U.S. patent application number 11/546713 was filed with the patent office on 2007-02-08 for pharmaceutical formulations.
This patent application is currently assigned to Abbott Laboratories. Invention is credited to Laman Alani, Soumojeet Ghosh.
Application Number | 20070032436 11/546713 |
Document ID | / |
Family ID | 37449891 |
Filed Date | 2007-02-08 |
United States Patent
Application |
20070032436 |
Kind Code |
A1 |
Alani; Laman ; et
al. |
February 8, 2007 |
Pharmaceutical formulations
Abstract
Improved pharmaceutical compositions are provided comprising one
or more solubilized HIV protease inhibiting compounds having
improved solubility properties in a medium and/or long chain fatty
acid, or mixtures thereof, a pharmaceutically acceptable alcohol,
and water.
Inventors: |
Alani; Laman; (Morris
Plains, NJ) ; Ghosh; Soumojeet; (Linderhurst,
IL) |
Correspondence
Address: |
ROBERT DEBERARDINE;ABBOTT LABORATORIES
100 ABBOTT PARK ROAD
DEPT. 377/AP6A
ABBOTT PARK
IL
60064-6008
US
|
Assignee: |
Abbott Laboratories
|
Family ID: |
37449891 |
Appl. No.: |
11/546713 |
Filed: |
October 12, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09576097 |
May 22, 2000 |
7141593 |
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11546713 |
Oct 12, 2006 |
|
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60137634 |
Jun 4, 1999 |
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60177020 |
Jan 19, 2000 |
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Current U.S.
Class: |
536/23.74 ;
514/370; 514/4.1 |
Current CPC
Class: |
A61K 31/425 20130101;
A61P 31/04 20180101; A61P 31/12 20180101; A61P 35/00 20180101 |
Class at
Publication: |
514/018 ;
514/370 |
International
Class: |
A61K 38/05 20070101
A61K038/05; A61K 31/427 20070101 A61K031/427 |
Claims
1. A method for improving the pharmacokinetics of a drug which is
metabolized by cytochrome P450 monooxygenease comprising
administering to a human in need thereof a combination of said drug
and
(2S,3S,5S)-5-(N--(N--((N-methyl-N-((2-isopropyl-4-thiazolyl)-methyl)amino-
)carbonyl)-L-valinyl)amino)-2-(N-((5-thiazolyl)methoxy-carbonyl)-amino)-1,-
6-diphenyl-3-hydroxyhexane (ritonavir), wherein said ritonavir is
comprised in a pharmaceutical composition which includes a solution
comprising: (a) ritonavir in an amount of from 1% to 50% by weight
of said solution; (b) a pharmaceutically acceptable medium and/or
long chain fatty acid, or a mixture of pharmaceutically acceptable
medium and/or long chain fatty acids, in an amount of from 30% to
75% by weight of said solution; (c) water in an amount of from 0.4%
to 3.5% by weight of said solution; and, optionally, (d) a
pharmaceutically acceptable surfactant.
2. The method of claim 1, wherein said drug is an
immunosuppressant, a chemotherapeutic agent, or an antibiotic.
3. The method of claim 1, wherein said solution comprises said
pharmaceutically acceptable surfactant which is in an amount of
from 2% to 20% by weight of said solution.
4. The method of claim 1, wherein said solution comprises ritonavir
in an amount of from 10 to 40% by weight of said solution.
5. The method of claim 1, wherein said solution comprises water in
an amount of from 0.4% to 1.5% by weight of said solution.
6. The method of claim 1, wherein said pharmaceutically acceptable
medium and/or long chain fatty acid is a mono-unsaturated
C.sub.16-C.sub.20 fatty acid which is liquid at room temperature,
and said mixture of pharmaceutically acceptable medium and/or long
chain fatty acids is a mixture of mono-unsaturated
C.sub.16-C.sub.20 fatty acids which are liquids at room
temperature.
7. The method of claim 1, wherein said pharmaceutically acceptable
medium and/or long chain fatty acid is oleic acid, and said mixture
of pharmaceutically acceptable medium and/or long chain fatty acids
includes oleic acid.
8. The method of claim 1, wherein said solution comprises oleic
acid in an amount of from 30% to 75% by weight of said
solution.
9. The method of claim 1, wherein said solution comprises polyoxyl
35 castor oil.
10. The method of claim 1, wherein said solution comprises: (a)
ritonavir in an amount from 1% to 30% by weight of said solution;
(b) a pharmaceutically acceptable medium and/or long chain fatty
acid in an amount of from 30% to 75% by weight of said solution;
(c) water in an amount of from 0.4% to 3.5% by weight of said
solution; and (d) a pharmaceutically acceptable surfactant in an
amount of from 0% to 20% by weight of said solution.
11. The method of claim 1, wherein said solution comprises: (a)
ritonavir in an amount from 1% to 30% by weight of said solution;
(b) oleic acid in an amount of from 30% to 75% by weight of said
solution; (c) water in an amount of from 0.4% to 3.5% by weight of
said solution; and (d) polyoxyl 35 castor oil in an amount of from
0% to 20% by weight of said solution.
12. The method of claim 1, wherein said pharmaceutical composition
further comprises a hard or soft elastic gelatin capsule which
encapsulates said solution.
13. The method of claim 11, wherein said pharmaceutical composition
further comprises a hard or soft elastic gelatin capsule which
encapsulates said solution.
14. A method for improving the pharmacokinetics of a drug which is
metabolized by cytochrome P450 monooxygenease comprising
administering to a human in need thereof a combination of said drug
and
(2S,3S,5S)-5-(N--(N--((N-methyl-N-((2-isopropyl-4-thiazolyl)-methyl)amino-
)carbonyl)-L-valinyl)amino)-2-(N-((5-thiazolyl)methoxy-carbonyl)-amino)-1,-
6-diphenyl-3-hydroxyhexane (ritonavir), wherein said ritonavir is
comprised in a pharmaceutical composition which includes a solution
comprising: (a) ritonavir in an amount of from 1% to 50% by weight
of said solution; (b) a pharmaceutically acceptable medium and/or
long chain fatty acid, or a mixture of pharmaceutically acceptable
medium and/or long chain fatty acids, in an amount of from 30% to
75% by weight of said solution; (c) ethanol or propylene glycol in
an amount of from 1% to 15% by weight of said solution; (d) water
in an amount of from 0.4% to 3.5% by weight of said solution; and,
optionally, (e) a pharmaceutically acceptable surfactant.
15. The method of claim 14, wherein said drug is an
immunosuppressant, a chemotherapeutic agent, or an antibiotic.
16. The method of claim 14, wherein said solution comprises said
pharmaceutically acceptable surfactant which is in an amount of
from 2% to 20% by weight of said solution.
17. The method of claim 14, wherein said solution comprises
ritonavir in an amount of from 10 to 40% by weight of said
solution.
18. The method of claim 14, wherein said solution comprises water
in an amount of from 0.4% to 1.5% by weight of said solution.
19. The method of claim 14, wherein said pharmaceutically
acceptable medium and/or long chain fatty acid is a
mono-unsaturated C.sub.16-C.sub.20 fatty acid which is liquid at
room temperature, and said mixture of pharmaceutically acceptable
medium and/or long chain fatty acids is a mixture of
mono-unsaturated C.sub.16-C.sub.20 fatty acids which are liquids at
room temperature.
20. The method of claim 14, wherein said pharmaceutically
acceptable medium and/or long chain fatty acid is oleic acid, and
said mixture of pharmaceutically acceptable medium and/or long
chain fatty acids includes oleic acid.
21. The method of claim 14, wherein said solution comprises oleic
acid in an amount of from 30% to 75% by weight of said
solution.
22. The method of claim 14, wherein said solution comprises
polyoxyl 35 castor oil.
23. The method of claim 14, wherein said solution comprises: (a)
ritonavir in an amount from 1% to 30% by weight of said solution;
(b) a pharmaceutically acceptable long chain fatty acid in an
amount of from 30% to 75% by weight of said solution; (c) ethanol
in an amount of from 1% to 15% by weight of said solution; (d)
water in an amount of from 0.4% to 3.5% by weight of said solution;
and (e) a pharmaceutically acceptable surfactant in an amount of
from 0% to 20% by weight of said solution.
