U.S. patent application number 12/819542 was filed with the patent office on 2010-10-07 for low dose therapy for treating viral infections.
This patent application is currently assigned to ACHILLION PHARMACEUTICALS, INC.. Invention is credited to John POTTAGE.
Application Number | 20100256088 12/819542 |
Document ID | / |
Family ID | 35125653 |
Filed Date | 2010-10-07 |
United States Patent
Application |
20100256088 |
Kind Code |
A1 |
POTTAGE; John |
October 7, 2010 |
LOW DOSE THERAPY FOR TREATING VIRAL INFECTIONS
Abstract
A method of treating viral infections, particularly Hepatitis B
(HBV) and Human Immunodeficiency Virus (HIV), by administering a
low dose of Elvucitabine to a patient suffering viral infection, is
provided herein. The Elvucitabine dosages provided herein for
effective anti-viral therapy are approximately 10-fold less than
the effective dosages of currently marketed reverse transcriptase
inhibitors. The Elvucitabine dosage may be given BID, daily, once
ever 48 hours, or once weekly. Also provided herein are packaged
pharmaceutical formulations comprising Elvucitabine and
instructions for treating a viral infection by administering a low
BID, daily, once/48 hour period, or weekly dosage of Elvucitabine.
The low dose Elvucitabine formulations provided herein have the
additional benefit of improving patient compliance with anti-viral
therapy.
Inventors: |
POTTAGE; John; (Madison,
CT) |
Correspondence
Address: |
CANTOR COLBURN, LLP
20 Church Street, 22nd Floor
Hartford
CT
06103
US
|
Assignee: |
ACHILLION PHARMACEUTICALS,
INC.
New Haven
CT
|
Family ID: |
35125653 |
Appl. No.: |
12/819542 |
Filed: |
June 21, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11547179 |
Sep 29, 2006 |
7741334 |
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PCT/US05/11539 |
Apr 1, 2005 |
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12819542 |
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60558633 |
Apr 1, 2004 |
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Current U.S.
Class: |
514/49 |
Current CPC
Class: |
A61K 31/513 20130101;
A61P 31/18 20180101; A61P 31/20 20180101; A61K 31/505 20130101 |
Class at
Publication: |
514/49 |
International
Class: |
A61K 31/7068 20060101
A61K031/7068; A61P 31/18 20060101 A61P031/18; A61P 31/20 20060101
A61P031/20 |
Claims
1. A method of treating an HIV infection comprising administering
about 2.5 mg to about 10 mg Elvucitabine per day to a patient
suffering from an HIV infection.
2. The method of claim 1 wherein about 5 mg Elvucitabine is
administered BID.
3. The method of claim 1 wherein about 5 mg Elvucitabine is
administered once per day.
4. The method of claim 1 wherein about 7.5 mg Elvucitabine is
administered once per day.
5. The method of claim 1 wherein about 10 mg Elvucitabine is
administered once per day.
6-14. (canceled)
15. The method of claim 1 wherein the Elvucitabine is administered
as an oral dosage.
16. The method of claim 15 wherein the oral dosage is in the form
of a tablet or capsule.
17. A packaged pharmaceutical formulation comprising a
pharmaceutical formulation containing Elvucitabine and instructions
for using the formulation for treating an HIV infection by
administering about 2.5 mg to about 10 mg Elvucitabine per day to a
patient suffering from an HIV infection.
18. A packaged pharmaceutical formulation comprising a
pharmaceutical formulation containing Elvucitabine and instructions
for using the formulation for treating a viral infection by
administering about 5 mg to about 20 mg Elvucitabine once per 48
hour interval or about 40 to about 100 mg Elvucitabine once per one
week interval to a patient suffering from a viral infection.
19. The packaged pharmaceutical formulation of claim 18 where the
instructions are instructions for using the formulation for
treating an HIV or HBV infection.
20. The pharmaceutical formulation of claim 17 wherein the
formulation comprises an oral dosage form.
21-25. (canceled)
26. A method of treating an HIV infection or HBV infection in a
patient comprising administering an amount of elvucitabine to the
patient so that AUC at steady state for a 24 hour period is at
least 300 .mu.gh/L and C.sub.min is from about 2 .mu.g/L to about
23 .mu.g/L.
27. A method of treating HIV infection or HBV infection in a
patient comprising administering an effective amount of
elvucitabine to the patient once every 2 to 7 days.
28. The method of claim 27, wherein from about 5 mg to about 100 mg
elvucitabine are administered to the patient.
29. The method of claim 27, wherein about 20 mg elvucitabine are
administered to the patient once every 2 to 7 days.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. provisional patent
application No. 60/558,633, filed Apr. 1, 2004, which is hereby
incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] A method of treating viral infections, particularly
Hepatitis B (HBV) and Human Immunodeficiency Virus (HIV), by
administering a low dose of Elvucitabine to a patient suffering
viral infection is provided herein. The Elvucitabine dosage may be
given BID, daily, once ever 48 hours, or once weekly. Also provided
herein are packaged pharmaceutical formulations comprising
Elvucitabine and instructions for treating a viral infection by
administering a low BID, daily, once/48 hour, or weakly dosage of
Elvucitabine. Methods of improving patient compliance with
anti-viral therapy by providing a reverse transcriptase inhibitor
formulated for low dose administration are also included
herein.
[0003] The invention provides novel pharmaceutical formulations of
Elvucitabine. The invention also provides pharmaceutical
compositions and oral dosage forms having unique physical--chemical
properties.
BACKGROUND
[0004] Hepatitis B virus (HBV) infection is a major health problem
throughout the world. HBV is a causative agent of both an acute and
chronic form of hepatitis. It is estimated that more than 200
million people worldwide are chronic carriers of HBV.
[0005] HBV belongs to the family Hepadnaviridae, which includes a
number of related viruses that primarily infect small rodents. All
members of hepadnavirus family have a number of characteristics in
common such as morphological appearance, antigenic makeup and DNA
size and structure. Pathological findings following infection with
the members of this family are quite similar. Studies show that the
replication and spread of the viruses of this family are dependent
upon the reverse transcriptase of an RNA intermediate.
[0006] HBV is a double-stranded DNA virus. Its DNA polymerase
catalyzes both DNA-dependent and RNA-dependent RNA synthesis. The
life cycle of HBV involves the enzyme reverse transcriptase in its
DNA replication.
[0007] Although acute HBV infections are generally self-limiting,
in many instances the disease can progress to the chronic state.
HBV infection also creates a risk to fulminant hepatitis. In
addition, Hepatitis B viral infections are closely associated with
hepatocellular carcinoma.
[0008] AIDS is a generally fatal disease caused by a human
pathogenic retrovirus known as human immunodeficiency virus (HIV),
which includes HIV-1 and HIV-2. Reverse transcriptase plays an
essential role in the elaboration and life cycle of HIV and
consequently, the progress of the disease. Reverse transcriptase
inhibitors are currently used with other classes of anti-viral
agents to slow and in some cases halt the progress of HIV
infection.
[0009] Reverse transcriptase inhibitors are preferred therapeutics
for treating certain viral infections, particularly HBV and HIV
infections. Typically about 300 mg of a reverse transciptase
inhibitor must be administered daily for effective treatment of a
viral infections, sometimes on a once per day dosing schedule, but
more typically on a twice or three times per day dosing schedule.
Because patients suffering from HBV or HIV often take a number of
medications, a reverse transcriptase inhibitor efficacious at lower
dosages is urgently needed. A reverse transcriptase inhibitor that
can be administered once daily or less frequently is particularly
desirable.
