U.S. patent application number 10/047222 was filed with the patent office on 2003-03-06 for pharmaceutical composition having reduced tendency for drug crystallization.
Invention is credited to Dalga, Robert J., Forbes, James C., Gao, Ping, Hageman, Michael J., Hassan, Fred, Huang, Tiehua, Karim, Aziz, Morozowich, Walter, Stefanski, Kevin J..
Application Number | 20030045563 10/047222 |
Document ID | / |
Family ID | 26949305 |
Filed Date | 2003-03-06 |
United States Patent
Application |
20030045563 |
Kind Code |
A1 |
Gao, Ping ; et al. |
March 6, 2003 |
Pharmaceutical composition having reduced tendency for drug
crystallization
Abstract
An orally deliverable pharmaceutical composition is provided
comprising a drug of low water solubility, a solvent liquid that
comprises at least one pharmaceutically acceptable solvent, and a
turbidity-decreasing polymer, wherein (a) a substantial portion,
for example at least about 15% by weight, of the drug is in
dissolved or solubilized form in the solvent liquid, and (b) the
polymer is present in an amount sufficient to substantially inhibit
crystallization and/or precipitation of the drug in simulated
gastric fluid.
Inventors: |
Gao, Ping; (Portage, MI)
; Hageman, Michael J.; (Portage, MI) ; Morozowich,
Walter; (Kalamazoo, MI) ; Dalga, Robert J.;
(Kalamazoo, MI) ; Stefanski, Kevin J.; (Kalamazoo,
MI) ; Huang, Tiehua; (Kalamazoo, MI) ; Karim,
Aziz; (Skokie, IL) ; Hassan, Fred; (Peapack,
NJ) ; Forbes, James C.; (Glenview, IL) |
Correspondence
Address: |
Pharmacia Corporation
Patent Department
800 N. Lindbergh Boulevard-04E
St. Louis
MO
63167
US
|
Family ID: |
26949305 |
Appl. No.: |
10/047222 |
Filed: |
January 15, 2002 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60262555 |
Jan 18, 2001 |
|
|
|
60284608 |
Apr 17, 2001 |
|
|
|
Current U.S.
Class: |
514/406 ;
514/341; 514/602; 514/709 |
Current CPC
Class: |
A61K 31/415 20130101;
A61K 31/365 20130101; A61K 9/1075 20130101; A61K 31/42 20130101;
A61K 31/50 20130101; A61P 25/04 20180101; A61K 9/4816 20130101;
A61K 31/337 20130101; A61K 31/122 20130101; A61P 29/00 20180101;
A61P 43/00 20180101; A61K 31/00 20130101; A61P 25/06 20180101; A61K
9/4858 20130101; A61K 31/444 20130101; A61K 31/52 20130101; A61K
31/352 20130101; A61K 9/4866 20130101; B82Y 5/00 20130101; A61K
31/52 20130101; A61K 31/42 20130101; A61K 31/52 20130101; A61K
31/415 20130101; A61K 31/52 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/406 ;
514/341; 514/602; 514/709 |
International
Class: |
A61K 031/415; A61K
031/44; A61K 031/4439; A61K 031/18; A61K 031/10 |
Claims
What is claimed is:
1. An orally deliverable pharmaceutical composition comprising (a)
a drug of low water solubility; (b) a pharmaceutically acceptable
solvent liquid; and (c) a turbidity-decreasing polymer; wherein at
least a substantial portion of the drug is in dissolved or
solubilized form in the solvent liquid, and wherein said polymer is
present in an amount sufficient to substantially inhibit
crystallization and/or precipitation of the drug in simulated
gastric fluid.
2. The composition of claim 1 wherein the drug is present in a
therapeutically effective amount.
3. The composition of claim 1 wherein the drug is present in a
total amount of about 1% to about 75% by weight of the
composition.
4. The composition of claim 1 wherein at least about 15% of the
drug is present in the solvent liquid in dissolved or solubilized
form.
5. The composition of claim 1 wherein substantially all of the drug
is present in the solvent liquid in dissolved or solubilized
form.
6. The composition of claim 1 wherein the drug is a selective
cyclooxygenase-2 inhibitory drug.
7. The composition of claim 6 wherein the selective
cyclooxygenase-2 inhibitory drug is a compound having the formula
7where R.sup.3 is a methyl or amino group, R.sup.4 is hydrogen or a
C.sub.1-4 alkyl or alkoxy group, X is N or CR.sup.5 where R.sup.5
is hydrogen or halogen, and Y and Z are independently carbon or
nitrogen atoms defining adjacent atoms of a five- to six-membered
ring that is unsubstituted or substituted at one or more positions
with oxo, halo, methyl or halomethyl groups; or a prodrug of such a
compound.
8. The composition of claim 7 wherein the five- to six-membered
ring is selected from cyclopentenone, furanone, methylpyrazole,
isoxazole and pyridine rings substituted at no more than one
position.
9. The composition of claim 6 wherein the selective
cyclooxygenase-2 inhibitory drug is selected from the group
consisting of celecoxib, deracoxib, valdecoxib, rofecoxib,
etoricoxib, 2-(3,5-difluorophenyl)-3-[4-
-(methylsulfonyl)phenyl]-2-cyclopenten-1-one,
(S)-6,8-dichloro-2-(trifluor- omethyl)-2H-1-benzopyran-3-carboxylic
acid and 2-(3,4-difluorophenyl)-4-(3-
-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3-(2H)-pyridazino-
ne.