24. The method of claim 14, wherein said solution comprises: (a)
ritonavir in an amount from 1% to 30% by weight of said solution;
(b) oleic acid in an amount of from 30% to 75% by weight of said
solution; (c) ethanol in an amount of from 1% to 15% by weight of
said solution; (d) water in an amount of from 0.4% to 3.5% by
weight of said solution; and (e) polyoxyl 35 castor oil in an
amount of from 0% to 20% by weight of said solution.
25. The method of claim 14, wherein said solution comprises
polyoxyl 35 castor oil in an amount of from 2.5% to 10% by weight
of said solution.
26. The method of claim 14, wherein said pharmaceutical composition
further comprises a hard or soft elastic gelatin capsule which
encapsulates said solution.
27. The method of claim 24, wherein said pharmaceutical composition
further comprises a hard or soft elastic gelatin capsule which
encapsulates said solution.
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 09/576,097, filed May 22, 2000, now pending,
which claims the benefit of U.S. Provisional Application No.
60/137,634, filed Jun. 4, 1999, and U.S. Provisional Application
No. 60/177,020, filed Jan. 19, 2000, all of which are incorporated
herein by reference in their entireties.
TECHNICAL FIELD
[0002] This invention relates to improved pharmaceutical
formulations comprising at least one HIV protease inhibiting
compound in a pharmaceutically acceptable solution of a medium
and/or long chain fatty acid, ethanol or propylene glycol, and
water, wherein said HIV protease inhibiting compound contained
therein has improved solubility properties.
BACKGROUND OF THE INVENTION
[0003] Inhibitors of human immunodeficiency virus (HIV) protease
have been approved for use in the treatment of HIV infection for
several years. A particularly effective HIV protease inhibitor is
(2S,3S,5S)-5-(N--(N--((N-methyl-N-((2-isopropyl-4-thiazolyl)-methyl)amino-
)carbonyl)-L-valinyl)amino)-2-(N-((5-thiazolyl)methoxy-carbonyl)-amino)-1,-
6-diphenyl-3-hydroxyhexane (ritonavir), which is marketed as
NORVIR.RTM.. Ritonavir is known to have utility for the inhibition
of HIV protease, the inhibition of HIV infection, and the
enhancement of the pharmacokinetics of compounds which are
metabolized by cytochrome P.sub.450 monooxygenase. Ritonavir is
particularly effective for the inhibition of HIV infection when
used alone or in combination with one or more reverse transcriptase
inhibitors and/or one or more other HIV protease inhibitors.
[0004] HIV protease inhibiting compounds typically are
characterized by having poor oral bioavailability, and there is a
continuing need for the development of improved oral dosage forms
for HIV protease inhibitors having suitable oral bioavailability,
stability, and side effects profiles.
[0005] Ritonavir and processes for its preparation are disclosed in
U.S. Pat. No. 5,541,206, issued Jul. 30, 1996, the disclosure of
which is herein incorporated by reference. This patent discloses
processes for preparing ritonavir which produce a crystalline
polymorph of ritonavir, known as crystalline Form I.
[0006] Another process for the preparation of ritonavir is
disclosed in U.S. Pat. No. 5,567,823, issued Oct. 22, 1996, the
disclosure of which is herein incorporated by reference. The
process disclosed in this patent also produces ritonavir as
crystalline Form I.
[0007] Pharmaceutical compositions comprising ritonavir or a
pharmaceutically acceptable salt thereof are disclosed in U.S. Pat.
No. 5,541,206, issued Jul. 30, 1996; U.S. Pat. No. 5,484,801,
issued Jan. 16, 1996; U.S. Pat. No. 5,725,878, issued Mar. 10,
1998; and U.S. Pat. No. 5,559,158, issued Sep. 24, 1996 and in
International Application No. WO98/22106, published May 28, 1998
(corresponding to U.S. Ser. No. 08/966,495, filed Nov. 7, 1997),
the disclosures of all of which are herein incorporated by
reference.
[0008] The use of ritonavir to inhibit an HIV infection is
disclosed in U.S. Pat. No. 5,541,206, issued Jul. 30, 1996. The use
of ritonavir in combination with one or more reverse transcriptase
inhibitors to inhibit an HIV infection is disclosed in U.S. Pat.
No. 5,635,523, issued Jun. 3, 1997. The use of ritonavir in
combination with one or more HIV protease inhibitors to inhibit an
HIV infection is disclosed in U.S. Pat. No. 5,674,882, issued Oct.
7, 1997. The use of ritonavir to enhance the pharmacokinetics of
compounds metabolized by cytochrome P450 monooxygenase is disclosed
in WO 97/01349, published Jan. 16, 1997 (corresponding to U.S. Ser.
No. 08/687,774, filed Jun. 26, 1996). The disclosures of all of
these patents and patent applications are herein incorporated by
reference.
[0009] Examples of HIV protease inhibiting compounds include:
[0010]
N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-p-
yridylmethyl)-2(S)--N'-(t-butylcarboxamido)-piperazi
nyl))-pentaneamide (for example, indinavir) and related compounds,
disclosed in European Patent Application No. EP 541168, published
May 12, 1993, and U.S. Pat. No. 5,413,999, issued May 9, 1995, both
of which are herein incorporated by reference; [0011]
N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)--[[N-(2-qu
inolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-ca-
rboxamide (for example, saquinavir) and related compounds,
disclosed in U.S. Pat. No. 5,196,438, issued Mar. 23, 1993, which
is incorporated herein by reference; [0012]
5(S)-Boc-amino-4(S)-hydroxy-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L-
)-Phe-morpholin-4-ylamide and related compounds, disclosed in
European Patent Application No. EP532466, published Mar. 17, 1993,
which is incorporated herein by reference; [0013]
1-Naphthoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-butanoy-
l 1,3-thiazolidine-4-t-butylamide (for example,
1-Naphthoxyacetyl-Mta-(2S,3S)-AHPBA-Thz-NH-tBu),
5-isoquinolinoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-bu-
tanoyl-1,3-thiazolidine-4-t-butylamide, and related compounds,
disclosed in European Patent Application No. EP490667, published
Jun. 17, 1992 and Chem. Pharm. Bull. 40 (8) 2251 (1992), which are
both incorporated herein by reference; [0014] [1S-[1
R--(R--),2S*])--N.sup.1[3-[[[(1,1-dimethylethyl)amino]carbonyl](2-methylp-
ropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-2-[(2-quinolinylcarbonyl)am-
ino]-butanediamide (for example, SC-52151) and related compounds,
disclosed in PCT Patent Application No. W092/08701, published May
29, 1992 and PCT Patent Application No. W093/23368, published Nov.
25, 1993, both of which are herein incorporated by reference;
##STR1## (for example, VX-478) and related compounds, disclosed in
PCT Patent Application No. W0 94/05639, published Mar. 17, 1994,
which is incorporated herein by reference; ##STR2## (for example,
DMP-323) or ##STR3## (for example, DMP-450) and related compounds,
disclosed in PCT Patent Application No. WO 93/07128, published Apr.
15, 1993, which is incorporated herein by reference; ##STR4## (for
example, AG1343, (nelfinavir)), disclosed in PCT Patent Application
No. WO 95/09843, published Apr. 13, 1995 and U.S. Pat. No.
5,484,926, issued Jan. 16, 1996, which are both incorporated herein
by reference; ##STR5## (for example, BMS 186,318) disclosed in
European Patent Application No. EP580402, published Jan. 26, 1994,
which is incorporated herein by reference; ##STR6## (for example,
SC-55389a) and related compounds disclosed in PCT Patent
Application No. WO 9506061, published Mar. 2, 1995, which is
incorporated herein by reference and at 2nd National Conference on
Human Retroviruses and Related Infections, (Washington, D.C., Jan.
29-Feb. 2, 1995), Session 88; ##STR7## (for example, BILA 1096 BS)
and related compounds disclosed in European Patent Application No.
EP560268, published Sep. 15, 1993, which is incorporated herein by
reference; and ##STR8## (for example, U-140690 (tipranavir)) and
related compounds disclosed in PCT Patent Application No. WO
9530670, published Nov. 16, 1995, and U.S. Pat. No. 5,852,195,
issued Dec. 22, 1998, the disclosures of both of which are herein
incorporated by reference; or a pharmaceutically acceptable salt of
any of the above.