[0010] Elvucitabine is a nucleoside analog of the formula
##STR00001##
[0011] The anti-viral properties of Elvucitabine have been
described previously in U.S. Pat. Nos. 5,621,120, 5,627,160, and
5,839,881, and U.S. patent application Ser. No. 10/411,929, filed
Apr. 11, 2004, which are hereby incorporated by reference for their
teachings regarding the use of Elvucitabine for treating viral
infections, including HBV and HIV infections, and for teachings
regarding the chemical synthesis of Elvucitabine.
SUMMARY OF THE INVENTION
[0012] It has been discovered that Elvucitabine, a reverse
transcriptase inhibitor, is efficacious for treating viral
infections when administered at very low dosages. Furthermore it
has been discovered that this compound is an effective anti-viral
agent when administered as infrequently as one time per week.
[0013] Elvucitabine, a reverse transcriptase inhibitor, is
efficacious for treating viral infections, including HIV
infections, when administered at very low dosages. Furthermore,
Elvucitabine is an effective anti-viral agent (including anti-HIV
efficacay) when as little as about 2.5 mg to about 10 mg is
administered once a day. For some patients, including patients
having an HIV or HBV infection, Elvucitabine may be effective when
administered as infrequently as one time per week. Thus, methods of
treating viral infections, including HIV and HBV infections,
comprising administering about 2.5 mg to about 10 mg Elvucitabine
per day, or about 5 mg to about 20 mg Elvucitabine per 48 hour
interval, or about 40 mg to about 100 mg Elvucitabine per week to a
patient having a viral infection, such as an HIV or HBV
infection.
[0014] Methods of administering the Elvucitabine as an oral dosage
form are preferred.
[0015] Pharmaceutical compositions containing about 2.5 mg to about
10 mg Elvucitabine and suitable for once per day administration, or
containing about 5 mg to about 20 mg Elvucitabine and suitable for
administration once per 48 hour interval, or about 40 mg to about
100 mg Elvucitabine and suitable for once per week administration,
are provided herein.
[0016] Packaged pharmaceutical formulations comprising an
Elvucitabine pharmaceutical formulation and instructions for using
the formulation for treating a viral infection by administering
about 2.5 mg to about 10 mg Elvucitabine per day, about 5 mg to
about 20 mg Elvucitabine per 48 hour interval, or about 40 mg to
about 100 mg Elvucitabine per week, to a patient suffering from a
viral infection, such as an HIV or HBV infection, are provided
herein.
[0017] Also provided herein are methods of increasing patient
compliance with anti-viral therapy, such as treatment of an HIV or
HBV infection, by providing a reverse transcriptase inhibitor
formulated for low dose daily administration, administration once
every 48 hour interval, or once weekly administration. Elvucitibane
is the preferred reverse transcriptase inhibitor used in such
formulations.
BRIEF DESCRIPTION OF DRAWINGS
[0018] FIG. 1 illustrates a PK model of Elvucitabine;
[0019] FIG. 2 illustrates an example of individual fit using Pop PK
analysis (IT2S);
[0020] FIG. 3 illustrates the change in mean white blood cell count
from baseline for 5 mg, 20 mg, and 50 mg Elvucitabine PD study over
20 weeks;
[0021] FIG. 4 illustrates the change in mean absolute neutrophils
from baseline for 5 mg, 20 mg, and 50 mg Elvucitabine PD study over
20 weeks;
[0022] FIG. 5 illustrates simulated plasma concentrations and mean
observed ANC for 5 mg QD dose;
[0023] FIG. 6 illustrates simulated plasma concentrations and mean
observed ANC for 20 mg QD dose;
[0024] FIG. 7 illustrates simulated plasma concentrations and mean
observed ANC for 50 mg QD dose;
[0025] FIG. 8 is a schematic of the relationship of PK versus PD
for Elvucitabine;
[0026] FIG. 9 is an example of a simulated dosing regimen of a 10
mg QD;
[0027] FIG. 10 is an example of a simulated dosing regimen of a 40
mg Q1week.
DETAILED DESCRIPTION OF THE INVENTION
Terminology
[0028] Prior to setting forth the invention in detail, it may be
helpful to provide definitions of certain terms to be used herein.
Compounds of the present invention are described using standard
nomenclature. Unless defined otherwise, all technical and
scientific terms used herein have the same meaning as is commonly
understood by one of skill in the art to which this invention
belongs.
[0029] The use of the terms "a" and "an" and "the" and similar
referents in the context of describing the invention (especially in
the context of the following claims) are to be construed to cover
both the singular and the plural, unless otherwise indicated herein
or clearly contradicted by context. The terms "comprising",
"having", "including", and "containing" are to be construed as
open-ended terms (i.e., meaning "including, but not limited to")
unless otherwise noted. Recitation of ranges of values herein are
merely intended to serve as a shorthand method of referring
individually to each separate value falling within the range,
unless otherwise indicated herein, and each separate value is
incorporated into the specification as if it were individually
recited herein. All methods described herein can be performed in
any suitable order unless otherwise indicated herein or otherwise
clearly contradicted by context. The use of any and all examples,
or exemplary language (e.g., "such as") provided herein, is
intended merely to better illuminate the invention and does not
pose a limitation on the scope of the invention unless otherwise
claimed. "About" indicates an approximate amount, including the
quantity it modifies. When "about" is used to modify a quantity of
Elvucitabine, the free, unsalted form is the type of form of
elvucitabine referred to, unless another elvucitabine form is
expressly stated. No language in the specification should be
construed as indicating any non-claimed element as essential to the
practice of the invention.
[0030] The term "Elvucitabine" is meant to include solvates
(including hydrates) of the free compound or salt, crystalline and
non-crystalline forms, isotopically enriched or labeled forms, as
well as various polymorphs of Elvucitibane, i.e.
4-amino-5-fluoro-1-((2R,5S)-5-(hydroxymethyl)-2,5-dihydrofuran-2-yl)pyrim-
idin-2(1H)-one.
[0031] Elvucitabine, contains asymmetric elements and can exist in
different stereoisomeric forms. Elvucitabine can be, for example, a
racemate or optically active form. While the
4-amino-5-fluoro-1-((2R,5S)-5-(hydroxymethyl)-2,5-dihydrofuran-2-yl)pyrim-
idin-2(1H)-one is preferred, methods of using racemic mixtures of
Elvucitabine, and other optically pure stereoisomers of this
compounds are withing the scope of this invention. "Elvucitabine"
particularly includes pharmaceutically acceptable salts of this
compound.
[0032] Isotopes include those atoms having the same atomic number
but different mass numbers. By way of general example, and without
limitation, isotopes of hydrogen include tritium and deuterium and
isotopes of carbon include .sup.11C, .sup.13C, and .sup.14C.
[0033] In some embodiments the second active agent is a "low dose
active agent." Within the art of HIV treatment certain compounds
that enhance the activity of antiviral agents by inhibiting liver
enzymes that breakdown antiviral agents are sometimes referred to
as "low dose active agents". Ritonovir (NORVIR, Abbot Laboratories,
Abbott Park, Ill.) is an example of such a compound. While low
dosages of Elvucitabine may be administered with ritonovir, the
term "low dose active agent" is used herein to describe compounds
that retain therapeutic efficacy when administered in small
amounts, typically about 2.5 mg to about 10 mg daily, about 5 to
about 20 mg every 48 hours, or about 40 to about 100 mg once
weekly, or on another infrequent dosage schedule, typically once
daily or less frequently.
