U.S. patent application number 11/568826 was filed with the patent office on 2008-06-05 for compositions for delivering acyclovir.
This patent application is currently assigned to Emisphere Technologies, Inc.. Invention is credited to Amy C. Adams, Nikhil Dhoot, Shingai Majuru, Brahma N. Singh.
Application Number | 20080132527 11/568826 |
Document ID | / |
Family ID | 35428245 |
Filed Date | 2008-06-05 |
United States Patent
Application |
20080132527 |
Kind Code |
A1 |
Adams; Amy C. ; et
al. |
June 5, 2008 |
Compositions For Delivering Acyclovir
Abstract
The present invention relates to an acyclovir formulation having
improved bioavailability resulting in better efficacy and/or
requiring less frequent administration.
Inventors: |
Adams; Amy C.; (Fishers,
IN) ; Singh; Brahma N.; (Syosset, NY) ; Dhoot;
Nikhil; (Dombivli (East), IN) ; Majuru; Shingai;
(Brewster, NY) |
Correspondence
Address: |
Emisphere Technologies, Inc
240 Cedar Knolls Road, Suite # 200
Cedar Knolls
NJ
07927
US
|
Assignee: |
Emisphere Technologies,
Inc.
Tarrytown
NJ
|
Family ID: |
35428245 |
Appl. No.: |
11/568826 |
Filed: |
May 19, 2005 |
PCT Filed: |
May 19, 2005 |
PCT NO: |
PCT/US05/17815 |
371 Date: |
November 19, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60573003 |
May 19, 2004 |
|
|
|
Current U.S.
Class: |
514/263.38 |
Current CPC
Class: |
A61K 9/0019 20130101;
A61P 31/22 20180101; A61K 47/18 20130101; A61P 31/12 20180101; A61K
9/2013 20130101; A61K 31/522 20130101; A61P 35/00 20180101; A61P
27/02 20180101; A61K 9/08 20130101; A61P 43/00 20180101; A61P 11/00
20180101; A61P 15/00 20180101; A61K 47/12 20130101 |
Class at
Publication: |
514/263.38 |
International
Class: |
A61K 31/522 20060101
A61K031/522; A61P 31/12 20060101 A61P031/12 |
Claims
1. A pharmaceutical composition comprising (a) acyclovir and (b) a
delivery agent of the formula ##STR00005## or a salt thereof,
wherein: Ar is phenyl or naphthyl; Ar is optionally substituted
with one or more of --OH, halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkenyl, C.sub.1-C.sub.4 alkoxy or C.sub.1-C.sub.4
haloalkoxy; R.sup.7is C.sub.4-C.sub.20 alkyl, C.sub.4-C.sub.20
alkenyl, phenyl, naphthyl, (C.sub.1-C.sub.10 alkyl) phenyl,
(C.sub.1-C.sub.10 alkenyl)phenyl, (C.sub.1-C.sub.10 alkyl)
naphthyl, (C.sub.1-C.sub.10 alkenyl) naphthyl,
phenyl(C.sub.1-C.sub.10 alkyl), phenyl(C.sub.1-C.sub.10 alkenyl),
naphthyl(C.sub.1-C.sub.10 alkyl), or naphthyl(C.sub.1-C.sub.10
alkenyl); R.sup.8 is hydrogen, C.sub.1 to C.sub.4 alkyl, C.sub.2 to
C.sub.4 alkenyl, C.sub.1 to C.sub.4 alkoxy, or C.sub.1-C.sub.4
haloalkoxy; R.sup.7 is optionally substituted with C.sub.1 to
C.sub.4 alkyl, C.sub.2 to C.sub.4 alkenyl, C.sub.1 to C.sub.4
alkoxy, C.sub.1-C.sub.4 haloalkoxy, --OH, --SH, --CO.sub.2R.sup.9,
or any combination thereof; R.sup.9 is hydrogen, C.sub.1 to C.sub.4
alkyl, or C.sub.2 to C.sub.4 alkenyl; and R.sup.7 is optionally
interrupted by oxygen, nitrogen, sulfur or any combination.
2. A pharmaceutical composition comprising (a) acyclovir and (b) a
delivery agent of the formula ##STR00006## or a salt thereof,
wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently H,
--H, halogen, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.1-C.sub.4 alkoxy, --C(O)R.sup.8, --NO.sub.2,
--NR.sup.9R.sup.10, or --N.sup.+R.sup.9R.sup.10R.sup.11
(R.sup.12)--; R.sup.5 is H, --OH, --NO.sub.2, halogen, --CF.sub.3,
--NR.sup.14R.sup.15, --N.sup.+R.sup.14R.sup.15R.sup.16
(R.sup.13)--, amide, C.sub.1-C.sub.12 alkoxy, C.sub.1-C.sub.12
alkyl, C.sub.2-C.sub.12 alkenyl, carbamate, carbonate, urea, or
--C(O)R.sup.18; R.sup.5 is optionally substituted with halogen,
--OH, --SH, or --COOH; R.sup.6 is optionally interrupted by O, N,
S, or --C(O)--; R.sup.6 is a C.sub.1-C.sub.12 alkylene,
C.sub.2-C.sub.12 alkenylene, or arylene; R.sup.6 is optionally
substituted with a C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.1-C.sub.4 alkoxy, --OH, --SH, halogen, --NH.sub.2, or
--CO.sub.2R.sup.8; R.sup.6 is optionally interrupted by O or N;
R.sup.7 is a bond or arylene; R.sup.7 is optionally substituted
with --OH, halogen, --C(O)CH.sub.3, --NR.sup.10R.sup.11, or
--N.sup.+R.sup.10R.sup.11R.sup.12 (R.sup.13)--; each occurrence of
R.sup.8 is independently H, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4
alkenyl, or --NH.sub.2; R.sup.9, R.sup.10, R.sup.11, and R.sup.12
are independently H or C.sub.1-C.sub.10 alkyl; R.sup.13 is a
halide, hydroxide, sulfate, tetrafluoroborate, or phosphate; and
R.sup.14, R.sup.15 and R.sup.16 are independently H,
C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 alkyl substituted with
--COOH, C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkenyl
substituted with --COOH, or --C(O)R.sup.17; R.sup.17 is --OH,
C.sub.1-C.sub.10 alkyl, or C.sub.2-C.sub.12 alkenyl; and R.sup.18
is H, C.sub.1-C.sub.6 alkyl, --OH, --NR.sup.14R.sup.15, or
N.sup.+R.sup.14R.sup.15R.sup.16 (R.sup.13)--.