[0015] Another example of an HIV protease inhibiting compound
includes a compound of formula I: ##STR9## or a pharmaceutically
acceptable salt thereof, disclosed in PCT Patent Application No. W0
94/14436, published Jul. 7, 1994, and U.S. Pat. No. 5,541,206,
issued Jul. 30, 1996, the disclosures of both of which are herein
incorporated by reference.
[0016] The compounds of formula I are useful to inhibit HIV
infections and, thus, are useful for the treatment of AIDS.
[0017] Another example of an HIV protease inhibiting compound is a
compound of formula II: ##STR10## and related compounds, or a
pharmaceutically-acceptable salt thereof, as disclosed in U.S.
patent application Ser. No. 08/572,226, filed Dec. 13, 1996 and
U.S. patent application Ser. No. 08/753,201, filed Nov. 21, 1996,
and International Patent Application No. WO 97/21685, published
Jun. 19, 1997, the disclosures of which are herein incorporated by
reference. A preferred compound of formula II is known as ABT-378
and has a chemical name of
(2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2S-(1-tetrahy-
dropyrimid-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane, or a
pharmaceutically-acceptable salt thereof. The preparation of this
compound is disclosed in U.S. Pat. No. 5,914,332, issued Jun. 22,
1999, the disclosure of which is herein incorporated by
reference.
[0018] Solubility is an important factor in the formulation of HIV
protease inhibiting compounds. Compounds of formula I typically
have an aqueous solubility of approximately 6 micrograms per
milliliter at pH>2. This is considered to be extremely poor
aqueous solubility and, therefore, a compound of formula I in the
free base form would be expected to provide very low oral
bioavailability. In fact, the free base form of a compound of
formula I, administered as an unformulated solid in a capsule
dosage form, is characterized by a bioavailability of less than 2%
following a 5 mg/kg oral dose in dogs.
[0019] Acid addition salts of a compound of formula I (for example,
bishydrochloride, bis-tosylate, bis-methane sulfonate and the like)
have aqueous solubilities of <0.1 milligrams/milliliter. This is
only a slight improvement over the solubility of the free base.
This low aqueous solubility would not make practical the
administration of therapeutic amounts of an acid addition salt of a
compound of formula I as an aqueous solution. Furthermore, in view
of this low aqueous solubility, it is not surprising that the
bis-tosylate of a compound of formula I, administered as an
unformulated solid in a capsule dosage form, is characterized by a
bioavailability of less than 2% following a 5 mg/kg oral dose in
dogs.
[0020] In order to have a suitable oral dosage form of a compound
of formula I, the oral bioavailability of a compound of formula I
should be at least 20%. Preferably, the oral bioavailability of a
compound of formula I from the dosage form should be greater than
about 40% and, more preferably, greater than about 50%.
[0021] One measure of the potential usefulness of an oral dosage
form of a pharmaceutical agent is the bioavailability observed
after oral administration of the dosage form. Various factors can
affect the bioavailability of a drug when administered orally.
These factors include aqueous solubility, drug absorption, dosage
strength and first pass effect. Aqueous solubility is one of the
most important of these factors. When a drug has poor aqueous
solubility, attempts are often made to identify salts or other
derivatives of the drug which have improved aqueous solubility.
When a salt or other derivative of the drug is identified which has
good aqueous solubility, it is generally accepted that an aqueous
solution formulation of this salt or derivative will provide the
optimum oral bioavailability. The bioavailability of the oral
solution formulation of a drug is then generally used as the
standard bioavailability against which other oral dosage forms can
be measured.
[0022] For a variety of reasons, such as patient compliance and
taste masking, a solid dosage form, such as capsules, is usually
preferred over a liquid dosage form. However, oral solid dosage
forms, such as a tablet or a powder, and the like, of a drug
generally provide a lower bioavailability than oral solutions of
the drug. One goal of the development of a suitable capsule dosage
form is to obtain a bioavailability of the drug that is as close as
possible to the bioavailability demonstrated by the oral solution
formulation of the drug.
[0023] While some drugs would be expected to have good solubility
in organic solvents, it would not necessarily follow that oral
administration of such a solution would give good bioavailability
for the drug. It has been found that a compound of formula I has
good solubility in pharmaceutically acceptable organic solvents and
that the solubility in such solvents is enhanced in the presence of
a pharmaceutically acceptable long chain fatty acid. Administration
of the solution as an encapsulated dosage form (soft elastic
capsules or hard gelatin capsules) provides an oral bioavailability
of as high as about 60% or more.
[0024] Thus, it would be an important contribution to the art to
provide an improved pharmaceutical formulation comprising at least
one solubilized HIV protease inhibiting compound having enhanced
solubility properties.
[0025] In addition, the administration of ritonavir and a compound
which is metabolized by cytochrome P450 monooxygenase is useful for
improving in humans the pharmacokinetics of the compound which is
metabolized by cytochrome P450 monooxygenase.
[0026] A method of improving the pharmacokinetics of a drug (or a
pharmaceutically acceptable salt thereof) which is metabolized by
cytochrome P450 monooxygenase comprises coadministering ritonavir
or a pharmaceutically acceptable salt thereof. When administered in
combination, the two therapeutic agents can be formulated as
separate compositions which are administered at the same time or
different times, or the two therapeutic agents can be administered
as a single composition.
[0027] Drugs which are metabolized by cytochrome P450 monooxygenase
and which benefit from coadministration with ritonavir include the
immunosuppressants cyclosporine, FK-506 and rapamycin, the
chemotherapeutic agents taxol and taxotere, the antibiotic
clarithromycin and the HIV protease inhibitors A-77003, A-80987,
MK-639, saquinavir, VX-478, AG1343, DMP-323, XM-450, BILA 2011 BS,
BILA 1096 BS, BILA 2185 BS, BMS 186,318, LB71262, SC-52151, SC-629
(N,N-dimethylglycyl-N-(2-hyrdoxy-3-(((4-methoxyphenyl)sulphonyl)(2-methyl-
propyl)amino)-1-(phenylmethyl)propyl)-3-methyl-L-valinamide),
KNI-272, CGP 53437, CGP 57813 and U-103017.
[0028] A method for improving the pharmacokinetics of an HIV
protease inhibitor (or a pharmaceutically acceptable salt thereof)
which is metabolized by cytochrome P450 monooxygenase comprises
coadministering ritonavir or a pharmaceutically acceptable salt
thereof. Such a combination of ritonavir or a pharmaceutically
acceptable salt thereof and an HIV protease inhibitor or a
pharmaceutically acceptable salt thereof which is metabolized by
cytochrome P450 monooxygenase is useful for inhibiting HIV protease
in humans and is also useful for inhibition, treatment or
prophylaxis of an HIV infection or AIDS (acquired immune deficiency
syndrome) in humans. When administered in combination, the two
therapeutic agents can be formulated as separate compositions which
are administered at the same time or different times, or the two
therapeutic agents can be administered as a single composition.
[0029] The total daily dose of ritonavir to be administered to a
human or other mammal host in single or divided doses may be in
amounts, for example, from 0.001 to 300 mg/kg body weight daily and
more usually 0.1 to 50 mg/kg and even more usually 0.1 to 25 mg/kg.
Dosage unit compositions may contain such amounts of submultiples
thereof to make up the daily dose.
[0030] The total daily dose of the drug which is metabolized by
cytochrome P450 monooxygenase to be administered to a human or
other mammal is well known and can be readily determined by one of
ordinary skill in the art. Dosage unit compositions may contain
such amounts of submultiples thereof to make up the daily dose.
[0031] Liquid dosage forms for oral administration may include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs containing inert diluents commonly used in the
art, such as water. Such compositions may also comprise adjuvants,
such as wetting agents, emulsifying and suspending agents, and
sweetening, flavoring, and perfuming agents.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] FIG. 1 illustrates the powder X-ray diffraction pattern of
the substantially pure Form I crystalline polymorph of
ritonavir.
[0033] FIG. 2 illustrates the powder X-ray diffraction pattern of
the substantially pure Form II crystalline polymorph of
ritonavir.
[0034] FIG. 3 illustrates the equilibrium solubility of Ritonavir
Form II in the premix provided in Example 9.