[0034] "Pharmaceutically acceptable salts" includes derivatives of
the disclosed compounds, wherein the parent compound is modified by
making non-toxic acid or base addition salts thereof, and further
refers to pharmaceutically acceptable solvates, including hydrates,
of such compounds and such salts. Examples of pharmaceutically
acceptable salts include, but are not limited to, mineral or
organic acid addition salts of basic residues such as amines;
alkali or organic addition salts of acidic residues such as
carboxylic acids; and the like, and combinations comprising one or
more of the foregoing salts. The pharmaceutically acceptable salts
include non-toxic salts and the quaternary ammonium salts of the
parent compound formed, for example, from non-toxic inorganic or
organic acids. For example, non-toxic acid salts include those
derived from inorganic acids such as hydrochloric, hydrobromic,
sulfuric, sulfamic, phosphoric, nitric and the like; other
acceptable inorganic salts include metal salts such as sodium salt,
potassium salt, cesium salt, and the like; and alkaline earth metal
salts, such as calcium salt, magnesium salt, and the like, and
combinations comprising one or more of the foregoing salts.
[0035] Pharmaceutically acceptable organic salts include salts
prepared from organic acids such as acetic, trifluoroacetic,
propionic, succinic, glycolic, stearic, lactic, malic, tartaric,
citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic,
glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic,
2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane
disulfonic, oxalic, isethionic, HOOC--(CH.sub.2).sub.n--COOH where
n is 0-4, and the like; organic amine salts such as triethylamine
salt, pyridine salt, picoline salt, ethanolamine salt,
triethanolamine salt, dicyclohexylamine salt,
N,N'-dibenzylethylenediamine salt, and the like; and amino acid
salts such as arginate, asparginate, glutamate, and the like, and
combinations comprising one or more of the foregoing salts.
[0036] "BID administration" is twice daily administration of a
compound. Typically, each day two equal dosages of a therapeutic
compound are given during waking hours. "TID administration" is
administration of a therapeutic compound three times daily.
Typically three equal dosages are given each day during waking
hours. Some compounds administered BID or TID equal dosages are
given with food, several hours apart, during waking hours.
[0037] The term "effective amount" means an amount effective, when
administered to a human or non-human patient, to provide a
therapeutic benefit such as an amelioration of symptoms, e.g., an
amount effective to decrease the symptoms of a viral infection, and
preferably an amount sufficient to reduce the symptoms of an HBV or
HIV infection. In certain circumstances a patient suffering from a
viral infection may not present symptoms of being infected. Thus a
therapeutically effective amount of a compound is also an amount
sufficient to prevent a significant increase or significantly
reduce the detectable level of virus or viral antibodies in the
patient's blood, serum, or tissues. A significant increase or
reduction in the detectable level of virus or viral antibodies is
any detectable change that is statistically significant in a
standard parametric test of statistical significance such as
Student's T-test, where p<0.05.
[0038] The term "dosage form" denotes a form of a formulation that
contains an amount sufficient to achieve a therapeutic effect with
a single administration.
[0039] The term "oral dosage form" is meant to include a unit
dosage form prescribed or intended for oral administration. An oral
dosage form may or may not comprise a plurality of subunits such
as, for example, microcapsules or microtablets, packaged for
administration in a single dose.
[0040] "Pharmacokinetic parameters," (PK) are parameters, which
describe the in vivo characteristics of Elvucitabine over time,
including for example the in vivo dissolution characteristics and
plasma concentration of mecaymylamine or other active agent. By
"C.sub.max" is meant the measured concentration of Elvucitabine in
the plasma at the highest observed concentration. By "C.sub.24" is
meant the concentration of Elvucitabine in the plasma at about 24
hours. The term "T.sub.max" refers to the time at which the
concentration of Elvucitabine in the plasma is the highest. "AUC"
is the area under the curve of a graph of the concentration of
Elvucitabine (typically plasma concentration) vs. time, measured
from one time to another.
[0041] By "subunit" is meant to include a composition, mixture,
particle, etc., that can provide an oral dosage form alone or when
combined with other subunits. By "part of the same subunit" is
meant to refer to a subunit comprising certain ingredients. For
example, a subunit comprising Elvucitabine or other active agent
and an additional active ingredient may be placed together with
additional subunits in a capsule to provide an oral dosage
form.
Pharmacokinetics and Pharmacodynamics Modeling to Optimize the
Therapeutic Index of Elvucitabine
[0042] Pharmacokinetics and pharmacodynamics modeling was used to
explore potential dosing regimens for Elvucitabine. A
pharmacokinetics (PK) model was developed to describe both the
plasma concentration-time data and excreted urinary amounts from
previously completed studies with Elvucitabine. With the PK model
in hand and pharmacodynamics (PD) results of previously completed
studies, the relationship of PK and PD from an efficacy and
toxicity standpoint is obtained. From the results of the PK and PD
studies, a therapeutic window of Elvucitabine is defined and
simulated dosing regimens ranging from 5 mg BID to 100 mg Q1week
were explored using ADAPT II.RTM. Pharmacokinetic and
Pharmacodynamic Systems Analysis Software. From the simulated
dosing regimen results, ten dosing regimens were identified
allowing maintenance therapy with Elvucitabine at levels effective
against both HIV and HBV while avoiding bone toxicity.
Pharmacokinetics:
[0043] The PK model created included an individual compartmental PK
analysis using ADAPT-II.RTM. and Population PK analysis using an
iterative two-stage population modeling technique (IT2S.RTM.) of
plasma and urine data from a study of healthy subjects, n=29,
1.times.20 mg tablet PO (ACH443-011). FIG. 1 illustrates the PK
model of Elvucitabine according to a three compartment model
characterized by two absorption peaks, each associated with a lag
time and a first order absorption rate constant.
[0044] The Population PK parameters of Elvucitabine include a large
apparent volume of distribution (Vss) of 1600 L; an early
distribution (.lamda..sub.1) half-life of 0.59 hour, followed by
another distribution (.lamda..sub.2) half-life of 30 hours; and an
elimination (.lamda..sub.z) half-life of 175 hours. Additional
parameters include an oral clearance (CL/F) of 16 L/h and the
fraction of drug excreted unchanged in urine was about 40%. Table 1
provides the Population PK parameters of Elvucitabine. FIG. 2
illustrates an example of individual fit using a Population PK
analysis (IT2S).
TABLE-US-00001 TABLE 1 Population PK Parameters of Elvucitabine:
Alpha 0.338 Tlag1 1.46 h Ka1 1.1 l/h Tlag2 2.76 h Ka2 0.292 l/h
Vss/F 1632 L Vc/F 30.6 L Vp1/F 1232 L Vp2/F 369 L CL/F 15.8 L/h
CLnr/F 9.51 L/h Fu 39.6% CLr 6.29 L/h T.sub.half1 0.586 h K10 0.515
l/h T.sub.half2 30.5 h K12 0.246 l/h T.sub.half3 175 h K13 0.409
l/h K21 0.006 l/h K31 0.034 l/h
Pharmacodynanzics:
[0045] Pharmacodynamics of Elvucitabine was explored by analysis of
hematology (absolute neutrophil count, ANC) data obtained from a 12
week study in HBV patients. FIG. 3 illustrates the change in mean
white blood cell count from baseline for three dosages of
Elvucitabine (5 mg, 20 mg, and 50 mg), 100 mg 3TC, and placebo.
Only the highest dose of Elvucitabine (50 mg) showed a significant
decrease in white blood cell count. FIG. 4 is a graphic
representation of the change in absolute neutrophils from baseline
for the same study. Table 2 provides absolute neutrophil count at
10.sup.9/L for the three doses resulting in a baseline estimated as
the mean ANC of about 4.times.10.sup.9/L. A 25 percent decrease in
the mean ANC corresponds to about 3.times.10.sup.9/L, the threshold
for the start of toxicity.