3. A pharmaceutical composition comprising (a) acyclovir and (b) a
delivery agent of the formula ##STR00007## or a salt thereof,
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R are independently
H, --CN, --OH, --OCH.sub.3, or halogen, at least one of R.sup.1,
R.sup.2, R.sup.3, R.sup.4 and R.sup.5 being --CN; and R.sup.6 is a
C.sub.1-C.sub.12 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]-amino)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-hydroxybelizoyl]-amino)decanoic acid or a pharmaceutically
acceptable salt thereof.
7. 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.RTM. under U.S. FDA NDA No. 18828, 19909, or 20089 when:
(1) 200, 400, or 800 mg of the acyclovir formulation is
administered every 4 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 is 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 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 method 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.
Description
[0001] 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
[0002] 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
[0003] 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.
(J. Med. Chem. 14:367 (1971)), U.S. Pat. No. 4,199,574, and UK
Patent Specification No. 1,523,865, all of which are hereby
incorporated by reference.
[0004] 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, S1:74-81 (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.
[0005] 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 AHFS Drug Information, American Society of Health
System Pharmacists, Bethesda, Md., 2005, which is incorporated by
reference herein.
[0006] Acyclovir, is currently marketed as capsules, tablets and
suspension for oral administration. Orally administered acyclovir
is slowly and erratically absorbed with 15-30% bioavailability.
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, S1:39-44 (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 S1:128-133 (1993). An
acyclovir preparation for oral delivery which permitted lower
dosing and less frequent administration would facilitate
compliance.
[0007] Previous attempts have been made to improve the oral
delivery of acyclovir. U.S. Pat. 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 mg) of acyclovir. The tablets, however, do not
improve the bioavailability of the acyclovir.
[0008] U.S. Pat. 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.
[0009] Although, previous attempts have been made to improve the
delivery and bioavailability of acyclovir, these attempts have had
limited success. Therefore, there is a need for oral acyclovir
formulations having increased bioavailability.
SUMMARY OF THE INVENTION
[0010] The present invention provides a composition (e.g., a
pharmaceutical composition) comprising (a) at least one delivery
agent compound and (b) acyclovir or a salt, ester, or prodrug
thereof. Preferably, the composition includes a therapeutically
effective amount of acyclovir and the delivery agent compound. The
composition of the present invention facilitates the delivery of
acyclovir 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 acyclovir formulations marketed as
Zovirax.RTM. (U.S. FDA NDA No. 18828, 19909, or 20089) when: [0011]
(1) 200, 400, or 800 mg of acyclovir is administered every 4 hours
5 times daily, [0012] (2) 400 mg of acyclovir is administered 2
times daily, [0013] (3) 200 mg of acyclovir is administered 3 times
daily, [0014] (4) 200 mg of acyclovir is administered 4 times
daily, or [0015] (5) 200 mg of acyclovir is administered 5 times
daily.
[0016] Preferred delivery agent compounds include, but are not
limited to, N-(8-[2-hydroxybenzoyl]amino)caprylic acid,
N-(10-[2-hydroxybenzoyl]amino)decanoic acid,
4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (also known as
4-[(2-hydroxy-4-chlorobenzoyl)amino]butanoate),
8-(N-2-hydroxy-5-chlorobenzoyl)aminocaprylic acid,
8-(N-2-hydroxy-4-methoxybenzoyl)-amino-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.
[0017] In one embodiment, the composition comprises acyclovir or a
salt, ester, or prodrug thereof and at least one delivery agent of
the following structure or a salt (e.g., a pharmaceutically
acceptable salt) thereof:
##STR00001##
wherein
[0018] Ar is phenyl or naphthyl;
[0019] Ar is optionally substituted with one or more of --OH,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkenyl,
C.sub.1-C.sub.4 alkoxy or C.sub.1-C.sub.4 haloalkoxy;
[0020] R.sup.7 is C.sub.4-C.sub.20 alkyl, C.sub.4-C.sub.20 alkenyl,
phenyl, naphthyl, (C.sub.1-C.sub.10 alkyl) phenyl,
(C.sub.1-C.sub.10 alkenyl)phenyl, (C.sub.1-C.sub.10 alkyl)
naphthyl, (C.sub.1-C.sub.10 alkenyl) naphthyl,
phenyl(C.sub.1-C.sub.10 alkyl), phenyl(C.sub.1-C.sub.10 alkenyl),
naphthyl(C.sub.1-C.sub.10 alkyl), or naphthyl(C.sub.1-C.sub.10
alkenyl);
[0021] R.sup.8 is hydrogen, C.sub.1 to C.sub.4 alkyl, C.sub.2 to
C.sub.4 alkenyl, C.sub.1 to C.sub.4 alkoxy, or C.sub.1-C.sub.4
haloalkoxy;
[0022] R.sup.7 is optionally substituted with C.sub.1 to C.sub.4
alkyl, C.sub.2 to C.sub.4 alkenyl, C.sub.1 to C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkoxy, --OH, --SH, --CO.sub.2R.sup.9, or any
combination thereof;
[0023] R.sup.9 is hydrogen, C.sub.1 to C.sub.4 alkyl, or C.sub.2 to
C.sub.4 alkenyl; and
[0024] R.sup.7 is optionally interrupted by oxygen, nitrogen,
sulfur or any combination thereof. According to one embodiment, the
compounds are not substituted with an amino group in the position
alpha to the acid group.