[0035] FIG. 4 illustrates the equilibrium solubility of Ritonavir
Form I in the premix provided in Example 9.
[0036] FIG. 5 illustrates the effect of added water on the
solubility of Ritonavir Form II in oleic acid+ethanol co-solvent
system.
[0037] FIG. 6 illustrates the dissolution profile of Ritonavir Form
II crystals in the premix provided in Example 9.
[0038] FIG. 7 illustrates the 3D plots for the solubility of
Ritonavir Form I and II as a function of temperature, water, and
ethanol in the premix provided in Example 9.
SUMMARY OF THE INVENTION
[0039] The instant invention provides pharmaceutical compositions
comprising at least one solubilized HIV protease inhibiting
compound in a pharmaceutically acceptable solution of medium and/or
long chain fatty acids or mixtures thereof, a pharmaceutically
acceptable alcohol, and water, wherein said solubilized HIV
protease inhibiting compounds contained therein have improved
solubility properties.
DETAILED DESCRIPTION OF THE INVENTION
[0040] The instant invention comprises a solubilized HIV protease
inhibiting compound or a combination of solubilized HIV protease
inhibiting compounds, or pharmaceutically acceptable salts thereof,
in a pharmaceutically acceptable organic solvent comprising a
mixture of at least one pharmaceutically acceptable medium and/or
long chain fatty acid, a pharmaceutically-acceptable alcohol, and
water.
[0041] The compositions of the instant invention provide greatly
improved solubility for said solubilized HIV protease inhibiting
compounds contained therein when compared to analogous compositions
without the addition of water.
[0042] A preferred composition of the invention is a solution
comprising (a) a solubilized HIV protease inhibiting compound or a
combination of solubilized HIV protease inhibiting compounds
(preferably, a compound of the formula I or II, or saquinavir or
nelfinavir or indinavir or, more preferably, ritonavir or ABT-378
or saquinavir or nelfinavir or indinavir, or, most preferably,
ritonavir or ABT-378); or a combination of ritonavir or nelfinavir
and another HIV protease inhibitor (preferably, ABT-378 or
saquinavir or indinavir or nelfinavir, or, more preferably, a
combination of ritonavir or nelfinavir and another HIV protease
inhibitor (preferably, ABT-378 or saquinavir or indinavir or
nelfinavir), or, most preferably, a combination of ritonavir and
ABT-378) in the amount of from about 1% to about 50% (preferably,
from about 1% to about 40%; more preferably, from about 10% to
about 40% by weight of the total solution,
[0043] (b) a pharmaceutically acceptable organic solvent which
comprises (i) a pharmaceutically acceptable medium and/or long
chain fatty acid or mixtures thereof in the amount of from about
20% to about 99% (preferably, from about 30% to about 75% by weight
of the total solution or (ii) a mixture of (1) a pharmaceutically
acceptable medium and/or long chain fatty acid or mixtures thereof
in the amount of from about 20% to about 99% (preferably, from
about 30% to about 75% by weight of the total solution; (2) ethanol
in the amount of from about 1% to about 15% (preferably, from about
3% to about 12%) by weight of the total solution, or,
alternatively, propylene glycol in the amount of from about 1% to
about 15% (preferably, from about 5% to about 10%); (c) water in
the amount of from about 0.4% to about 3.5%; and optionally, (d) a
pharmaceutically acceptable surfactant in the amount of from about
0% to about 40% (preferably, from about 2% to about 20% and most
preferably, from about 2.5% to about 15%) by weight of the total
solution.
[0044] In a preferred embodiment of the invention, the solution is
encapsulated in a soft elastic gelatin capsule (SEC) or a hard
gelatin capsule, or orally ingested after further dilution in an
appropriate diluent or vehicle.
[0045] Specifically, preferred ratios (w/w) of ritonavir to ABT-378
are from about 1:16 to about 5:1. Even more preferred is a ratio of
ritonavir to ABT-378 of from about 1:8 to about 3:1. An even more
preferred ratio of ritonavir to ABT-378 is 1:4.
[0046] Solutions as described herein may include micellar
solutions, which are thermodynamically stable systems formed
spontaneously in water above a critical temperature and
concentration. Said micellar solutions contain small colloidal
aggregates (micelles), the molecules of which are in rapid
thermodynamic equilibrium with a measurable concentration of
monomers. Micellar solutions exhibit solubilization phenomena and
thermodynamic stability.
[0047] Preferably, the pharmaceutically acceptable organic solvent
comprises from about 50% to about 99% by weight of the total
solution. More preferably, the pharmaceutically acceptable organic
solvent or mixture of pharmaceutically acceptable organic solvents
comprises from about 50% to about 75% by weight of the total
solution.
[0048] The term "pharmaceutically acceptable medium and/or long
chain fatty acid" as used herein refers to saturated or unsaturated
C.sub.8 to C.sub.24 fatty acids. Preferred fatty acids are
mono-unsaturated C.sub.16-C.sub.20 fatty acids which are liquids at
room temperature. A most preferred fatty acid is oleic acid, with
or without additional medium and/or long chain fatty acids in the
mixture. One suitable source of said oleic acid is Henkel
Corporation.
[0049] The term "pharmaceutically acceptable alcohol" as used
herein refers to alcohols which are liquid at room temperature, for
example ethanol, propylene glycol, 2-2(ethoxyethoxy)ethanol
(Transcutol.RTM., Gattefosse, Westwood, N.J.), benzyl alcohol,
glycerol, polyethylene glycol 200, polyethylene glycol 300,
polyethylene glycol 400, and the like, or mixtures thereof.
[0050] Preferred pharmaceutically acceptable solvents comprise (1)
pharmaceutically acceptable medium and/or long chain fatty acid in
the amount of from about 40% to about 75% by weight of the total
solution; (2) ethanol or propylene glycol in the amount of from
about 1% to about 15% by weight of the total solution; and (3)
water in the amount of from about 0.4% to about 3.5% by weight of
the total solution. More preferred pharmaceutically acceptable
solvents comprise (1) a pharmaceutically acceptable medium and/or
long chain fatty acid in the amount of from about 40% to about 75%
by weight of the total solution and (2) ethanol or propylene glycol
in the amount of from about 3% to about 12% by weight of the total
solution. Even more preferred pharmaceutically acceptable solvents
comprise (1) oleic acid in the amount of from about 40% to about
75% by weight of the total solution and (2) ethanol or propylene
glycol in the amount of from about 3% to about 12% by weight of the
total solution.
[0051] In one embodiment of the invention, a more preferred
composition of the invention is a solution comprising (a)
solubilized ritonavir in the amount of from about 1% to about 30%
(preferably, from about 5% to about 25%) by weight of the total
solution, (b) a pharmaceutically acceptable organic solvent which
comprises (i) a pharmaceutically acceptable medium and/or long
chain fatty acid in the amount of from about 40% to about 99%
(preferably, from about 30% to about 75% by weight of the total
solution or (ii) a mixture of (1) a pharmaceutically acceptable
long chain fatty acid in the amount of from about 40% to about 99%
(preferably, from about 30% to about 75% by weight of the total
solution and (2) ethanol in the amount of from about 1% to about
15% (preferably, from about 3% to about 12%) by weight of the total
solution, (c) water in the amount of from about 0.4% to about 3.5%
and (d) a pharmaceutically acceptable surfactant in the amount of
from about 0% to about 20% (preferably, from about 2.5% to about
10%) by weight of the total solution.
[0052] In a more preferred embodiment of the invention, the
solution is encapsulated in a soft elastic gelatin capsule (SEC) or
a hard gelatin capsule.
[0053] An even more preferred composition of the invention is a
solution comprising (a) solubilized ritonavir in the amount of from
about 1% to about 30% (preferably, from about 5% to about 25%) by
weight of the total solution, (b) a pharmaceutically acceptable
organic solvent which comprises (i) oleic acid in the amount of
from about 15% to about 99% (preferably, from about 30% to about
75% by weight of the total solution or (ii) a mixture of (1) oleic
acid in the amount of from about 15% to about 99% (preferably, from
about 30% to about 75% by weight of the total solution and (2)
ethanol in the amount of from about 1% to about 15% (preferably,
from about 3% to about 12%) by weight of the total solution, (c)
water in the amount of from about 0.4% to about 3.5%, and (d)
polyoxyl 35 castor oil in the amount of from about 0% to about 20%
(preferably, from about 2.5% to about 10%) by weight of the total
solution.