TABLE-US-00002 TABLE 2 PD data: Absolute Neutrophil Count
(10.sup.9/L) Study Study Visit Week Treatment Week 0 Week 2 Week 4
Week 8 Week 12 5 mg PO daily (n = 17) Mean 4.1 3.4 3.4 3.5 3.6
(Range) (1.6-6.9) (1.5-6.8) (1.4-6.4) (1.1-5.9) (1.7-5.2) 20 mg PO
daily (n = 20) Mean 3.8 3.7 3.2 2.8 2.7 (Range) (1.8-6.2) (2.1-9.0)
(1.0-6.8) (1.1-4.8) (1.2-4.8) 50 mg PO daily (n = 19) Mean 4.1 3.1
2.3 2.2 2.6 (Range) (1.7-7.7) (1.5-8.2) (0.9-5.6) (0.8-5.7)
(1.0-5.7) Placebo (n = 8) Mean 4.3 4.3 4.9 4.1 3.6 (Range)
(1.8-8.4) (1.7-9.6) (1.8-10.7) (2.1-8.8) (2.4-6.4)
[0046] FIG. 5 provides a plot of the mean observed ANC and a
simulated concentration-time profile for the 5 mg QD dose. As shown
by the graph, the toxicity threshold is not met by the dosing
regimen. As provided in FIG. 6, the 20 mg QD dose crosses the
toxicity threshold at about 1008 hours. Increasing the dose to 50
mg QD results in reaching the toxicity threshold at 378 hours (FIG.
7).
[0047] From the foregoing results, a therapeutic window of
Elvucitabine was identified. It has been determined that a 5 mg QD
dose is effective for HBV and, therefore, a plasma AUCss/24 of 300
.mu.gh/L was identified as the efficacy threshold. Furthermore, as
Elvucitabine exhibits an in vitro IC.sub.50 for HIV of 4.8 nM,
which corresponds to 1.08 .mu.g/L, the C.sub.min for efficacy was
determined to be .gtoreq.23 .mu.g/L. The onset of toxicity
(ANC<3.times.10.sup.9/L) linked to the deepest (P1) compartment
is C.sub.max>40 .mu.L, which correlates to a central compartment
(plasma) C.sub.min.gtoreq.23 .mu.g/L. A conservative therapeutic
window is determined to have an AUCss/24>300 .mu.gh/L; C.sub.min
Central .gtoreq.2 .mu.g/L, but <23 .mu.g/L; and a C.sub.max
P1<40 .mu.g/L. FIG. 8 provides a schematic of the relationship
of PK versus PD where the targeted C.sub.min and AUC/24 that
provides efficacy without toxicity is desired.
[0048] From the PK and PD analyses, twenty-nine dosing regimens
were simulated using ADAPT II.RTM.. The dosing regimens simulated
ranged from 5 mg twice a day to 100 mg Q1week and are provided in
Table 3. An asterisk (*) indicates those results outside of the
defined therapeutic window. From the study, ten dosing regimens
were identified that meet the therapeutic window: one twice a day
regimen at 5 mg; three once a day regimens at 5 mg, 7.5 mg, and 10
mg; three once every 48 hour regimens at 10 mg, 15 mg, and 20 mg;
and three once a week regimens at 30 mg, 40 mg, and 50 mg.
Surprisingly, three regimens with a once weekly dosing have been
identified that would allow maintenance therapy with Elvucitabine
at levels effective against both HIV and HBV while avoiding bone
marrow toxicity. FIG. 9 provides a simulated concentration-time
profile of 10 mg QD dosing regimen while FIG. 10 provides a profile
for 40 mg Q1week dosing. The 40 mg Q1 week dosing regimen,
according to the model, provides the desired efficacy while at the
same time avoiding the toxicity threshold.
TABLE-US-00003 TABLE 3 Elvucitabine Dosing Regimens: Schedule
Parameters 5 mg 7.5 mg 10 mg 15 mg 20 mg 30 mg 40 mg 50 mg 75 mg
100 mg BID AUCtau Central/24 hr 634.1 951.1 1268 1902 2536 -- --
6341 -- -- Sim. end Cmin Central (last tau) 16.2 24.3* 32.4* 48.6*
64.8* 162* 2016 hr (336 Cmax P1 26.6 39.8 53.1* 79.7* 106* 266*
doses) QD AUCtau Central/24 hr 317 476 634 951 1269 -- -- 3172 --
-- Sim. end Cmin Central (last tau) 6.94 10.4 13.9 20.8 27.8* 69.4*
2016 hr (168 Cmax P1 13.4 20.1 26.8 40.2* 53.6* 134* doses) Q48H
AUCtau Central/24 hr 159* 238* 317 476 634 -- -- 1586 2378 3171
Sim. end Cmin Central (last tau) 3.05 4.58 6.11 9.16 12.2 30.5*
45.8* 61.1* 2016 hr (84 Cmax P1 6.87 10.3 13.7 20.6 27.5 68.7* 103*
137* doses) Q1 week AUCtau Central/24 hr -- 67.7* 90.3* 135* 181*
271* 361 451 677 903 Sim end Cmin Central (last tau) 0.811* 1.08*
1.62* 2.16 3.24 4.32 5.40 8.11 10.8 5376 hr (32 Cmax P1 3.36 4.48
6.72 8.96 13.4 17.9 22.4 33.6 44.8* doses) *Results are outside of
therapeutic window
Methods of Treatment
[0049] Provided herein is a method of treating a viral infection,
particulary an HIV infection, comprising administering about 2.5 mg
to about 20 mg Elvucitabine per day, to a patient suffering from a
viral infection.
[0050] About 5 mg Elvucitabine is administered twice a day, for
example.
[0051] About 2.5, about 5 mg, about 7.5 mg, or about 10 mg
Elvucitabine is administered once per day in other embodiments.
[0052] Also provided herein is method of treating a viral
infection, comprising administering about 5 mg to about 20 mg
Elvucitabine per 48 hour interval to a patient suffering from a
viral infection, for example and HBV or HIV infection.
[0053] In certain embodiments about 10 mg, about 15 mg, or about 20
mg Elvucitabine is administered once per 48 hour interval.
[0054] A method of treating a viral infection comprising
administering about 40 mg to about 100 mg Elvucitabine per week to
a patient suffering from a viral infection, is further provided.
Typically the viral infection treated will be an HBV or HIV
infection. Methods of administering the Elvucitabine as an oral
dosage form are preferred.
[0055] For example about 40 mg, about 50 mg, about 75 mg, or about
100 mg Elvucitabine is administered once per week. In one
embodiment, Elvucitabine is administered once every 2 to 7
days.
[0056] In certain embodiments described herein the Elvucitabine is
administered as an oral dosage form. Oral dosages of Elvucitabine
may be in the form of a tablet or capsule, or other
pharmaceutically acceptable form.
[0057] Also provided herein are methods of increasing patient
compliance with anti-viral therapy, such as treatment of an HIV or
HBV infection, by providing reverse transcriptase inhibitor
formulated for low dose daily administration. Methods of increasing
patient compliance with anti-HIV therapy by providing a reverse
transcriptase inhibitor formulated for administration of about 2.5
to about 10 mg of the reverse transcriptase inhibitor daily are
included in the invention. A method of increasing patient
compliance with anti-viral therapy by providing a reverse
transcriptase inhibitor formulated for administration of about 5 to
about 20 mg of the reverse transcriptase inhibitor once every 48
hour interval or of about 40 to about 100 mg of the reverse
transcriptase inhibitor once every one week interval are also
within the scope of the invention.
[0058] Elvucitibane is the preferred reverse transcriptase
inhibitor used in such formulations. In certain embodiments the
anti-viral therapy is treatment of an HBV or HIV infection.
Pharmaceutical Formulations
[0059] Provided herein are pharmaceutical formulations for low
dosage and/or low frequency administration, comprising Elvucitibine
or a salt thereof and at least one carrier or excipient.