[0025] In another embodiment, the composition comprises acyclovir
or a salt, ester, or prodrug thereof and at least one delivery
agent of the following structure or a salt (e.g., a
pharmaceutically acceptable salt) thereof:
##STR00002##
wherein
[0026] R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently H,
--OH, halogen, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.1-C.sub.4 alkoxy, --C(O)R.sup.8, --NO.sub.2,
--NR.sup.9R.sup.10, or --N.sup.+R.sup.9R.sup.10R.sup.11
(R.sup.12)--;
[0027] R.sup.5 is H, --OH, --NO.sub.2, halogen, --CF.sub.3,
--NR.sup.14R.sup.15, --N.sup.+R.sup.14R.sup.15R.sup.16
(R.sup.13)--, aride, C.sub.1-C.sub.12 alkoxy, C.sub.1-C.sub.12
alkyl, C.sub.2-C.sub.12 alkenyl, carbamate, carbonate, urea, or
--C(O)R.sup.18;
[0028] R.sup.5 is optionally substituted with halogen, --OH, --SH,
or --COOH;
[0029] R.sup.6 is optionally interrupted by O, N, S, or
--C(O)--;
[0030] R.sup.6 is a C.sub.1-C.sub.12 alkylene, C.sub.2-C.sub.12
alkenylene, or arylene;
[0031] R.sup.6 is optionally substituted with a C.sub.1-C.sub.4
alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.1-C.sub.4 alkoxy, --OH, --SH,
halogen, --NH.sub.2, or --CO.sub.2R.sup.8;
[0032] R.sup.6 is optionally interrupted by O or N;
[0033] R.sup.7 is a bond or arylene;
[0034] R.sup.7 is optionally substituted with --OH, halogen,
--C(O)CH.sub.3, --NR.sup.10R.sup.11, or
--N.sup.+R.sup.10R.sup.11R.sup.12 (R.sup.13)--;
[0035] each occurrence of R.sup.8 is independently H,
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, or --NH.sub.2;
[0036] R.sup.9, R.sup.10, R.sup.11, and R.sup.12 independently H or
C.sub.1-C.sub.10 alkyl;
[0037] R.sup.13 is a halide, hydroxide, sulfate, tetrafluoroborate,
or phosphate;
[0038] R.sup.14, R.sup.15 and R.sup.16 are independently H,
C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 alkyl substituted with
--COOH, C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkenyl
substituted with --COOH, or --C(O)R.sup.17;
[0039] R.sup.17 is --OH, C.sub.1-C.sub.10 alkyl, or
C.sub.2-C.sub.12 alkenyl; and
[0040] R.sup.1 is H, C.sub.1-C.sub.6 alkyl, --OH,
--NR.sup.14R.sup.15, or N.sup.+R.sup.14R.sup.15R.sup.16
(R.sup.13)--.
[0041] Optionally, when R.sup.1, R.sup.2, R.sup.3, R.sup.4, and
R.sup.5 are H, and R.sup.7 is a bond then R.sup.6 is not a
C.sub.1-C.sub.6, C.sub.9 or C.sub.10 alkyl.
[0042] Optionally, when R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are
H, R.sup.5 is --OH, R.sup.7 is a bond then R.sup.6 is not a
C.sub.1-C.sub.3 alkyl.
[0043] Optionally, when at least one of R.sup.1, R.sup.2, R.sup.3,
and R.sup.4 is not H, R.sup.5 is --OH, R.sup.7 is a bond, then
R.sup.6 is not a C.sub.1-C.sub.4 alkyl.
[0044] Optionally, when R.sup.1, R.sup.2, and R.sup.3 are H,
R.sup.4 is --OCH.sub.3, R.sup.5 is --C(O)CH.sub.3, and R.sup.6 is a
bond then R.sup.7 is not a C.sub.3 alkyl.
[0045] Optionally, when R.sup.1, R.sup.2, R.sup.4, and R.sup.5 are
H, R.sup.3 is --OH, and R.sup.7 is a bond then R.sup.6 is not a
methyl.
[0046] In yet another embodiment the composition comprises
acyclovir or a salt, ester, or prodrug thereof and at least one
delivery agent of the following structure or a salt (e.g., a
pharmaceutically acceptable salt) thereof:
##STR00003##
wherein
[0047] R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are
independently H, --CN, --OH, --OCH.sub.3, or halogen, at least one
of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 being --CN;
and
[0048] R.sup.6 is a C.sub.1-C.sub.12 linear or branched alkylene,
alkenylene, arylene, alkyl(arylene) or aryl(alkylene).
[0049] According to one embodiment, when R.sup.1 is --CN, R.sup.4
is H or --CN, and R.sup.2, R.sup.3, and R.sup.5 are H, then R.sup.6
is not methylene ((CH.sub.2).sub.1).
[0050] Also provided is a dosage unit form (e.g., an oral dosage
unit form) comprising the composition of the present invention. The
dosage unit form may be in the form of a liquid or a solid, such as
a tablet, capsule or particle, including a powder or sachet.
[0051] Another embodiment is a method for administering acyclovir
or a salt, ester, or prodrug thereof to an animal (preferably a
mammal and more preferably a human) in need thereof, by
administering the composition or dosage unit form(s) of the present
invention to the animal. The preferred route of administration is
oral.
[0052] Yet another embodiment is a method of treating conditions or
disorders caused by a virus in an animal (preferably a mammal and
more preferably a human)in need thereof by administering an
effective amount of the composition or dosage unit form(s) of the
present invention to the animal. In other words, an effective
amount of the delivery agent compound to facilitate the delivery of
the acyclovir or a salt, ester, or prodrug thereof and an effective
amount (e.g., a therapeutically effective amount) of acyclovir is
administered.
[0053] Yet another embodiment is a method for treating conditions
or disorders caused by a virus in an animal (preferably a mammal
and more preferably a human) by administering to the animal a
therapeutically effective amount of the composition or dosage unit
form(s) of the present invention. Such conditions and disorders,
include but are not limited to, those caused by viruses of the
herpes family, for example, herpes simplex 1 and 2 viruses (HSV 1
and HSV 2), varicella zoster virus (VZV), cytomegalovirus (CMV),
Epstein-Barr virus (EBV), and other herpes virus infections (e.g.
feline herpes virus infections).
[0054] Another embodiment is a method of treating virus infections,
especially herpes infections such as herpes simplex 1 and 2 viruses
(HSV 1, HSV 2), varicella zoster virus (VZV), cytomegalovirus (CMV)
and Epstein-Barr virus (EBV), and other herpes virus infections
(e.g. feline herpes virus infections) in a human or non-human
animal by administering an effective amount of the composition or
dosage unit form of the present invention.
[0055] Yet another embodiment is a method of treating clinical
conditions or symptoms which are caused by the viruses enumerated
above, including herpetic karatitis, herpetic encaphalitis, cold
sores and genital infections (caused by herpes simplex), chicken
pox and shingles (caused by varicella zoster) and CMV-pneumonia and
retinitis, particularly in immunocompromised patients including
renal and bone marrow transplant patients and patients with
Acquired Immune Deficiency Syndrome (AIDS) by administering an
effective amount of the composition or dosage unit form of the
present invention. Epstein-Barr virus (EVB) causes infectious
mononucleosis, and is also suggested as the causative agent of
nasopharyngeal cancer, immunoblastic lymphoma, Burkitt's lymphoma
and hairy leukoplakia.