[0054] In an even more preferred embodiment of the invention, the
solution is encapsulated in a soft elastic gelatin capsule (SEC) or
a hard gelatin capsule.
[0055] A most preferred composition of the invention is a solution
comprising (a) solubilized ritonavir in the amount of about 10% by
weight of the total solution, (b) a pharmaceutically acceptable
organic solvent which comprises a mixture of (1) oleic acid in the
amount of from about 70% to about 75% by weight of the total
solution and (2) ethanol in the amount of from about 3% to about
12%, preferably, about 12%, by weight of the total solution, (c)
water in the amount of from about 0.4% to about 1.5% and (d)
polyoxyl 35 castor oil in the amount of about 6% by weight of the
total solution.
[0056] In a most preferred embodiment of the invention, the
solution is encapsulated in a soft elastic gelatin capsule (SEC) or
a hard gelatin capsule and the solution also comprises an
antioxidant (preferably, BHT (butylated hydroxytoluene)) in the
amount of about 0.025% by weight of the total solution.
[0057] In one embodiment of the invention, a more preferred
composition of the invention is a solution comprising (a) a
combination of solubilized HIV protease inhibiting compounds which
are ritonavir and ABT-378 in the amount of from about 1% to about
45% (preferably, from about 5% to about 45%) by weight of the total
solution, and (b) a pharmaceutically acceptable organic solvent
which comprises (i) a pharmaceutically acceptable medium and/or
long chain fatty acid in the amount of from about 40% to about 99%
(preferably, from about 30% to about 75% by weight of the total
solution or (ii) a mixture of (1) a pharmaceutically acceptable
long chain fatty acid in the amount of from about 40% to about 99%
(preferably, from about 30% to about 75% by weight of the total
solution and (2) propylene glycol in the amount of from about 1% to
about 15% by weight of the total solution, (c) water in the amount
of from about 0.4% to about 3.5% and (d) a pharmaceutically
acceptable surfactant in the amount of from about 0% to about 20%
(preferably, from about 2.5% to about 10%) by weight of the total
solution.
[0058] In a more preferred embodiment of the invention, the
solution is encapsulated in a soft elastic gelatin capsule (SEC) or
a hard gelatin capsule.
[0059] An even more preferred composition of the invention is a
solution comprising (a) a combination of solubilized HIV protease
inhibiting compounds which are ritonavir and ABT-378 in the amount
of from about 1% to about 45% (preferably, from about 5% to about
45%) by weight of the total solution, (b) a pharmaceutically
acceptable organic solvent which comprises (i) oleic acid in the
amount of from about 15% to about 99% (preferably, from about 30%
to about 75% by weight of the total solution or (ii) a mixture of
(1) oleic acid in the amount of from about 15% to about 99%
(preferably, from about 30% to about 75% by weight of the total
solution and (2) propylene glycol in the amount of from about 1% to
about 8% by weight of the total solution, (c) water in the amount
of from about 0.4% to about 3.5%, and (d) polyoxyl 35 castor oil in
the amount of from about 0% to about 20% (preferably, from about
2.5% to about 10%) by weight of the total solution.
[0060] In an even more preferred embodiment of the invention, the
solution is encapsulated in a soft elastic gelatin capsule (SEC) or
a hard gelatin capsule.
[0061] A most preferred composition of the invention is a solution
comprising (a) a combination of solubilized HIV protease inhibiting
compounds which are ritonavir and ABT-378 in the amount of about
10% by weight of the total solution, (b) a pharmaceutically
acceptable organic solvent which comprises a mixture of (1) oleic
acid in the amount of from about 70% to about 75% by weight of the
total solution and (2) propylene glycol in the amount of from about
1% to about 15%, preferably, about 6%, by weight of the total
solution, (c) water in the amount of from about 0.4% to about 1.5%
and (d) polyoxyl 35 castor oil in the amount of about 6% by weight
of the total solution.
[0062] In a most preferred embodiment of the invention, the
solution is encapsulated in a soft elastic gelatin capsule (SEC) or
a hard gelatin capsule and the solution also comprises an
antioxidant (preferably, BHT (butylated hydroxytoluene)) in the
amount of about 0.025% by weight of the total solution.
[0063] The amount of water employed in the pharmaceutical
composition of the instant invention comprises from about 0.4% to
about 3.5% by weight of the total solution of water. Preferably,
the weight of the total solution of water is from about 0.4% to
about 2.0%; more preferably from about 0.4% to about 1.5%; and the
most preferred being about 1%.
[0064] In addition, the composition of the invention can comprise
antioxidants (for example, ascorbic acid, BHA (butylated
hydroxyanisole), BHT (butylated hydroxytoluene), vitamin E, and the
like) for chemical stability.
[0065] The term "pharmaceutically acceptable acid" as used herein
refers to (i) an inorganic acid such as hydrochloric acid,
hydrobromic acid, hydroiodic acid and the like, (ii) an organic
mono-, di- or tri-carboxylic acid (for example, formic acid, acetic
acid, adipic acid, alginic acid, citric acid, ascorbic acid,
aspartic acid, benzoic acid, butyric acid, camphoric acid, gluconic
acid, glucuronic acid, galactaronic acid, glutamic acid, heptanoic
acid, hexanoic acid, fumaric acid, lactic acid, lactobionic acid,
malonic acid, maleic acid, nicotinic acid, oxalic acid, pamoic
acid, pectinic acid, 3-phenylpropionic acid, picric acid, pivalic
acid, propionic acid, succinic acid, tartaric acid, undecanoic acid
and the like) or (iii) a sulfonic acid (for example,
benzenesulfonic acid, sodium bisulfate, sulfuric acid,
camphorsulfonic acid, dodecylsulfonic acid, ethanesulfonic acid,
methanesulfonic acid, isethionic acid, naphthalenesulfonic acid,
p-toluenesulfonic acid and the like).
[0066] The term "pharmaceutically acceptable surfactant" as used
herein refers to a pharmaceutically acceptable non-ionic surfactant
for example, polyoxyethylene castor oil derivatives (for example,
polyoxyethyleneglyceroltriricinoleate or polyoxyl ethylene 35
castor oil (Cremophor.RTM. EL, BASF Corp.) or
polyoxyethyleneglycerol oxystearate (Cremophor.RTM. RH 40 (glycerol
polyethyleneglycol oxystearate) or Cremophor.RTM. RH 60
(polyethyleneglycol 60 hydrogenated castor oil), BASF Corp., and
the like) or block copolymers of ethylene oxide and propylene
oxide, also known as polyoxyethylene polyoxypropylene block
copolymers or polyoxyethylenepolypropylene glycol, such as
Poloxamer.RTM.124, Poloxamer.RTM. 188, Poloxamer.RTM. 237,
Poloxamer.RTM. 338, Poloxamer.RTM. 407, and the like, (BASF
Wyandotte Corp.) or a mono fatty acid ester of polyoxyethylene (20)
sorbitan (for example, polyoxyethylene (20) sorbitan monooleate
(Tween.RTM. 80), polyoxyethylene (20) sorbitan monostearate
(Tween.RTM. 60), polyoxyethylene (20) sorbitan monopalmitate
(Tween.RTM. 40), polyoxyethylene (20) sorbitan monolaurate
(Tweens.RTM. 20)) and the like) or a sorbitan fatty acid ester
(including sorbitan laurate, sorbitan oleate, sorbitan palmitate,
sorbitan stearate and the like). A preferred pharmaceutically
acceptable surfactant is polyoxyl 35 castor oil (Cremophor.RTM. EL,
BASF Corp.), polyoxyethylene (20) sorbitan monolaurate (Tween.RTM.)
20), polyoxyethylene (20) sorbitan monooleate (Tween.RTM. 80) or a
sorbitan fatty acid ester, for example sorbitan oleate. A most
preferred pharmaceutically acceptable surfactant is polyoxyl 35
castor oil (Cremophor.RTM. EL, BASF Corp.).
[0067] As used herein, the term "substantially pure", when used in
reference to a polymorph of ritonavir, refers to a polymorph of
ritonavir, Form I or Form II, which is greater than about 90% pure.