[0060] The pharmaceutical formulation may be in the form suitable
for administration, but is preferably an oral dosage form such as a
tablet or capsule.
Dosage Forms Characterized by AUC
[0061] Elvucitabine forms for low dosage administration described
herein exhibit characteristic plasma concentrations over time. When
integrated the graph of plasma concentration over time provides a
characteristic "area under the curve" or AUC.
[0062] Preferred Elvucitabine dosage forms described herein exhibit
an AUC at steady state for a 24 hour period of about 300 microgram
hour/liter (.mu.g h/L).
Exemplary Formulations
[0063] The low dosage formulations provided herein may be
formulated by a variety of methods apparent to those of skill in
the art of pharmaceutical formulation. Suitable formulations
include, for example, tablets, capsules, press coat formulations,
easily administered formulations, etc.
Preparation of Dosage Forms
[0064] The term "dosage form" denotes a form of a formulation that
contains an amount sufficient to achieve a therapeutic effect with
a single administration. Suitable formulations include, for
example, tablets, capsules, press coat formulations, etc.
[0065] When the formulation is a tablet or capsule, the dosage form
is usually one such tablet or capsule. The frequency of
administration that will provide the most effective results in an
efficient manner without overdosing will vary with the
characteristics of the particular formulation, including both its
pharmacological characteristics and its physical characteristics
such as solubility, and with the characteristics of the swellable
matrix such as its permeability, and the relative amounts of the
active agent and polymer. In most cases, the dosage form will be
such that effective results will be achieved with administration no
more frequently than once every eight hours or more, preferably
once every twelve hours or more, and even more preferably once
every twenty-four hours or more.
[0066] The dosage form can be prepared by various conventional
mixing, comminution and fabrication techniques readily apparent to
those skilled in the chemistry of drug formulations. Examples of
such techniques are as follows:
[0067] (1) Direct compression, using appropriate punches and dies;
the punches and dies are fitted to a suitable rotary tableting
press;
[0068] (2) Injection or compression molding using suitable molds
fitted to a compression unit
[0069] (3) Granulation followed by compression; and
[0070] (4) Extrusion in the form of a paste, into a mold or to an
extrudate to be cut into lengths.
[0071] When particles are made by direct compression, the addition
of lubricants may be helpful and sometimes important to promote
powder flow and to prevent capping of the particle (breaking off of
a portion of the particle) when the pressure is relieved. Useful
lubricants are magnesium stearate (in a concentration of from 0.05%
to 3% by weight, preferably less than 1% by weight, in the powder
mix), and hydrogenated vegetable oil (preferably hydrogenated and
refined triglycerides of stearic and palmitic acids at about 1% to
5% by weight, most preferably about 2% by weight. Additional
excipients may be added to enhance powder flowability and reduce
adherence.
Preparation of Elvucitabine Containing Subunits
[0072] Elvucitabine and any optional additives may be prepared in
many different ways, for example as subunits. Pellets comprising an
active agent can be prepared, for example, by a melt pelletization
technique. In this technique, the active agent in finely divided
form is combined with a binder and other optional inert
ingredients, and thereafter the mixture is pelletized, e.g., by
mechanically working the mixture in a high shear mixer to form the
pellets (e.g., pellets, granules, spheres, beads, etc.,
collectively referred to herein as "pellets"). Thereafter, the
pellets can be sieved in order to obtain pellets of the requisite
size. The binder material may also be in particulate form and has a
melting point above about 40.degree. C. Suitable binder substances
include, for example, hydrogenated castor oil, hydrogenated
vegetable oil, other hydrogenated fats, fatty alcohols, fatty acid
esters, fatty acid glycerides, and the like, and combinations
comprising one or more of the foregoing bidders.
[0073] Oral dosage form may be prepared to include an effective
amount of melt-extruded subunits containing Elvucitabine in the
form of multiparticles within a capsule. For example, a plurality
of the melt-extruded muliparticulates can be placed in a gelatin
capsule in an amount sufficient to provide an effective release
dose when ingested and contacting by gastric fluid.
[0074] Subunits, e.g., in the form of multiparticulates, can be
compressed into an oral tablet using conventional tableting
equipment using standard techniques. The tablet formulation may
include excipients such as, for example, an inert diluent such as
lactose, granulating and disintegrating agents such as cornstarch,
binding agents such as starch, and lubricating agents such as
magnesium stearate.
[0075] Alternatively, the subunits containing Elvucitabine are
added during the extrusion process and the extrudate can be shaped
into tablets by methods know in the art. The diameter of the
extruder aperture or exit port can also be adjusted to vary the
thickness of the extruded strands. Furthermore, the exit part of
the extruder need not be round; it can be oblong, rectangular, etc.
The exiting strands can be reduced to particles using a hot wire
cutter, guillotine, etc.
[0076] A melt-extruded multiparticulate system can be, for example,
in the foil of granules, spheroids, pellets, or the like, depending
upon the extruder exit orifice. The terms "melt-extruded
multiparticulate(s)" and "melt-extruded multiparticulate system(s)"
and "melt-extruded particles" are used interchangeably herein and
include a plurality of subunits, preferably within a range of
similar size and/or shape. The melt-extruded multiparticulates can
be about 0.1 to about 12 mm in length and have a diameter of about
0.1 to about 5 mm. In addition, the melt-extruded multiparticulates
can be any geometrical shape within this size range. Alternatively,
the extrudate can simply be cut into desired lengths and divided
into unit doses of active agent without the need of a
spheronization step.
[0077] The melt-extruded dosage forms can further include
combinations of melt-extruded multiparticulates containing one or
more of the therapeutically active agents before being
encapsulated.
[0078] The oral dosage form containing active agent may be in the
form of micro-tablets enclosed inside a capsule, e.g. a gelatin
capsule. For this, a gelatin capsule as is employed in
pharmaceutical formulations can be used, such as the hard gelatin
capsule known as CAPSUGEL, available from Pfizer.
Particles
[0079] Some oral dosage forms described herein contain Elvucitabine
in the form of particles. Such particles may be compressed into a
tablet, present in a core element of a coated dosage form, such as
a taste masked dosage form, a press coated dosage form, or an
enteric coated dosage form, or may be contained in a capsule,
osmotic pump dosage form, or other dosage form.
[0080] For particles, such as powder particles, present in the core
element of a coated dosage form, the core element may have a
particle size distribution with a median of about 100 .mu.m. The
particles in the distribution may vary from about 1 .mu.m to about
250 .mu.m, more preferably from 25 .mu.m to about 250 .mu.m, most
preferably about 35 .mu.m to about 125 .mu.m. If the median of the
distribution is close to either extreme of the distribution, the
taste masking or sustained-release characteristics may be affected.
In a particle size range of about 25 .mu.m to about 250 .mu.m, no
more than about 25% of particles can be less than about 25 .mu.m,
and no more than about 25% can be over about 250 .mu.m.
[0081] Another parameter to consider is particle shape. Particle
shape can influence the coverage and stability of the coat. Both
the crystallinity of the active agent and the aspect ratio of the
particles are related to particle shape. In certain embodiments it
is desirable for the Elvucitabine of the coated dosage forms have
crystalline morphology, however, sharp angles on a crystal can
cause weaknesses in the coat. These sharp corners may lead to
stress points on the coat and cause weaknesses in the structure
possibly leading to premature release of active agent from the
dosage form. Furthermore, areas of thin coating are susceptible to
breaking and cracking and hence ineffective for sustained-release
and taste masking.
[0082] Regarding the aspect ratio, a low aspect ratio is preferred.
The aspect ratio is a measure of the thickness to diameter. For
example, a low aspect ratio of about 1 would be a box or sphere.