[0056] Yet another embodiment is a method of treating viral
infections in an animal (preferably a mammal and more preferably a
human) in need thereof by administering to the animal a
therapeutically effective amount of the composition or dosage unit
form(s) of the present invention. Generally, the viral infections
are those treatable with acyclovir or a salt, ester, or prodrug
thereof.
[0057] Yet another embodiment is a method for acute treatment of
herpes zoster (also known as shingles) in a human in need thereof
by administering (preferably orally) an effective amount of the
pharmaceutical composition of the present invention. Preferably,
the pharmaceutical composition is orally administered every 5 or
more hours and less than 5 times daily. Preferably, the
pharmaceutical composition provides bioavailability (i.e., AUC)
substantially equivalent to the current acyclovir formulations
marketed as Zovirax.RTM. (U.S. FDA NDA No. 18828, 19909, or 20089)
when 200 mg of acyclovir is administered every 4 hours 5 times
daily. The treatment may be continued for 7 to 10 days.
[0058] Yet another embodiment is a method for treatment of initial
episodes and/or the management of recurrent episodes of genital
herpes in a human in need thereof by administering (preferably
orally) an effective amount of the pharmaceutical composition of
the present invention. Preferably for the treatment of initial
genetic herpes, the pharmaceutical composition (e.g., 400 mg of
acyclovir or a molar equivalent of a salt or prodrug thereof) is
administered every 5 or more hours and less than 5 times daily. The
treatment may be continued for 10 days. Preferably, the
pharmaceutical composition provides bioavailability (i.e., AUC)
substantially equivalent to the current acyclovir formulations
marketed as Zovirax.RTM. (U.S. FDA NDA No. 18828, 19909, or 20089)
when 800 mg of acyclovir is administered every 4 hours 5 times
daily.
[0059] Preferably for chronic suppressive therapy for recurrent
genital herpes, the composition is administered once daily or less
frequently. The treatment may be continued for up to 12 months,
followed by re-evaluation. Preferably, the composition provides
bioavailability (i.e., AUC) substantially equivalent to the current
acyclovir formulations marketed as Zovirax.RTM. (U.S. FDA NDA No.
18828, 19909, or 20089) when: [0060] (1) 400 mg of acyclovir is
administered 2 times daily, [0061] (2) 200 mg of acyclovir is
administered 3 times daily, [0062] (3) 200 mg of acyclovir is
administered 4 times daily, or [0063] (4) 200 mg of acyclovir is
administered 5 times daily.
Treatment may be continued for up to 12 months, followed by
re-evaluation.
[0064] Yet another embodiment is a method for treatment of
chickenpox in a human in need thereof by administering (preferably
orally) an effective amount of the composition of the present
invention. Preferably the composition (e.g., 80 mg/kg/day of
acyclovir or a molar equivalent of a salt or prodrug thereof) is
administered every 5 or more hours and less than 4 times daily. For
children (2 years of age and older), an amount of the composition
can be orally administered to provide the equivalent
bioavailability as 20 mg/kg per dose 4 times daily of the current
acyclovir formulations marketed as Zoviraxe (U.S. FDA NDA No.
18828, 19909, or 20089). For adults or children over 40 kg, an
amount of the composition can be orally administered to provide the
equivalent bioavailability as 800 mg of the current acyclovir
formulations marketed as Zovirax.RTM. (U.S. FDA NDA No. 18828,
19909, or 20089) administered 4 times daily.
[0065] Yet another embodiment is a method of preparing a
composition of the present invention by mixing at least one
delivery agent compound and acyclovir or a salt, ester, or prodrug
thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0066] FIG. 1 is a graph of the serum concentrations
(ng/ml.+-.standard error) of acyclovir versus time after oral
administration with and without the delivery agent SNAC or SNAD by
the procedure described in Example 1.
[0067] FIGS. 2, 4, and 6-10 are graphs of the serum concentrations
(ng/ml.+-.standard error) of acyclovir versus time after
intravenous or oral administration with or without the delivery
agent SNAC of formulations 1, 3, and 5-9 shown in table 2,
respectively, by the procedure described in Example 2.
[0068] FIG. 3 shows graphs of the serum concentrations
(ng/ml.+-.standard error) of acyclovir versus time after oral
administration of (1) 400 mg of acyclovir (without a delivery
agent) of formulation 5 (shown in table 2) or (2) 80 mg of
acyclovir and 240 mg of the delivery agent SNAC of formulation 2
(shown in table 2), respectively, by the procedure described in
Example 2.
[0069] FIG. 5 is a graph of the serum concentration
(ng/ml.+-.standard error) of acyclovir versus time after oral
administration of valacyclovir (without a delivery agent) of
formulation 4 shown in table 2, respectively, by the procedure
described in Example 2.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0070] The term "hydrate" as used herein includes, but is not
limited to, (i) a substance containing water combined in the
molecular form and (ii) a crystalline substance containing one or
more molecules of water of crystallization or a crystalline
material containing free water.
[0071] The term "solvate" as used herein includes, but is not
limited to, a molecular or ionic complex of molecules or ions of a
solvent with molecules or ions of the delivery agent compound or
salt thereof, or hydrate or solvate thereof.
[0072] The term "delivery agent" refers to any of the delivery
agent compounds disclosed herein.
[0073] The term "SNAC" refers to the monosodium salt of
N-(8-[2-hydroxybenzoyl]-amino)caprylic acid, unless otherwise
indicated. Unless otherwise noted, the term "SNAC" refers to all
forms of SNAC, including all amorphous and polymorphic forms of
SNAC, such as SNAC trihydrate and those described in U.S. Ser. Nos.
60/619,418 and 60/569,476, both of which are hereby incorporated by
reference. The term "SNAC trihydrate" as used herein refers to a
crystalline form of SNAC in which three molecules of water are
associated with each molecule of SNAC. SNAC can be prepared by the
procedures described in U.S. Pat. No. 5,650,386 and International
Publication Nos. WO00/46182 and WO00/59863.
[0074] The term "SNAD" refers to the monosodium salt of
N-(10-[2-hydroxybenzoyl]-amino)decanoic acid, unless otherwise
indicated. The term "disodium salt of SNAD" refers to the disodium
salt of N-(10-[2-hydroxybenzoyl]-amino)decanoic acid.
[0075] An "effective amount of acyclovir" is an amount of acyclovir
which is effective to treat or prevent a condition in a living
organism to whom it is administered over some period of time, e.g.,
provides a therapeutic effect during a desired dosing interval.
