least one del1very agent of the follow1ng structure or a salt (e.g., a pharmaceut1caltv acceotable salf1 thereof:
where1n
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WO 2005/112937 PCT/US2005/017815
R1, R2, R3, and R4 are independently H, -OH, halogen, C1-C4 alkyl, C2-C* alkenyl, C1-C4 aikoxy, -C(O)Rg, -NO2, -NR9Ri0, or-NVR'V1 (R12)';
R5 is H, -OH, -NO2, halogen, -CF3, -NR14R15, -N*R14RI5R16 (RI3y, amide, d-dz alkoxy, C1-C12 alkyl, C2-CJ2 alkenyl, carbamate, carbonate, urea, or -C(O)R ;
R5 is optionally substituted with halogen, -OH, -SH, or -COOH;
R5 is optionally interrupted by O, N, S, or -C(O)-;
R6 is a C1-C12 alkylene, C2-C12 alkenylene, or arylene;
R6 is optionally substituted with a C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, -OH, -SH, halogen, -NH2, or -CO2R8;
R6 is optionally interrupted by O or N;
R7 is a bond or arylene;
R7 is optionally substituted with -OH, halogen, -C(O)CH3, -NR1ORU, or -
each occurrence of R8 is independently H, C1-C4 alkyl, C2-C4 alkenyl, or-NH2;
R9, R10, Rn, and R12 independently H or Ci-Cio alkyl;
R13 is a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate;
R14, R15 and R16 are independently H, C1-C10 alkyl, C1-C10 alkyl substituted with-COOH, C2-C12 alkenyl, C2-Ci2 alkenyl substituted with -COOH, or -C(O)R17;
R17 is -OH, C1-C10 alkyl, or C2-C12 alkenyl; and
R18 is H, Cj-Cs alkyl, -OH, -NR14R15, orN^R^'R16 (R13)".
Optionally, when R1, R2, R3, R4, and R5 are H, and R7 is a bond then R6 is not a Ci-C6, C9 or C10 alkyl.
Optionally, when R1, R2, R3, anrtl14R15R16 (R13)", amide, Q-Cu alkoxy,
1 ft
C1-C12 alkyl, C2-C12 alkenyl, carbamate, carbonate, urea, or-C(O)R ;
R5 is optionally substituted with halogen, -OH, -SH, or -COOH;
R5 is optionally interrupted by O, N, S, or -C(O)-;
R6 is a C1-C12 alkylene, C2-C12 alkenylene, or arylene;
R6 is optionally substituted with a C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, -OH, -SH, halogen, -NH2, or -CO2R8;
R is optionally interrupted by O or N;
R is a bond or arylene;
R7 is optionally substituted with OH, halogen, ~C(O)CH3, -NR10Rn, or - N+R10R11Rn
CR13)-;
each occurrence of R8 is independently H, C1-C4 alkyl, C2-C4 alkenyl, or-NH2; R9, R10, Ru, and R12 are independently H or c1-C10 alkyl; R is a halide, hydroxide, sulfate; tetrafluoroborate, or phosphate; and R14, R15 and R16 are independently H, c1-C10 alkyl, C1-C10 alkyl substituted with -COOH, C2-C12 alkenyl, C2-C12 alkenyl substituted with-COOH, or -C(O)R17; R17 is -OH, C1-C10 alkyl, or C2-C12 alkenyl; and R18 is H, C,-C6 alkyl, -OH, -NR14R15, or N+R^R16 CR-13)"-
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WO 2005/112937 PCT/US2005/017815
3. A pharmaceutical composition comprising (a) acyclovir and (b) a delivery agent
of the formula
or a salt thereof, wherein
R1, R2, R3, R4 and R5 are independently H, -CN, -OH, -OCH3, or halogen, at least one of R1, R2, R3, R4 and R5 being -CN; and
R6 is a C1-C12 linear or branched alkylene, alkenylene, arylene, alkyl(arylene) or aryl(alkylene).
4. A pharmaceutical composition of any one of Claims 1,2 or 3, wherein the
delivery agent is selected from the group consisting of Delivery agents is SNAC or SNAD or a
pharmaceutically acceptable salt thereof.
5. The pharmaceutical composition of Claim 1 wherein the delivery agent is N-(8-
[2-hydroxybenzoyl]-amin6)caprylic acid or a pharmaceutically acceptable salt thereof.
6. The pharmaceutical composition of Claim 1 -wherein the delivery agent is wherein
the delivery agent is N~(10-[2-hydroxybenzoyl]-amino)decanoic acid or a pharmaceutically
acceptable salt thereof.
1. The pharmaceutical composition of any claims 1-6, wherein the pharmaceutical composition provides bioavailability (i.e., AUC) substantially equivalent to the acyclovir formulation marketed as Zovirax® under U.S. FDANDANo. 18828,19909, or 20089 when: (1) 200,400, or 800 mg of the acyclovir formulation is administered every 4
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hours 5 times daily,
(2) 400 mg of the acyclovir formulation is administered 2 times daily,
(3) 200 mg of the acyclovir formulation is administered 3 times daily,
(4) 200 mg of the acyclovir formulation in administered 4 times daily, or
(5) 200 mg of the acyclovir formulation is administered 5 times daily.
8. A dosage unit form comprising:
(A) the pharmaceutical compositions of any one of the preceding
claims; and
(B) (a) an excipient,
(b) a diluent,
(c) a disintegrant,
(d) a lubricant,
(e) a plasticizer,
(f) a colorant,
(g) a dosing vehicle, or
(h) any combination thereof.
9. The dosage unit form of Claim 8, wherein the dosage unit form is in the form of a
tablet, a capsule, a particle, a powder, a sachet, or a liquid.
10. The dosage unit form of Claim 8, wherein the dosing vehicle is a liquid selected
from the group consisting of water, aqueous propylene glycol, phosphate buffer, 1,2-propane
diol, ethanol, and any combination thereof.
11. A method for administering an effective amount of acyclovir a patient in need of
thereof, comprising the step of orally administering the pharmaceutical composition of any one
of claims 1-8.
12. A method of treating a viral infection in a patient in need thereof, comprising the
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step of administering to the patient an effective amount of the pharmaceutical composition of any one of claims 1-8.
13. A method of treating a condition or disorder caused by a virus in a patient in need
thereof, comprising the step of administering an animal an effective amount of the
pharmaceutical composition of any one of claims 1-8.
14. The method of Claim 13, wherein the condition or disorder is caused by a virus
selected from the group consisting of herpes simplex 1, herpes simplex 2, varicella zoster virus,
cytomegalovirus and Epstein-Barr virus.
15. A method of improving the bioavailability of acyclovir in an animal in need
thereof, the methed comprising the step of administering a formulation of any one of claims 1,2
or 3.
16. A method of preparing a pharmaceutical composition comprising the step of
mixing at least one delivery agent compound and acyclovir or a salt or prodrug thereof.
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