This means that the polymorph of ritonavir does not contain more
than about 10% of any other compound and, in particular, does not
contain more than about 10% of any other form of ritonavir. More
preferably, the term "substantially pure" refers to a polymorph of
ritonavir, Form I or Form II, which is greater than about 95% pure.
This means that the polymorph of ritonavir does not contain more
than about 5% of any other compound and, in particular, does not
contain more than about 5% of any other form of ritonavir. Even
more preferably, the term "substantially pure" refers to a
polymorph of ritonavir, Form I or Form II, which is greater than
about 97% pure. This means that the polymorph of ritonavir does not
contain more than about 3% of any other compound and, in
particular, does not contain more than about 3% of any other form
of ritonavir.
[0068] As used herein, the term "substantially pure", when used in
reference to amorphous ritonavir, refers to amorphous ritonavir
which is greater than about 90% pure. This means that the amorphous
ritonavir does not contain more than about 10% of any other
compound and, in particular, does not contain more than about 10%
of any other form of ritonavir. More preferably, the term
"substantially pure", when used in reference to amorphous
ritonavir, refers to amorphous ritonavir, which is greater than
about 95% pure. This means that the amorphous ritonavir does not
contain more than about 5% of any other compound and, in
particular, does not contain more than about 5% of any other form
of ritonavir. Even more preferably, the term "substantially pure",
when used in reference to amorphous ritonavir, refers to amorphous
ritonavir which is greater than about 97% pure. This means that the
amorphous ritonavir does not contain more than about 3% of any
other compound and, in particular, does not contain more than about
3% of any other form of ritonavir.
[0069] The composition and preparation of soft elastic gelatin
capsules is well known in the art. The composition of a soft
elastic gelatin capsule typically comprises from about 30% to about
50% by weight of gelatin NF & EP, from about 20% to about 30%
by weight of a plasticizer, and from about 25% to about 40% by
weight of water. Plasticizers useful in the preparation of soft
elastic gelatin capsules are glycerin, sorbitol, or propylene
glycol and the like, or combinations thereof. A preferred soft
elastic gelatin capsule has a composition comprising gelatin NF
& EP (Type 195) (about 42.6% by weight), glycerin (USP) (about
96% active; about 13.2% by weight), purified water (USP) (about
27.4% by weight), sorbitol special (about 16% by weight) and
titanium dioxide (USP) (about 0.4% by weight).
[0070] The soft elastic gelatin capsule material can also comprise
additives such as preservatives, opacifiers, dyes or flavors, and
the like.
[0071] Various methods can be used for manufacturing and filling
the soft elastic gelatin capsules, for example, a seamless capsule
method, a rotary method (developed by Scherer) or a method using a
Liner.RTM. machine or an Accogel.RTM. machine, and the like. Also
various manufacturing machines can be used for manufacturing the
capsules.
[0072] Hard gelatin capsules are purchased from Capsugel,
Greenwood, S.C. Capsules are filled manually or by capsule filling
machine. The target filling volume/weight depends on the potency of
the filling solution in combination with the desired dosage
strength.
[0073] In general, the compositions of this invention can be
prepared in the following manner. The pharmaceutically acceptable
medium and/or long chain fatty acid and ethanol or propylene glycol
and water are mixed at a temperature from 15-30.degree. C., along
with the antioxidant. The HIV protease inhibitor, or mixture of HIV
protease inhibitors, is added and stirred until dissolved. The
pharmaceutically acceptable surfactant is added with mixing. The
appropriate volume of the resulting mixture needed to provide the
desired dose of the HIV protease inhibiting compound(s) is filled
into hard gelatin capsules or soft elastic gelatin capsules.
[0074] Similar increases in the solubility of HIV protease
inhibitors in oral solution formulations may be obtained by the
addition of water in ranges as disclosed herein. Oral solution
formulations are disclosed in U.S. Pat. No. 5,484,801, issued Jan.
16, 1996, the disclosure of which is herein incorporated by
reference.
EXAMPLES
[0075] The following Examples will serve to further illustrate the
instant invention.
[0076] Powder X-ray diffraction analysis of samples was conducted
in the following manner. Samples for X-ray diffraction analysis
were prepared by spreading the sample powder (with no prior
grinding required) in a thin layer on the sample holder and gently
flattening the sample with a microscope slide.
[0077] A Nicolet 12/V X-ray Diffraction System was used with the
following parameters: X-ray source: Cu--K.alpha.1; Range:
2.00-40.00.degree. Two Theta; Scan Rate: 1.00 degree/minute; Step
Size: 0.02 degrees; Wavelength: 1.540562 angstroms.
[0078] Characteristic powder X-ray diffraction pattern peak
positions are reported for polymorphs in terms of the angular
positions (two theta) with an allowable variability of
.+-.0.1.degree.. This allowable variability is specified by the
U.S. Pharmacopeia, pages 1843-1844 (1995). The variability of
.+-.0.1.degree. is intended to be used when comparing two powder
X-ray diffraction patterns. In practice, if a diffraction pattern
peak from one pattern is assigned a range of angular positions (two
theta) which is the measured peak position .+-.0.1.degree. and a
diffraction pattern peak from the other pattern is assigned a range
of angular positions (two theta) which is the measured peak
position .+-.0.1.degree. and if those ranges of peak positions
overlap, then the two peaks are considered to have the same angular
position (two theta). For example, if a diffraction pattern peak
from one pattern is determined to have a peak position of
5.20.degree., for comparison purposes the allowable variability
allows the peak to be assigned a position in the range of
5.10.degree.-5.30.degree.. If a comparison peak from the other
diffraction pattern is determined to have a peak position of
5.35.degree., for comparison purposes the allowable variability
allows the peak to be assigned a position in the range of
5.25.degree.-5.45.degree.. Because there is overlap between the two
ranges of peak positions (for example, 5.10.degree.-5.30.degree.
and 5.25.degree.-5.45.degree.) the two peaks being compared are
considered to have the same angular position (two theta).
[0079] Solid state nuclear magnetic resonance analysis of samples
was conducted in the following manner. A Bruker AMX-400 MHz
instrument was used with the following parameters: CP-MAS
(cross-polarized magic angle spinning); spectrometer frequency for
13C was 100.627952576 MHz; pulse sequence was cp2lev; contact time
was 2.5 milliseconds; temperature was 27.0.degree. C.; spin rate
was 7000 Hz; relaxation delay was 6.000 sec; 1st pulse width was
3.8 microseconds; 2nd pulse width was 8.6 microseconds; acquisition
time was 0.034 seconds; sweep width was 30303.0 Hz; 2000 scans.
[0080] FT near infrared analysis of samples was conducted in the
following manner. Samples were analyzed as neat, undiluted powders
contained in a clear glass 1 dram vial. A Nicolet Magna System 750
FT-IR spectrometer with a Nicolet SabIR near infrared fiber optic
probe accessory was used with the following parameters: the source
was white light; the detector was PbS; the beamsplitter was CaF2;
sample spacing was 1.0000; digitizer bits was 20; mirror velocity
was 0.3165; the aperture was 50.00; sample gain was 1.0; the high
pass filter was 200.0000; the low pass filter was 11000.0000; the
number of sample scans was 64; the collection length was 75.9
seconds; the resolution was 8.000; the number of scan points was
8480; the number of FFT points was 8192; the laser frequency was
15798.0 cm.sup.-1; the interferogram peak position was 4096; the
apodization was Happ-Genzel; the number of background scans was 64
and the background gain was 1.0.
[0081] FT mid infrared analysis of samples was conducted in the
following manner. Samples were analyzed as neat, undiluted powders.
A Nicolet Magna System 750 FT-IR spectrometer with a Spectra-Tech
InspectIR video microanalysis accessory and a Germanium attenuated
total reflectance (Ge ATR) crystal was used with the following
parameters: the source was infrared; the detector was MCT/A; the
beamsplitter was KBr; sample spacing was 2.0000; digitizer bits was
20; mirror velocity was 1.8988; the aperture was 100.00; sample
gain was 1.0; the high pass filter was 200.0000; the low pass
filter was 20000.0000; the number of sample scans was 128; the
collection length was 79.9 seconds; the resolution was 4.000; the
number of scan points was 8480; the number of FFT points was 8192;
the laser frequency was 15798.0 cm.sup.-1; the interferogram peak
position was 4096; the apodization was triangular; the number of
background scans was 128 and the background gain was 1.0.