[0076] An "effective amount of delivery agent" is an amount of the
delivery agent which enables and/or facilitates the absorption of a
desired amount of acyclovir via any route of administration (such
as those discussed in this application including, but not limited
to, the oral (e.g., across a biological membrane in the
gastrointestinal tract), nasal, pulmonary, dermal, buccal, vaginal,
and/or ocular route).
[0077] The term "mean", when preceding a pharmacokinetic value
(e.g., mean Peak) represents the arithmetic mean value of the
pharmacokinetic value unless otherwise specified.
[0078] As used herein and in the appended claims, the singular
forms "a," "an," and "the," include plural referents unless the
context clearly indicates otherwise. Thus, for example, reference
to "a molecule" includes one or more of such molecules, "a reagent"
includes one or more of such different reagents, reference to "an
antibody" includes one or more of such different antibodies, and
reference to "the method" includes reference to equivalent steps
and methods known to those of ordinary skill in the art that could
be modified or substituted for the methods described herein.
[0079] The term "about" generally means within 10%, preferably
within 5%, and more preferably within 1% of a given value or
range.
[0080] The terms "alkyl" and "alkenyl" as used herein include
linear and branched alkyl and alkenyl substituents,
respectively.
[0081] The phrase "pharmaceutically acceptable" refers to additives
or compositions that are physiologically tolerable and do not
typically produce an allergic or similar untoward reaction, such as
gastric upset, dizziness and the like, when administered to a
mammal.
[0082] By "condition or disorder caused by a virus" is meant any
condition or disorder in an animal that is either caused by,
complicated by, or aggravated by a virus. Such conditions or
disorders include, but are not limited to, those caused by viruses
of the herpes family, for example, herpes simplex 1 and 2 viruses
(HSV 1, HSV 2), varicella zoster virus (VZV), cytomegalovirus
(CMV), Epstein-Barr virus (EBV), and other herpes virus infections
(e.g. feline herpes virus infections).
[0083] As used herein, the term "treat" includes one or more of the
following: [0084] (a) arresting, delaying the onset (i.e., the
period prior to clinical manifestation of a disorder) and/or
reducing the risk of developing or worsening a disorder; [0085] (b)
relieving or alleviating at least one symptom of a disorder in a
mammal, including for example, hypercalcemia; or [0086] (c)
relieving or alleviating the intensity and/or duration of a
manifestation of a disorder experienced by a mammal including ,but
not limited to, those which are in response to a given stimulus
(e.g., pressure, tissue injury or cold temperature). The term
"treat" also includes prophylactically preventing, curing, healing,
alleviating, relieving, altering, remedying, ameliorating,
improving, or affecting a condition (e.g., a disease), the symptoms
of the condition, or the predisposition toward the condition.
Acyclovir
[0087] The term "acyclovir" refers to 9-(2-hydroxyethoxymethyl)
guanine. Suitable salts (e.g., pharmaceutically acceptable salts)
and esters of acyclovir are described in U.S. Pat. No. 4,199,574,
which is hereby incorporated by reference, and include, but are not
limited to, sodium acyclovir and acyclovir valerate. Acyclovir also
forms acid addition salts, such as with hydrochloric, sulphuric,
phosphoric, maleic, fumaric, citric, tartaric, lactic and acetic
acid.
[0088] A synthesis of acyclovir is disclosed in U.S. Pat. No.
4,199,574, which is hereby incorporated by reference. Acyclovir is
commercially available from GlaxoSmithKline (Research Triangle
Park, N.C.) under the tradename Zovirax.TM..
[0089] Any prodrug which is converted in vivo to
9-(2-hydroxyethoxymethyl) guanine can also be used. The term
"prodrug" as used herein includes pharmaceutically acceptable salts
of the drug. Acyclovir prodrugs include, substituted purines of the
formula:
##STR00004##
or salts thereof, wherein:
[0090] R is hydrogen, hydroxy, or amino;
[0091] X is oxygen or sulphur;
[0092] Y is hydrogen or hydroxymethyl; and
[0093] Z is --H, C.sub.1-16 alkyl, or --OCOCH(R.sub.1)NH.sub.2,
wherein R.sub.1 is --CH[CH.sub.3].sub.2.
[0094] Suitable acyclovir prodrugs, include but are not limited to,
those described in U.S. Pat. Nos. 4,609,662, 4,758,572 and
4,957,924, all of which are hereby incorporated by reference. A
non-limiting example of such a prodrug is
2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester
(valacyclovir) and its pharmaceutically acceptable salts.
Valacyclovir is commercially available as its hydrochloride salt
from Glaxo SmithKline (Research Triangle Park, N.C.) under the
tradename Valtrex.TM..
[0095] Therapeutically effective amounts of a acyclovir for use in
treatment of all conditions and disorders described herein, is an
amount sufficient to suppress or alleviate conditions associated
with the viral infection. As will be recognized by those in the
field, an effective amount of therapeutic agent will vary with many
factors including the potency of the acyclovir or salt, ester, or
prodrug thereof, the age and weight of the patient, and the
severity of the condition or disorder to be treated.
[0096] According to one embodiment, the acyclovir (or a salt,
ester, prodrug thereof) is administered (e.g. peripherally) at a
dose of about 0.1 to about 250 mg per kilogram of body weight of
the recipient per day (mg/kg/day), about 1 to about 100 mg/kg/day,
or about 5 to about 20 mg/kg/day (based on the weight of
acyclovir). According to another embodiment, the dose is about 10
mg/kg/day. The desired dose may be administered either as a single
or divided dose.
[0097] The acyclovir and delivery agent compound may be
administered separately or together with one or more other active
agents. For example, the acyclovir and delivery agent compound may
be administered separately or together with compounds or
compositions that exhibit antiviral activity, such as compounds
used to treat retroviral infections (particularly HIV infections),
e.g., 3'-azido-3'-deoxythymidine (AZT) and/or compounds or
compositions that exhibit activity as ribonucleotide reductase
inhibitors. Suitable ribonucleotide reductase inhibitors include,
but are not limited to, thiocarbonohydrazone ribonucleotide
reductase inhibitors, such as those disclosed in U.S. Pat. No.
5,393,883, which is hereby incorporated by reference.