Crystals with a high aspect ratio are more pointed with needle-like
crystals. Crystals with a high aspect ratio may result in a
relatively thin coat at the crystal needle tips leading to a more
rapid release rate of active agent than is preferred. A low aspect
ratio spherical shape of the particle is advantageous for both
solubility of the coat and high payload of active agent. Therefore,
it is most preferable that the aspect ratio is less than about 1,
more preferably about 0.5 to about 1, and most preferably
approximately about 0.5 to about 0.6 providing a substantially
rounded shape.
[0083] Inconsistencies in size and shape can lead to inconsistent
coating. Where the particles containing active agent are of
different size and shape, polymeric coating materials such as ethyl
cellulose may deposit differently on each particle. It is therefore
preferable for coated dosage forms that substantially all particles
of the dosage form have substantially the same size and shape so
that the coating process is better controlled and maintained.
Tablets and Capsules
[0084] Tablets typically comprise conventional pharmaceutically
compatible adjuvants as inert diluents, such as calcium carbonate,
sodium carbonate, mannitol, lactose and cellulose; binders such as
starch, methylcellulose, microcrystalline cellulose, gelatin, and
sucrose; disintegrants such as starch, alginic acid, sodium starch
glycolate, and croscarmelose; and lubricants such as magnesium
stearate, stearic acid and talc. Buffering agents such as potassium
phosphate, potassium citrate, and sodium phosphate may also be
present. Glidants such as silicon dioxide can be used to improve
flow characteristics of the powder mixture. Coloring agents, such
as the FD&C dyes, can be added for app earance. Sweeteners and
flavoring agents, such as aspartame, saccharin, menthol,
peppermint, and fruit flavors, are useful adjuvants for chewable
tablets. Capsules (including time release and sustained release
formulations) typically comprise one or more solid diluents
disclosed above. The selection of carrier components often depends
on secondary considerations like taste, cost, and shelf
stability.
[0085] Such compositions may also be coated by conventional
methods, typically with pH or time-dependent coatings, such that
the subject compound is released in the gastrointestinal tract in
the vicinity of the desired topical application, or at various
times to extend the desired action. Such dosage forms typically
include, but are not limited to, one or more of cellulose acetate
phthalate, polyvinylacetate phthalate, hydroxypropyl
methylcellulose phthalate, ethyl cellulose, Eudragit coatings,
waxes and shellac.
[0086] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or an oil medium, for example peanut
oil, liquid paraffin or olive oil.
[0087] Particular embodiments provided herein include capsules or
tables comprising from about 2.5 to about 20 mg Elvucitabine for
daily administration, preferably about 5 mg to about 10 mg for
daily administration, from about 10 mg to about 20 mg for
administration once every 48 hour interval, and from about 40 mg to
about 100 mg for once weekly administration.
[0088] Pharmaceutical formulations for use in tablets may have
certain desirable physical properties. For example the invention
provides a pharmaceutical formulation of Elvucitabine having a
tensile of from about 1400 KPa to 2100 KPa.
[0089] Also provided is pharmaceutical formulation of Elvucitabine
having a compression range of 150 to 260 Mpa.
[0090] The invention also provides an oral dosage form of
Elvucitabine having a hardness of about 3 KGF to about 11.5
KGF.
[0091] The invention includes an Elvucitabine oral dosage form, for
example a tablet, wherein the core has an aspect ratio of 0.50 to
0.55. The invention includes coated Elvucitabine tablets, wherein
the tablet has an aspect ratio of from 0.51 to 0.56.
[0092] The invention includes coated tablets 2.5 mg Elvucitabine,
wherein the tablet has a an aspect ration of from 0.51 to 0.56 and
a diameter of 40 mm or less.
Optional Additional Additives for Formulations
Excipients
[0093] Excipients are components added to active agent
pharmaceutical formulation other than Elvucitabine, and include
inert substances used as a diluent or vehicle for active agent.
Excipients may be added to facilitate manufacture, enhance
stability, control release, enhance product characteristics,
enhance bioavailability, enhance patient acceptability, etc.
Pharmaceutical excipients include binders, disintegrants,
lubricants, glidants, compression aids, colors, sweeteners,
preservatives, suspending agents, dispersing agents, film formers,
flavors, printing inks, etc. Binders hold the ingredients in the
dosage form together. Exemplary binders include, for example,
polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, methylcellulose, and hydroxyethyl cellulose,
sugars, and combinations comprising one or more of the foregoing
binders. Disintegrants expand when wet causing a tablet to break
apart. Exemplary disintegrants include water swellable substances,
for example, low-substituted hydroxypropyl cellulose, e.g. L-HPC;
cross-linked polyvinyl pyrrolidone (PVP-XL), e.g. Kollidon.RTM. CL
and Polyplasdone.RTM. XL; cross-linked sodium
carboxymethylcellulose (sodium croscarmellose), e.g.
Ac-di-sol.RTM., Primellose.RTM.; sodium starch glycolate, e.g.
Primojel.RTM.; sodium carboxymethylcellulose, e.g. Nymcel
ZSB10.RTM.; sodium carboxymethyl starch, e.g. Explotab.RTM.;
ion-exchange resins, e.g. Dowex.RTM. or Amberlite.RTM.;
microcrystalline cellulose, e.g. Avicel.RTM.; starches and
pregelatinized starch, e.g. Starch 1500.RTM., Sepistab ST200 .RTM.;
formalin-casein, e.g. Plas-Vita.RTM., and combinations comprising
one or more of the foregoing water swellable substances.
Lubricants, for example, aid in the processing of powder materials.
Exemplary lubricants include calcium stearate, glycerol behenate,
magnesium stearate, mineral oil, polyethylene glycol, sodium
stearyl fumarate, stearic acid, talc, vegetable oil, zinc stearate,
and combinations comprising one or more of the foregoing
lubricants. Glidants include, for example, silicon dioxide.
[0094] In certain embodiments described herein the invention
includes a pharmaceutical composition comprising Elvucitabine,
lactose monohydrate, and anhydrous lactose. The formulation may
also include other ingredients such as crospovidone, calcium
silicate, and magnesium stearate.
[0095] In certain embodiment the lactose monohydrate and anhydrous
lactose taken together comprise about 60 percent to about 90
percent of the Elvucitabine formulation by weight.
[0096] The invention provides a pharmaceutical formulation wherein
less than 2.0%, less than 1.5%, less than 1.0%, or less than 0.5%
is magnesium stearate. The invention also provides a pharmaceutical
formulation containing Elvucitabine and magnesium stearate, wherein
from about 0.05 to about 1 percent, or is some embodiments from
about 0.10 to about 0.50 percent, or about 0.05 to about 0.50
percent, of the composition is magnesium stearate.
Fillers
[0097] Certain dosage forms described herein contain a filler, such
as a water insoluble filler, water soluble filler, and combinations
thereof. The filler may be a water insoluble filler, such as
silicon dioxide, titanium dioxide, talc, alumina, starch, kaolin,
polacrilin potassium, powdered cellulose, microcrystalline
cellulose, and combinations comprising one or more of the foregoing
fillers. Exemplary water-soluble fillers include water soluble
sugars and sugar alcohols, preferably lactose, glucose, fructose,
sucrose, mannose, dextrose, galactose, the corresponding sugar
alcohols and other sugar alcohols, such as mannitol, sorbitol,
xylitol, and combinations comprising one or more of the foregoing
fillers.