[0082] Differential scanning calorimetric analysis of samples was
conducted in the following manner. A T.A. Instruments Thermal
Analyzer 3100 with Differential Scanning Calorimetry module 2910
was used, along with Modulated DSC software version 1.1A. The
analysis parameters were: Sample weight: 2.28 mg, placed in a
covered, uncrimped aluminum pan; Heating rate: room temperature to
150.degree. C. at 5C./minute under a nitrogen purge.
Example 1
Preparation of Amorphous Ritonavir
[0083] Form I crystalline polymorph of ritonavir (100 g) was melted
at 125.degree. C. by heating Form I. The melt was maintained at a
temperature of 125.degree. C. for 3 hours. The melt was rapidly
cooled by placing the container holding the melt into a Dewar flask
containing liquid nitrogen. The resulting glass was ground with a
mortar and pestle to provide amorphous ritonavir (100 g). Powder
X-ray diffraction analysis confirmed that the product was
amorphous. Differential scanning calorimetric analysis determined
that the glass transition point was from about 45.degree. C. to
about 49.degree. C. (Measured onset at 45.4.degree. C. and which
ends at 49.08.degree. C., with a midpoint of 48.99.degree. C.).
Example 2
Preparation of Crystalline Ritonavir (Form II)
[0084] Amorphous ritonavir (40.0 g) was dissolved in boiling
anhydrous ethanol (100 mL). Upon allowing this solution to cool to
room temperature, a saturated solution was obtained. After standing
overnight at room temperature, the resulting solid was isolated
from the mixture by filtration and was air dried to provide Form II
(approximately 24.0 g).
Example 3
Preparation of
(2S)--N-((1S)-1-Benzyl-2-((4S,5S)-4-benzyl-2-oxo-1,3-oxazolidin-5-yl)ethy-
l)-2-((((2-isopropyl-1,3-thiazol-4-yl)methyl)amino)carbonyl)amino)-3-methy-
lbutanamide
Example 3a
Preparation of
(4S,5S)-5-((2S)-2-t-butyloxycarbonylamino-3-phenylpropyl)-4-benzyl-1,3-ox-
azolidin-2-one
[0085]
(2S,3S,5S)-2-Amino-3-hydroxy-5-t-butyloxycarbonylamino-1,6-dipheny-
lhexane succinate salt (30 g, 63 mmol; U.S. Pat. No. 5,654,466),
((5-thiazolyl)methyl)-(4-nitrophenyl)carbonate hydrochloride (22.2
g; U.S. Pat. No. 5,597,926) and sodium bicarbonate (16.2 g) were
mixed with 300 mL of water and 300 mL of ethyl acetate and the
mixture was stirred at room temperature for about 30 minutes. The
organic layer was then separated and heated at about 60.degree. C.
for 12 hours, and then stirred at 20-25.degree. C. for 6 hours. 3
mL of ammonium hydroxide (29% ammonia in water) was added and the
mixture stirred for 1.5 hours. The resulting mixture was washed
with 4.times.200 mL of 10% aqueous potassium carbonate and the
organic layer was separated and evaporated under vacuum to provide
an oil. The oil was suspended in about 250 mL of heptane. The
heptane was evaporated under vacuum to provide a yellow solid. The
yellow solid was dissolved in 300 mL of THF and 25 mL of 10%
aqueous sodium hydroxide was added. After stirring for about 3
hours, the mixture was adjusted to pH 7 by addition of 4N HCl
(about 16 mL). The THF was evaporated under vacuum to leave an
aqueous residue, to which was added 300 mL of distilled water.
After stirring this mixture, a fine suspension of solids resulted.
The solid was collected by filtration and the filtered solid was
washed with water (1400 mL) in several portions, resulting in the
desired product.
Example 3b
Preparation of
(4S,5S)-5-((2S)-2-amino-3-phenylpropyl)-4-benzyl-1,3-oxazolidin-2-one
[0086] The crude, wet product of Example 3a was slurried in 1N HCl
(192 mL) and the slurry was heated to 70.degree. C. with stirring.
After 1 hour, THF (100 mL) was added and stirring at 65.degree. C.
was continued for 4 hours. The mixture was then allowed to cool to
20-25.degree. C. and was stirred overnight at 20-25.degree. C. The
THF was removed by evaporation under vacuum and the resulting
aqueous solution was cooled to about 5.degree. C., causing some
precipitation to occur. The aqueous mixture was adjusted to pH 7 by
addition of 50% aqueous sodium hydroxide (about 18.3 g). The
resulting mixture was extracted with ethyl acetate (2.times.100 mL)
at about 15.degree. C. The combined organic extracts were washed
with 100 mL of brine and the organic layer was separated and
stirred with sodium sulfate (5 g) and Darco G-60 (3 g). This
mixture was warmed on a hot plate for 1 hour at 45.degree. C. The
hot mixture was then filtered through a bed of diatomaceous earth
and the filter pad was washed with ethyl acetate (100 mL). The
filtrate was evaporated under vacuum to provide an oil. The oil was
redissolved in methylene chloride (300 mL) and the solvent was
evaporated under vacuum. The resulting oil was dried at room
temperature under vacuum to provide the desired product (18.4 g) as
a glassy syrup.
Example 3c
Preparation of
(2S)--N-((1S)-1-Benzyl-2-((4S,5S)-4-benzyl-2-oxo-1,3-oxazolidin-5-yl)ethy-
l)-2-((((2-isopropyl-1,3-thiazol-4-yl)methyl)amino)carbonyl)amino)-3-methy-
lbutanamide
[0087]
N--((N-Methyl-N((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L--
valine (10.6 g, 33.9 mmol; U.S. Pat. No. 5,539,122 and
International Patent Application No. WO 98/00410), the product of
Example 3b (10.0 g, 32.2 mmol) and 1-hydroxybenzotriazole (5.2 g,
34 mmol) were dissolved in THF (200 mL).
1,3-dicylclohexylcarbodiimide (DCC, 7.0 g, 34 mmol) was then added
to the THF mixture and the mixture was stirred at 22.degree. C. for
4 hours. Citric acid (25 mL of 10% aqueous solution) was added and
stirring continued for 30 minutes. The THF was then evaporated
under vacuum. The residue was dissolved in ethyl acetate (250 mL)
and washed with 10% citric acid solution (175 mL). NaCl (5 g) was
added to accelerate the separation of the layers. The organic layer
was sequentially washed with 10% aq. sodium carbonate (2.times.200
mL) and water (200 mL). The organic layer was then dried over
sodium sulfate (20 g), filtered and evaporated under vacuum. The
resulting product (20.7 g of a foam) was dissolved in hot ethyl
acetate (150 mL) and then heptane (75 mL) was added. Upon cooling,
another 75 mL of heptane was added and the mixture was heated to
reflux. Upon cooling to room temperature, no precipitate formed.
The solvents were evaporated under vacuum and the residue was
redissolved in a mixture of 200 mL ethyl acetate/100 mL heptane.
The small amount of undissolved solid was removed by filtration.
The filtrate was evaporated under vacuum and the residue was
dissolved in a mixture of 100 mL ethyl acetate/50 mL heptane,
giving a clear solution. The solution was cooled to -10.degree. C.
and a white precipitate formed. The mixture was allowed to sit at
-15.degree. C. for 24 hours. The resulting solid was collected by
filtration, washed with 1:1 ethyl acetate/heptane (2.times.24 mL)
and dried in a vacuum oven at 55.degree. C. to provide the desired
product as a beige solid (16.4 g).
Example 4
Preparation of Crystalline Ritonavir (Form II)
[0088] To a solution of 1.595 g of ritonavir Form I in 10 mL of 200
proof ethanol was added approximately 50 micrograms of the product
of Example 3c. This mixture was allowed to stand at about 5.degree.
C. for 24 hours. The resulting crystals were isolated by filtration
through 0.45 micron nylon filter and air dried to provide ritonavir
Form II.
Example 5
Alternative Preparation of Crystalline Ritonavir (Form II)
[0089] Ethyl acetate (6.0 L/kg of ritonavir) was added to ritonavir
(Form I or a mixture of Form I and Form II) in a reaction vessel.