Delivery Agent Compounds
[0098] The delivery agent compound may be any of those described in
Pat. Nos. 6,699,467, 6,663,898, 6,693,208, 6,693,073, 6,693,898,
6,663,887, 6,646,162, 6,642,411, 6,627,228, 6,623,731, 6,610,329,
6,558,706, 6,525,020, 6,461,643, 6,461,545, 6,440,929, 6,428,780,
6,413,550, 6,399,798, 6,395,774, 6,391,303, 6,384,278, 6,375,983,
6,358,504, 6,346,242, 6,344,213, 6,331,318, 6,313,088, 6,245,359,
6,242,495, 6,221,367, 6,180,140, 6,100,298, 6,100,285, 6,099,856,
6,090,958, 6,084,112, 6,071,510, 6,060,513, 6,051,561, 6,051,258,
6,001,347, 5,990,166, 5,989,539, 5,976,569, 5,972,387, 5,965,121,
5,962,710, 5,958,451, 5,955,503, 5,939,381, 5,935,601, 5,879,681,
5,876,710, 5,866,536, 5,863,944, 5,840,340, 5,824,345, 5,820,881,
5,811,127, 5,804,688, 5,792,451, 5,776,888, 5,773,647, 5,766,633,
5,750,147, 5,714,167, 5,709,861, 5,693,338, 5,667,806, 5,650,386,
5,643,957, 5,629,020, 5,601,846, 5,578,323, 5,541,155, 5,540,939,
5,451,410, 5,447,728, 5,443,841, and 5,401,516; International
Publication Nos. WO94/23767, WO95/11690, WO95/28920, WO95/28838,
WO96/10396, WO96/09813, WO96/12473, WO97/36480, WO 2004/4104018, WO
2004080401, WO 2004062587, WO 2003/057650, WO 2003/057170, WO
2003/045331, WO 2003/045306, WO 2003/026582, WO 2002/100338, WO
2002/070438, WO 2002/069937, WO 02/20466, WO 02/19969, WO 02/16309,
WO 02/15959, WO 02/02509, WO 01/92206, WO 01/70219, WO 01/51454, WO
01/44199, WO 01/34114, WO 01/32596, WO 01/32130, WO 00/07979, WO
00/06534, WO 00/06184, WO 00/59863, WO 00/59480, WO 00/50386, WO
00/48589, WO 00/47188, WO 00/46182, WO 00/40203, WO 99/16427, WO
98/50341, WO 98/49135, WO 98/34632, WO 98/25589, WO 98/21951, WO
97/47288, WO 97/31938, WO 97/10197, WO 96/40076, WO 96/40070, WO
96/39835, WO 96/33699, WO 96/30036, WO 96/21464, WO 96/12475, and
WO 96/12474; and U.S. Published Application Nos. 20040110839,
20040106825, 20040068013, 20040062773, 20040022856, 20030235612,
20030232085, 20030225300, 20030198658, 20030133953, 20030078302,
20030072740, 20030045579, 20030012817, 20030008900, 20020155993,
20020127202, 20020120009, 20020119910, 20020102286, 20020065255,
20020052422, 20020040061, 20020028250, 20020013497, 20020001591,
20010039258, and 20010003001. Each of the above listed U.S. patents
and U.S. and International published applications are herein
incorporated by reference.
[0099] Non-limiting examples of delivery agent compounds include
N-(8-[2-hydroxybenzoyl]-amino)caprylic acid,
N-(10-[2-hydroxybenzoyl]-amino)decanoic acid,
8-(2-hydroxy-4-methoxybenzoylainino)octanoic acid,
8-(2,6-dihydroxybenzoylamino)octanoic acid,
8-(2-hydroxy-5-bromobenzoylamino)octanoic acid,
8-(2-hydroxy-5-chlorobenzoylamino)octanoic acid,
8-(2-hydroxy-5-iodobenzoylamino)octanoic acid,
8-(2-hydroxy-5-methylbenzoylamino)octanoic acid,
8-(2-hydroxy-5-fluorobenzoylamino)octanoic acid,
8-(2-hydroxy-5-methoxybenzoylamino)octanoic acid,
8-(3-hydroxyphenoxy)octanoic acid, 8-(4-hydroxyphenoxy)octanoic
acid, 6-(2-cyanophenoxy)hexanoic acid,
8-(2-Hydroxyphenoxy)octyl-diethanolamine,
8-(4-hydroxyphenoxy)octanoate, 8-(4-hydroxyphenoxy)octanoate,
8-(2-hydroxy-4-methoxybenzoylainino)octanoic acid,
8-(2-hydroxy-5-methoxybenzoylamino)-octanoic acid., and salts
thereof. Preferred salts include, but are not limited to,
monosodium and disodium salts.
[0100] The delivery agent compounds may be in the form of the
carboxylic acid or pharmaceutically acceptable salts thereof, such
as sodium salts, and hydrates and solvates thereof. The salts may
be mono- or multi-valent salts, such as monosodium salts and
disodium salts. The delivery agent compounds may contain different
counter ions chosen for example due to their effect on modifying
the dissolution profile of the carrier.
[0101] The delivery agent compounds may be prepared by methods
known in the art, such as those discussed in the aforementioned
publications (e.g., International Publication Nos. WO 98/34632, WO
00/07979, WO 01/44199, WO 01/32596, WO 02/20466, and WO 03/045306).
SNAC, SNAD, and the free acid and other salts thereof may be
prepared by methods known in the art, such as those described in
U.S. Pat. Nos. 5,650,386 and 5,866,536.
[0102] Salts of the delivery agent compounds of the present
invention may be prepared by methods known in the art. For example,
sodium salts may be prepared by dissolving the delivery agent
compound in ethanol and adding aqueous sodium hydroxide.
[0103] The delivery agent compound may be purified by
recrystallization or by fractionation on one or more solid
chromatographic supports, alone or linked in tandem. Suitable
recrystallization solvent systems include, but are not limited to,
acetonitrile, methanol, and tetrahydrofuran. Fractionation may be
performed on a suitable chromatographic support such as alumina,
using methanol/n-propanol mixtures as the mobile phase; reverse
phase chromatography using trifluoroacetic acid/acetonitrile
mixtures as the mobile phase; and ion exchange chromatography using
water or an appropriate buffer as the mobile phase. When anion
exchange chromatography is performed, preferably a 0-500 mM sodium
chloride gradient is employed.
Delivery Systems
[0104] The composition of the present invention comprises one or
more delivery agent compounds of the present invention and
acyclovir. The delivery agent compound and acyclovir are typically
mixed prior to administration to form an administration
composition.
[0105] The administration compositions may be in the form of a
liquid. The solution medium may be water, 25% aqueous propylene
glycol, or phosphate buffer. Other dosing vehicles include
polyethylene glycol. Dosing solutions may be prepared by mixing a
solution of the delivery agent compound with a solution of the
active agent, just prior to administration. Alternately, a solution
of the delivery agent compound (or acyclovir) may be mixed with the
solid form of acyclovir (or delivery agent compound). The delivery
agent compound and acyclovir may also be mixed as dry powders. The
delivery agent compound and acyclovir can also be admixed during
the manufacturing process.