Coatings
[0098] The formulations described herein may be coated with a
functional or non-functional coating. The coating may comprise
about 0 to about 40 weight percent of the composition. The coating
material may include a polymer, preferably a film-forming polymer,
for example, methyl cellulose, ethyl cellulose, hydroxypropyl
cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl
cellulose, cellulose acetate, cellulose propionate (lower, medium
or higher molecular weight), cellulose acetate propionate,
cellulose acetate butyrate, cellulose acetate phthalate,
carboxymethyl cellulose, cellulose triacetate, cellulose sulphate
sodium salt, poly(methyl methacrylate), poly(ethyl methacrylate),
poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl
methacrylate), poly(phenyl methacrylate), poly(methyl acrylate),
poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl
acrylate), poly(ethylene), poly(ethylene) low density,
poly(ethylene) high density, (poly propylene), poly(ethylene glycol
poly(ethylene oxide), poly(ethylene terephthalate), poly(vinyl
alcohol), poly(vinyl isobutyl ether), poly(vinyl acetate),
poly(vinyl chloride), polyvinyl pyrrolidone, and combinations
comprising one or more of the foregoing polymers.
[0099] The coating may form a moisture barrier, act as sealant, or
as an enteric coat. Appropriate coatings for these purposes include
Aquacoat.RTM. ECD, Opadry.RTM. AMB, Sepifilm.TM. LP,
Surelease.RTM.. The coating may also be an enteric coating such as
Aquacoat.RTM. CPD or Acryl-Eze.RTM..
[0100] In applications such as taste-masking, the polymer can be a
water-insoluble polymer. Water insoluble polymers include ethyl
cellulose or dispersions of ethyl cellulose, acrylic and/or
methacrylic ester polymers, cellulose acetates, butyrates or
propionates or copolymers of acrylates or methacrylates having a
low quaternary ammonium content, and the like, and combinations
comprising one or more of the foregoing polymers.
[0101] In controlled-release applications, for example, the coating
can be a hydrophobic polymer that modifies the release properties
of active agent from the formulation. Suitable hydrophobic or water
insoluble polymers for controlled-release include, for example,
methacrylic acid esters, ethyl cellulose, cellulose acetate,
polyvinyl alcohol-maleic anhydride copolymers, .beta.-pinene
polymers, glyceryl esters of wood resins, and combinations
comprising one or more of the foregoing polymers.
[0102] The inclusion of an effective amount of a plasticizer in the
coating composition may improve the physical properties of the
film. For example, because ethyl cellulose has a relatively high
glass transition temperature and does not form flexible films under
normal coating conditions, it may be advantageous to add
plasticizer to the ethyl cellulose before using the same as a
coating material. Generally, the amount of plasticizer included in
a coating solution is based on the concentration of the polymer,
e.g., most often from about 1 to about 50 percent by weight of the
polymer. Concentrations of the plasticizer, however, can be
determined by routine experimentation.
[0103] Examples of plasticizers for ethyl cellulose and other
celluloses include plasticizers such as dibutyl sebacate, diethyl
phthalate, triethyl citrate, tributyl citrate, triacetin, and
combinations comprising one or more of the foregoing plasticizers,
although it is possible that other water-insoluble plasticizers
(such as acetylated monoglycerides, phthalate esters, castor oil,
etc.) can be used.
[0104] Examples of plasticizers for acrylic polymers include citric
acid esters such as triethyl citrate 21, tributyl citrate, dibutyl
phthalate, 1,2-propylene glycol, polyethylene glycols, propylene
glycol, diethyl phthalate, castor oil, triacetin, and combinations
comprising one or more of the foregoing plasticizers, although it
is possible that other plasticizers (such as acetylated
monoglycerides, phthalate esters, castor oil, etc.) can be
used.
[0105] An example of a functional coating comprises a coating agent
comprising a poorly water-permeable component (a) such as, an alkyl
cellulose, for example an ethylcellulose, such as AQUACOAT (a 30%
dispersion available from FMC, Philadelphia, Pa.) or SURELEASE (a
25% dispersion available from Colorcon, West Point, Pa.) and a
water-soluble component (b), e.g., an agent that can form channels
through the poorly water-permeable component upon the hydration or
dissolution of the soluble component. The functional coating may
also be an enteric coating, which facilitates drug dissolution in
the intestine rather than in the stomach.
[0106] The functional coating may comprise about 1% to about 40%,
or about 3% to about 30%, or about 5% to about 25%, and or about 8%
to about 25% of the total formulation. For pellet formulations it
is preferred that the coating comprise from about 1% to about 40%,
or from about 5% to about 25%, or from about 10% to about 25% of
the total pellet weight. For tablet formulations the coating may
comprise from about 5% to about 40%, or from about 8% to about 25%,
or about 17.5% of the total formulation.
[0107] In certain embodiments, particularly where the coating
provides taste masking, it is preferred that the coating is
substantially continuous coat and substantially hole-free. By
"substantially continuous coating" is meant a coating, which
retains a smooth and continuous appearance when magnified 1000
times under a scanning electron microscope and wherein no holes or
breakage of the coating are evident.
[0108] Suitable methods can be used to apply the coating to active
agent. Processes such as simple or complex coacervation,
interfacial polymerization, liquid drying, thermal and ionic
gelation, spray drying, spray chilling, fluidized bed coating, pan
coating, electrostatic deposition, may be used. A substantially
continuous nature of the coating may be achieved, for example, by
spray drying from a suspension or dispersion of active agent in a
solution of the coating composition including a polymer in a
solvent in a drying gas having a low dew point.
[0109] When a solvent is used to apply the coating, the solvent is
preferably an organic solvent that constitutes a good solvent for
the coating material, but is substantially a non-solvent or poor
solvent for an active agent. While an active agent may partially
dissolve in the solvent, it is preferred that the active ingredient
will precipitate out of the solvent during the spray drying process
more rapidly than the coating material. The solvent may be selected
from alcohols such as methanol, ethanol, halogenated hydrocarbons
such as dichloromethane (methylene chloride), hydrocarbons such as
cyclohexane, and combinations comprising one or more of the
foregoing solvents. Dichloromethane (methylene chloride) has been
found to be particularly suitable.
[0110] The concentration of polymer in the solvent will normally be
less than about 75% by weight, and typically about 10 to about 30%
by weight. After coating, the coated dosage forms may be allowed to
cure for at least about 1 to about 2 hours at a temperature of
about 50.degree. C. to about 60.degree. C., more preferably of
about 55.degree. C.
[0111] The coatings may be about 0.005 micrometers to about 25
micrometers thick, preferably about 0.05 micrometers to about 5
micrometers.
Packaged Formulations
[0112] Packaged pharmaceutical formulations comprising an
Elvucitabine pharmaceutical formulation and instructions for using
the formulation for treating a viral infection, such as an HIV
infection, by administering about 2.5 to about 10 mg Elvucitabine
per day, or treating a patient having a viral infection by
administering about 5 mg to about 20 mg Elvucitabine per 48 hour
interval, or about 40 mg to about 100 mg Elvucitabine per week to a
patient suffering from a viral infection are further provided
herein. Typically the instructions will be instructions for using
the formulation to treat an HBV or HIV infection. Packaged
formulations in which the Elvuticabine is present as an oral dosage
form are disclosed herein.
[0113] The invention includes providing prescribing information,
for example, to a patient or health care provider, or as a label in
a packaged pharmaceutical formulation. Prescribing information may
include for example efficacy, dosage and administration,
contraindication and adverse reaction information pertaining to the
pharmaceutical formulation.
EXAMPLES
[0114] The following examples further illustrate the invention but,
of course, should not be construed as in any way limiting its
scope.
Example 1
Low Dose Elvucitabine Tablets
[0115] Elvucitabine exhibits adhesion (to metal surfaces) and
limited compactibility Typical excipients used to resolve such
issues in a direct blend are not preferable based on the excipient
compatibility results. Excipients that increase compactability,
decrease adhesion, and are not acidic are desirable to addresses
processing challenges.