The mixture was stirred and heated to 70.degree. C. until all
solids were dissolved. The solution was filtered (utilizing a
centrifuge pump and 5.times.20 inch cartridge filters having a
porosity of 1.2 microns) and the filtrate was allowed to cool to
52.degree. C. at a rate of 2-10.degree. C./hour. To this solution
was added ritonavir Form II seed crystals (about 1.25 g of Form II
seed crystals/kg of ritonavir) and the mixture was stirred at
52.degree. C. for not less than 1 hour at an agitation rate of 15
RPM. The mixture was then allowed to cool to 40.degree. C. at a
rate of 10.degree. C./hour. Heptane (2.8 L/kg of ritonavir) was
added at a rate of 7 L/minute with mixing. The mixture was allowed
to cool to 25.degree. C. at a rate of 10.degree. C./hour with
mixing. Then the mixture was stirred for not less than 12 hours at
25.degree. C. The product was isolated by filtration using a
Heinkel type centrifuge (run time approximately 16 hours). The
product was dried at 55.degree. C. under vacuum (50 mm Hg) for
16-25 hours to provide ritonavir crystal Form II.
Example 6
Preparation of Amorphous Ritonavir
[0090] Ritonavir Form I (40 g) was dissolved in methylene chloride
(60 mL). This solution was slowly added over 15 minutes to a round
bottom flask equipped with an overhead stirrer and containing
hexanes (3.5 L). The resulting slurry was allowed to stir for 10
minutes. The precipitate was filtered and dried at room temperature
in a vacuum oven to provide amorphous ritonavir (40 g).
Example 7
Preparation of Amorphous Ritonavir
[0091] Ritonavir Form I (5 g) was dissolved in methanol (8 mL).
This solution was slowly added to a round bottom flask equipped
with an overhead stirrer and containing distilled water (2 L),
while maintaining the internal temperature near 0.degree. C. The
resulting solid was filtered to give a sticky solid which was dried
in a vacuum oven to give amorphous ritonavir (2.5 g).
Example 8
Comparative Solubilities
[0092] Solubility experiments were performed for ritonavir Form I
and Form II in various formulation mediums. Data is provided in
FIGS. 3-7.
[0093] Tables 1 and 2 provided hereinbelow illustrate the
pharmaceutical composition without water. Examples 9 and 10
illustrate the pharmaceutical composition with water.
TABLE-US-00001 TABLE 1 Composition of Formulations T-1 and T-2. T-1
T-2 Components mg/g mg/cap mg/g mg/cap Ritonavir 200.0 200.0 200.0
200.0 Alcohol, dehydrated, USP 100.0 100.0 100.0 100.0 Oleic acid,
NF 650.0 650.0 600.0 600.0 Polyoxyl 35 Castor Oil 50.0 50.0 100.0
100.0 (Cremophor EL .RTM.) BHT 0.01 0.01 0.01 0.01
[0094] TABLE-US-00002 TABLE 2 Composition of Formulation T-1B. T-1B
Components mg/g mg/cap Ritonavir 200.0 200.0 Alcohol, dehydrated,
USP 120.0 120.0 Oleic acid, NF 619.5 619.5 Polyoxyl 35 Castor Oil
60.0 60.0 (Cremophor EL .RTM.) BHT 0.5 0.5
Example 9
Preparation of Norvir.RTM. (100 mg) Soft Gelatin Capsules
[0095] The following protocol is employed in the preparation of
1000 soft gelatin capsules: TABLE-US-00003 Scale Amount
(mg/capsule) Name (g) Q.S. Nitrogen, N.F. Q.S. 118.0 Ethanol, 118.0
dehydrated, USP, 200 Proof 2.0 Ethanol, 2.0 dehydrated, USP, 200
Proof 0.25 Butylated Hydroxytoluene, NF 0.25 704.75 Oleic Acid, NF
704.75 100.0 Ritonavir 100.0 10.0 Water, purified, USP (distilled)
10.0 60.0 Polyoxyl 35 Castor Oil, NF 60.0 5.000 Oleic Acid, NF
5.000
[0096] A mixing tank and suitable container are purged with
nitrogen. 118.0 g of ethanol is weighed, blanketed with nitrogen,
and held for later use. The second aliquot of ethanol (2 g) is then
weighed, and mixed with 0.25 g of butylated hydroxytoluene until
clear. The mixture is blanketed with nitrogen and held. The main
mixing tank is heated to 28.degree. C. (not to exceed 30.degree.
C.). 704.75 g of oleic acid is then charged into the mixing tank.
100.0 g of ritonavir is then added to the oleic acid with mixing.
The ethanol/butylated hydroxytoluene is then added to the mixing
tank, followed by the 118.0 g of ethanol measured previously, and
mixed for at least 10 minutes. 10 g of water is then charged into
the tank and mixed until the solution is clear (for not less than
30 minutes). The sides of the vessel are scraped for ritonavir, and
mixed for not less than an additional 30 minutes. 60.0 g of
Polyoxyl 35 castor oil is charged into the tank and mixed until
uniform. The solution is stored at 2-8.degree. C. until
encapsulation. 1.0 g of the solution is filled into each soft
gelatin capsule (die: 18 oblong [18BE]; gel: 005L2DDXHB-EP; gel
dyes: white 920P). The soft gelatin capsules are then dried, and
stored at 2-8.degree. C.
Example 10
Preparation of ABT-378/Norvir.RTM. (133.3/33.3 mg) Soft Gelatin
Capsules
[0097] The following protocol is employed in the preparation of
1000 soft gelatin capsules: TABLE-US-00004 Scale Amount
(mg/capsule) Name (g) Q.S. Nitrogen, N.F. Q.S. 578.6 Oleic Acid, NF
578.6 33.3 Ritonavir 33.3 64.1 Propylene Glycol, USP 64.1 4.3
Water, purified, USP (distilled) 4.3 133.3 ABT-378 133.3 10.0 Oleic
Acid, NF 10.0 21.4 Polyoxyl 35 Castor Oil, NF 21.4 10.0 Oleic Acid,
NF 10.0
[0098] A mixing tank and suitable container are purged with
nitrogen. 578.6 g of oleic acid is then charged into the mixing
tank. The mixing tank is heated to 28.degree. C. (not to exceed
31.degree. C.) and mixing is started. 33.3 g of ritonavir is then
added to the oleic acid with mixing. The propylene glycol and water
are added to the mixing tank, and mixing is continued until the
solution is clear. 133.3 g of ABT-378 is then added into the mixing
tank, and mixing is continued. 10 g of oleic acid is then charged
into the tank and mixed until the solution is clear. 21.4 g of
polyoxy 35 Castor Oil, NF is added to the mixing tank, and mixing
is continued, followed by the addition of 10 g of Oleic Acid. NF. A
sample is collected, and the solution is stored at 2-8.degree. C.
until encapsulation. 0.855 (+/13%) g of the solution is filled into
each soft gelatin capsule (die: 12BF; gel: L1.25DDXHBHM-EP; gel
dye: Orange 419T-EP). The soft gelatin capsules are then inspected
and cleaned, and stored at 2-8.degree. C.
Example 11
Protocol for Oral Bioavailability
[0099] Dogs (beagle dogs, mixed sexes, weighing 7-14 kg) were
fasted overnight prior to dosing, but were permitted water ad
libitum. Each dog received a 100 .mu.g/kg subcutaneous dose of
histamine approximately 30 minutes prior to dosing. Each dog
received a single dosage form corresponding to a 5 mg/kg dose of
the drug. The dose was followed by approximately 10 milliliters of
water. Blood samples were obtained from each animal prior to dosing
and 0.25, 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours after drug
administration. The plasma was separated from the red cells by
centrifugation and frozen (-30.degree. C.) until analysis.
Concentrations of parent drug were determined by reverse phase HPLC
with low wavelength UV detection following liquid-liquid extraction
of the plasma samples. The parent drug area under the curve was
calculated by the trapezoidal method over the time course of the
study. The absolute bioavailability of each test composition was
calculated by comparing the area under the curve after oral dosing
to that obtained from a single intravenous dose. Each capsule or
capsule composition was evaluated in a group containing at least
six dogs; the values reported are averages for each group of
dogs.
* * * * *