[0106] The dosing solutions may optionally contain additives such
as phosphate buffer salts, citric acid, glycols, or other
dispersing agents. Stabilizing additives may be incorporated into
the solution, preferably at a concentration ranging between about
0.1 and 20% (w/v).
[0107] For example, the compositions useful in the invention can be
provided as parenteral compositions (e. g., injection or infusion).
According to one embodiment, the composition is suspended in an
aqueous carrier, such as in an isotonic buffer solution at a pH of
about 3.0 to about 8.0. Suitable buffers include, but are not
limited to, sodium citrate-citric acid and sodium
phosphate-phosphoric acid, and sodium acetate/acetic acid
buffers.
[0108] A form of repository or "depot" slow release preparation may
also be used so that therapeutically effective amounts of the
preparation are delivered into the bloodstream over many hours or
days following transdermal injection or delivery.
[0109] The administration compositions may alternately be in the
form of a solid, such as a tablet, capsule or particle, such as a
powder or sachet. Solid dosage forms may be prepared by mixing the
solid form of the compound with the solid form of acyclovir.
Alternately, a solid may be obtained from a solution of compound
and acyclovir by methods known in the art, such as freeze-drying
(lyophilization), precipitation, crystallization and solid
dispersion. Alternatively, the administration can be a semi-solid,
in the form of a gel, paste, colloid, gelatin, emulsion, suspension
and the like.
[0110] The administration compositions of the present invention may
also include one or more enzyme inhibitors. Such enzyme inhibitors
include, but are not limited to, compounds such as actinonin or
epiactinonin and derivatives thereof. Other enzyme inhibitors
include, but are not limited to, aprotinin (Trasylol) and
Bowman-Birk inhibitor.
[0111] The amount of acyclovir used in an administration
composition of the present invention is an amount effective to
treat the target indication. However, the amount can be less than
that amount when the composition is used in a dosage unit form
because the dosage unit form may contain a plurality of delivery
agent compound/acyclovir, such compositions may contain a divided
effective amount. The total effective amount can then be
administered in cumulative units containing, in total, an effective
amount of acyclovir. Moreover, those skilled in the filed will
recognize that an effective amount of acyclovir will vary with many
factors including the age and weight of the patient, the patient's
physical condition, as well as other factors.
[0112] The total amount of acyclovir to be used of can be
determined by methods known to those skilled in the art. However,
because the compositions of the invention may deliver acyclovir
more efficiently than compositions containing acyclovir lower
amounts of acyclovir than those used in prior dosage unit forms or
delivery systems can be administered to the subject, while still
achieving the same blood levels and/or therapeutic effects.
[0113] According to one embodiment, the acyclovir (or a salt,
ester, prodrug thereof) is administered (e.g. peripherally) at a
dose of about 0.1 to about 250 mg per kilogram of body weight of
the recipient per day (mg/kg/day), about 1 to about 100 mg/kg/day,
or about 5 to about 20 mg/kg/day (based on the weight of
acyclovir). According to another embodiment, the dose is about 10
mg/kg/day. The desired dose may be administered either as a single
or divided dose.
[0114] The present invention also includes pharmaceutical
compositions and dosage forms which include the aforementioned
amounts of acyclovir and at least one delivery agent
[0115] Generally an effective amount of delivery agent to
facilitate the delivery acyclovir is administered with acyclovir.
According to one embodiment, the amount of delivery agent to
acyclovir on a molar basis ranges from about 20:1 to about 1:1,
from about 10:1 to about 2:1, or from about 5:1 to about 2:1.
[0116] The presently disclosed delivery agent compounds facilitate
the delivery of acyclovir, particularly in oral, intranasal,
sublingual, intraduodenal, subcutaneous, buccal, intracolonic,
rectal, vaginal, mucosal, pulmonary, transdermal, intradermal,
parenteral, intraperitoneal, intravenous, intramuscular and ocular
systems, as well as traversing the blood-brain barrier. The
compositions and dosage unit forms of the present invention can be
administered by any of the aforementioned routes.
[0117] Dosage unit forms can also include any one or combination of
excipients, diluents, disintegrants, lubricants, plasticizers,
colorants, flavorants, taste-masking agents, sugars, sweeteners,
salts, and dosing vehicles, including, but not limited to, water,
1,2-propane diol, ethanol, olive oil, or any combination
thereof.
[0118] The compositions of the subject invention are useful for
administering biologically or chemically active agents to any
animals, including but not limited to birds such as chickens; fish,
reptiles, mammals, such as rodents, cows, pigs, dogs, cats,
primates, and particularly humans, and insects.
Methods of Treatment
[0119] The composition of the present invention can treat any
disorder which is treatable with acyclovir or its salts (e.g.,
acyclovir sodium) or prodrugs (e.g., valacyclovir), including those
described in the Physicians' Desk Reference (58.sup.th Ed., 2004,
Medical Economics Company, Inc., Montvale, N.J.). Such disorders
include, but are not limited to, those described above or in the
patents or other publications above. Non-limiting examples are:
[0120] (1) herpes simplex 1 virus (HSV 1), [0121] (2) herpes
simplex 2 virus (HSV 2), [0122] (3) varicella zoster virus (VZV),
[0123] (4) cytomegalovirus (CMV), [0124] (5) Epstein-Barr virus
(EBV), [0125] (6) other herpes virus infections (e.g. feline herpes
virus infections), [0126] (7) herpetic karatitis, [0127] (8)
herpetic encaphalitis, [0128] (9) cold sores and genital infections
(caused by herpes simplex), [0129] (10) chicken pox, [0130] (11)
shingles (caused by varicella zoster), [0131] (12) CMV-pneumonia
and retinitis, particularly in immunocompromised patients including
renal and bone marrow transplant patients and patients with
Acquired Immune Deficiency Syndrome (AIDS), [0132] (13)
Epstein-Barr virus (EVB) caused infectious mononucleosis,
nasopharyngeal cancer, immunoblastic lymphoma, Burkitt's lymphoma
and hairy leukoplakia, [0133] (14) herpes zoster, and [0134] (15)
initial episodes and/or the management of recurrent episodes of
genital herpes.
EXAMPLES
[0135] The following examples illustrate the invention without
limitation. All parts are given by weight unless otherwise
indicated.