[0116] All tablets are compressed using 1/4'' standard concave
tooling.
[0117] The following 5 mg dosage form is made at a 150 gram batch
size and large enough to run a few rotations on the automated
press. The 20 mg dosage form is made at smaller batch sizes (40
grams) to conserve drug, and therefore is not evaluated under full
conditions of an automated press. However the tablets made from
hand turning of the wheel resulted in tablets with good surfaces,
hardness and friability. The 5 mg tablets pass content uniformity
specifications (range: 85%-115%; % RSD</=6%) with CU=87.8% and %
RSD=1.7.
TABLE-US-00004 g/1000 Component % mg/tablet tablets Elvucitabine
3.33 5 5.0 Lactose (Fast Flo) 45.21 67.815 67.815 Lactose
(Anhydrous - 45.21 67.815 67.815 Direct tableting Grade)
Crospovidone 3 4.5 4.5 Calcium Silicate 2 3.0 3.0 Magnesium
Stearate 1.25 1.875 1.875 TOTALS 100% 150 mg 150 g Hardness: 5.3
Kp, Friability: 0.34%, no cappping
TABLE-US-00005 g/200 Component % mg/tablet tablets Elvucitabine 10
20 4.0 Lactose (Fast Flo) 41.875 83.75 16.75 Lactose (Anhydrous -
41.875 83.75 16.75 Direct tableting Grade) Crospovidone 3 6 1.2
Calcium Silicate 2 4 0.8 Magnesium Stearate 1.25 2.5 0.5 TOTALS
100% 200 mg 40 g Hardness: 5.9 Kp, Friability: 0%, no cappping
TABLE-US-00006 g/200 Component % mg/tablet tablets Elvucitabine 25
50 10 Lactose (Fast Flo) 34.375 68.75 13.75 Lactose (Anhydrous -
34.375 68.75 13.75 Direct tableting Grade) Crospovidone 3 6 1.2
Calcium Silicate 2 4 0.8 Magnesium Stearate 1.25 2.5 0.5 TOTALS
100% 200 mg 40 g Hardness: 4.5 Kp, Friability: 0%, no capping
[0118] Two additional batches are made for the 5 mg and 20 mg dose
with an additional blending step. Content uniformity results are
also presented below. The extra blending step results in a more
optimum content uniformity. The 5 mg and 20 mg dose are formulated
to a total tablet weight of 150 mg and the 50 mg dose is tableted
to a total tablet weight of 200 mg.
TABLE-US-00007 5 mg dose 20 mg dose Component % mg/tablet %
mg/tablet Elvucitabine 3.33 5.0 13.33 20.00 Lactose (Fast Flo)
45.21 67.81 40.21 60.32 Lactose (Anhydrous - 45.21 67.81 40.21
60.32 Direct tableting Grade) Crospovidone 3.00 4.50 3.00 4.50
Calcium Silicate 2.00 3.00 2.00 3.00 Magnesium Stearate 1.25 1.88
1.25 1.87 TOTALS 100 150 100 150
TABLE-US-00008 Content Uniformity Data % CU % RSD 5 mg dose 89.4
4.6 20 mg dose 93.2 4.4
Example 2
Coated Tablets
[0119] Coated tablets are prepared with the application of a
"base-coat" of hydroxypropylmethylcellulose (OpaDry). This coating
agent smoothes tablet surface imperfections, providing a suitable
surface for adhesion of the enteric coat.
TABLE-US-00009 Core Elvucitabine (20 mg) Tablets Load 100 tabs
15.033 g Coating System Sureteric (15% dispersion) Target Coating
Level 14% Coated Product (20 mg) Enteric Coated Tablets (Sureteric)
Coated tablets appear to have a uniform, slightly rough, off-white
coat. Six tablets tested in 0.1 N HCl - all passed.
TABLE-US-00010 Core Elvucitabine (20 mg) Tablets Load 100 tabs
15.031 g Coating System Eudragit L30 D55 with 10% Triethylcitrate
Target Coating Level 14% Coated Product (20 mg) Enteric Coated
Tablets (Eudragit) Acceptable tablets obtained - slightly rough
surface with glossy finish. Six tablets tested in 0.1 N HCl - all
passed.
TABLE-US-00011 Core Elvucitabine (20 mg) Tablets Load 100 tabs
15.01 g Coating System Opadry followed by Eudragit L30 D55 with 2%
TEC Target Coating Level 14% (2% Opadry/12% Eudragit) Coated
Product ACH 126,443 (20 mg) Enteric Coated Tablets
(Opadry/Eudragit) 15% dispersion of Opadry Clear (YS-1-7472) Opadry
coat = excellent, glossy surface.
Example 3
Additional Coated Tablets
[0120] The following formulations are prepared by blending the
first five ingredients, Elvucitabine, lactose fast flow, lactose
anhydrous, crospovidone, and calcium silicate for 13 minutes.
Magnesium stearate is then added. Formulations having more that 0.5
percent magnesium stearate by weight are blended approximately 3
minutes longer. Formulations containing about 0.5% magnesium
stearate or less are blended and additional 20-25 minutes.
Tabletting is performed as described in Example 1 and the enteric
and final coat are applied.
TABLE-US-00012 Ingredient 2.5 mg Strength mg/tablet % mg/tablet %
Elvucitabine 2.5 3.33 2.5 3.33 Lactose fast flow 36.626 44.835
34.406 45.785 Lactose Anhydrous 36.626 44.835 34.406 45.785
Crospovidone 4.5 3.00 4.5 3.00 Calcium Silicate 3.0 2.00 3.0 2.00
Magnesium 3.0 2.00 0.15 0.10 Stearate Total 75.0 100.0 75.0
150.0
TABLE-US-00013 Ingredient 5 mg Strength mg/tablet % mg/tablet %
Elvucitabine 5.0 3.33 5.0 3.33 Lactose fast flow 67.25 44.835
68.678 45.785 Lactose Anhydrose 67.25 44.835 68.678 45.785
Crospovidone 4.5 3.00 4.5 3.00 Calcium Silicate 3.0 2.00 3.0 2.00
Magnesium 3.0 2.00 0.15 0.10 Stearate Total 150.0 100.0 150.0
150.0
TABLE-US-00014 Ingredient 20 mg Strength mg/tablet % mg/tablet %
Elvucitabine 20.0 13.33 20.0 13.33 Lactose fast flow 59.75 39.83
61.095 40.73 Lactose Anhydrose 59.75 39.83 61.095 40.73
Crospovidone 4.5 3.00 4.5 3.00 Calcium Silicate 3.0 2.00 3.0 2.00
Magnesium 3.0 2.00 0.30 0.20 Stearate Total 150 100 150 100
TABLE-US-00015 Ingredient 50 mg Strength mg/tablet % mg/tablet %
Elvucitabine 50.0 25.0 50.0 25.0 Lactose fast flow 68.0 34.0 69.85
34.925 Lactose Anhydrose 68.0 34.0 69.85 34.925 Crospovidone 6.0
3.00 3.00 3.00 Calcium Silicate 4.0 2.00 2.00 2.00 Magnesium 4.0
2.00 0.225 0.15 Stearate Total 150 100 150 100
TABLE-US-00016 Ingredient 5 mg Strength mg/tablet % Elvucitabine
5.0 3.33 Lactose fast flow 68.37 45.58 Lactose Anhydrose 68.37
45.58 Crospovidone 4.5 3.00 Calcium Silicate 3.0 2.00 Magnesium
Stearate 0.75 0.50
TABLE-US-00017 Tablet Coating Dispersion % Tablet weight System
Concentration gain Base coat Opadry II 15% 2 Enteric coat Eudragit
L30 28.5%/5% 12 D55/TEC
* * * * *