Example 1
Solid Oral Delivery of Acyclovir in Rats
[0136] The dose of Acyclovir used was 25 mg/kg body weight. The
dose of delivery agent was either 50 or 75 mg/kg body weight.
[0137] Approximately 6.25 mg/tablet of acyclovir was blended with
either 12.5 or 18.75 mg/tablet (50 and 75 mg/kg, respectively) of
delivery agent compound. Upper punch, lower punch and die of a
Carver 4350 manual pellet press with a Caplet shape model sold by
Natoli Engineering Company, Inc. were treated with magnesium
stearate (0.1%). Approximately 6.25 mg (Acyclovir alone), 18.75 mg
(Acyclovir+50 mg/kg delivery agent compound), or 25 mg
(Acyclovir+75 mg/kg delivery agent compound) of mixed powder was
fed into the die and a mini bead shape tablet was made at about
1000 PSI bar pressure. The resulting solid dosage forms were 2.65
mm in diameter and approximately 8.40 mm in length for the 25 mg
tablets, 6.3 mm in length for the 18.75 mg tablets, and 2.1 mm in
length for the 6.25 mg tablets.
[0138] Male Sprague Dawley rats (.about.250 g) were fasted
overnight and then anesthesized by standard CO.sub.2 inhalation
technique for approximately 10 seconds, resulting in an
anesthesized state for less then one minute.
[0139] An oral dosing tube was used. The dosing tube was inserted
into the rat's mouth and carefully threaded down the pharynx and
esophagus about 8 cm to about 15 cm depending on the weight of the
rat (typically about 11 cm). The solid dosage form was delivered
into the distal esophagus and/or stomach by pressing the plunger of
the oral dosing tube.
[0140] Blood samples were collected serially from the retro-orbital
sinus at 0, 15, 30, 45, and 60 minutes. Samples were collected on
wet ice into heparin-containing tubes. Samples were centrifuged and
plasma was extracted. Plasma samples were stored in a -20.degree.
C. freezer until analysis. Plasma Acyclovir concentrations were
quantified using a LC-MS-MS method (analysis performed by Quest
Pharmaceutical Services, Newark, Del.). Results from the animals in
each group were averaged for each time point. The maximum of these
averages (i.e., the mean peak plasma Acyclovir
concentration.+-.standard deviation (SD)) is reported below in
Table 1. The results are also shown in FIG. 1.
TABLE-US-00001 TABLE 1 Oral Delivery of Acyclovir in Rats Mean
plasma peak Delivery Agent Acyclovir of Acyclovir Delivery Agent
dose (mg/kg) (mg/kg) (ng/ml) .+-. SD None -- 25 95.11 .+-. 73.75 1
50 25 1719.32 .+-. 676.52 1 75 25 2759.93 .+-. 1699.39 2 50 25
778.12 .+-. 491.9 2 75 25 1694.65 .+-. 1133.57 Delivery Agent 1 is
the monosodium salt of N-(8-[2-hydroxybenzoyl]-amino)caprylic acid
(SNAC). Delivery Agent 2 is the monosodium salt of
N-(10-[2-hydroxybenzoyl]-amino)decanoic acid (SNAD).
Example 2
Delivery of Acyclovir in Dogs
[0141] Six different oral dosage forms (tablets) were administered
to dogs: (1) unitary solid oral dosage forms comprising 80 mg of
acyclovir and 240 mg of the delivery agent, the monosodium salt of
N-(8-[2-hydroxybenzoyl]-amino)caprylic acid (SNAC), (2) a solid
oral dosage form comprising 400 mg of acyclovir (Zovirax.TM.,
commercially available from GlaxoSmithKline), (3) a solid oral
dosage form comprising 800 mg dosage of (Zovirax.TM., commercially
available from GlaxoSmithKline), (4) a solid oral dosage form
comprising 500 mg dosage of valacyclovir (Valtrex.TM., commercially
available from GlaxoSmithKline) and (6) unitary solid oral dosage
comprising 240 mg of acyclovir and 240 mg of the delivery agent
SNAC. Oral administration of acylcovir alone and with a delivery
agent was compared to an interveneous dosage form comprising 80 mg
of acyclovir (Zovirax.TM. for injection, commercially available
from GlaxoSmithKline).
[0142] Unitary dosages of acyclovir and delivery agent were
prepared as follows. Approximately 240 mg/tablet of SNAC was
blended with either 80 or 240 mg/tablet of acyclovir. Upper punch,
lower punch and die of a Carver 4350 manual pellet press with a
Caplet shape model sold by Natoli Engineering Company, Inc. were
treated with magnesium stearate (0.1%). Approximately 320 mg (80 mg
acyclovir and 240 mg SNAC), or 480 mg (240 mg acyclovir and 240 mg
SNAC) of mixed powder was fed into the die and a mini bead shape
tablet was made at about 1000 PSI bar pressure.
[0143] Each dog was dosed as described in Table 2. Plasma acyclovir
concentrations were quantified using a LC-MS-MS method. The maximum
peak plasma acyclovir concentration and the area under the curve
(AUC) are reported below in Table 2. The results for experiments
1-9 are also shown in FIGS. 2-10, respectively.
TABLE-US-00002 TABLE 2 Delivery of Acyclovir in Dogs Mean plasma
peak of Formulation Route of Delivery Acyclovir Acyclovir AUC No.
Administration Agent (mg) (mg) (ng/ml) (ng/ml * min) 1 (n = 3)
Intravenous -- 80 12186 2177300 2 (n = 4) Oral -- 400 2685 423925 3
(n = 4) Oral -- 800 5029 1317130 4 (n = 4) Oral -- .sup. 500.sup.1
30516 6822910 (valacyclovir) 5 (n = 4) Oral 240 80 2982 492338 6 (n
= 4) Oral 240 80 2592 525056 7 (n = 4) Oral 240 240 13142 3268320 8
(n = 4) Oral 240 240 20591 4811610 9 (n = 4) Oral .sup. 480.sup.2
.sup. 480.sup.2 19144 4988940 .sup.1Delivered as valacyclovir
(Valtrex .TM., commercially available from GlaxoSmithKline)
.sup.2Delivered as two tablets comprising 240 mg Acyclovir and 240
mg of delivery agent
[0144] The above-mentioned patents, applications, test methods, and
publications are hereby incorporated by reference in their
entirety.
[0145] Many variations of the present invention will suggest
themselves to those skilled in the art in light of the above
detailed description. All such obvious variations are within the
fully intended scope of the appended claims.
* * * * *