10. The composition of claim 9 wherein the selective
cyclooxygenase-2 inhibitory drug is celecoxib.
11. The composition of claim 10 that comprises one or more dose
units each comprising about 10 mg to about 1000 mg of
celecoxib.
12. The composition of claim 10 that comprises one or more dose
units each comprising about 50 mg to about 400 mg of celecoxib.
13. The composition of claim 9 wherein the drug is valdecoxib.
14. The composition of claim 1 wherein the turbidity-decreasing
polymer is selected from the group consisting of
polyvinylpyrrolidone and cellulosic polymers.
15. The composition of claim 1 wherein the turbidity-decreasing
polymer is a cellulosic polymer selected from the group consisting
of sodium carboxymethylcellulose, hydroxypropylmethylcellulose,
methylcellulose, hydroxypropylcellulose and ethylcellulose.
16. The composition of claim 15 wherein the cellulosic polymer is
hydroxypropylmethylcellulose.
17. The composition of claim 16 wherein the
hydroxypropylmethylcellulose has about 15% to about 35% methoxyl
substitution and about 3% to about 15% hydroxypropoxyl
substitution.
19. The composition of claim 16 wherein the
hydroxypropylmethylcellulose has about 19% to about 30% methoxyl
substitution and about 4% to about 12% hydroxypropoxyl
substitution.
20. The composition of claim 16 wherein the
hydroxypropylmethylcellulose has about 19% to about 24% methoxyl
substitution and about 7% to about 12% hydroxypropoxyl
substitution.
21. The composition of claim 6 further comprising a vasomodulator,
wherein the selective cyclooxygenase-2 inhibitory drug and the
vasomodulator are present in total and relative amounts effective
to relieve pain in headache or migraine.
22. The composition of claim 6 further comprising an alkylxanthine
compound, wherein the selective cyclooxygenase-2 inhibitory drug
and the alkylxanthine compound are present in total and relative
amounts effective to relieve pain in headache or migraine.
23. The composition of claim 22 where in the alkylxanthine compound
is selected from the group consisting of caffeine, theophylline and
theobromine.
24. The composition of claim 22 wherein the alkylxanthine compound
is caffeine.
25. The composition of claim 1 wherein the turbidity-decreasing
polymer is present in the solvent liquid in an amount of about 1%
to about 20% by weight of the solvent liquid.
26. The composition of claim 1 wherein the turbidity-decreasing
polymer is present in the solvent liquid in an amount of about 1%
to about 15% by weight of the solvent liquid.
27. The composition of claim 1 that is an imbibable liquid.
28. The composition of claim 1 further comprising a water-soluble
capsule wall wherein the drug and solvent liquid are
encapsulated.
29. The composition of claim 28 wherein the turbidity-decreasing
polymer is present in the capsule wall in an amount of about 5% to
about 100% by weight of the wall.
30. The composition of claim 28 wherein the turbidity-decreasing
polymer is present in the capsule wall in an amount of about 15% to
about 100% by weight of the wall.
31. The composition of claim 1 wherein the solvent liquid comprises
a solvent selected from the group consisting of pharmaceutically
acceptable glycols and glycol ethers.
32. The composition of claim 31 wherein the solvent is polyethylene
glycol.
33. The composition of claim 32 wherein the polyethylene glycol has
an average molecular weight of about 100 to about 10,000.
34. The composition of claim 32 wherein the polyethylene glycol has
an average molecular weight of about 100 to about 1,000.
35. The composition of claim 32 wherein the polyethylene glycol has
an average molecular weight of about 375 to about 450.
36. The composition of claim 32 wherein the polyethylene glycol is
of liquid grade.
37. An orally deliverable pharmaceutical composition comprising (a)
a drug of low water solubility; (b) a pharmaceutically acceptable
solvent liquid; and (c) a cellulosic polymer; wherein at least a
substantial portion of the drug is in dissolved or solubilized form
in the solvent liquid, and wherein said cellulosic polymer is
present in an amount sufficient to substantially inhibit
crystallization and/or precipitation of the drug in simulated
gastric fluid.
38. The composition of claim 37 wherein the drug is present in a
therapeutically effective amount.
39. The composition of claim 37 wherein the drug is present in a
total amount of about 1% to about 75% by weight of the
composition.
40. The composition of claim 37 wherein at least about 15% of the
drug is present in the solvent liquid in dissolved or solubilized
form.
41. The composition of claim 37 wherein substantially all of the
drug is present in the solvent liquid in dissolved or solubilized
form.
42. The composition of claim 37 wherein the drug is a selective
cyclooxygenase-2 inhibitory drug.
43. The composition of claim 42 wherein the selective
cyclooxygenase-2 inhibitory drug is a compound having the formula
8where R.sup.3 is a methyl or amino group, R.sup.4 is hydrogen or a
C.sub.1-4 alkyl or alkoxy group, X is N or CR.sup.5 where R.sup.5
is hydrogen or halogen, and Y and Z are independently carbon or
nitrogen atoms defining adjacent atoms of a five- to six-membered
ring that is unsubstituted or substituted at one or more positions
with oxo, halo, methyl or halomethyl groups; or a prodrug of such a
compound.
44. The composition of claim 43 wherein the five- to six-membered
ring is selected from cyclopentenone, furanone, methylpyrazole,
isoxazole and pyridine rings substituted at no more than one
position.
45. The composition of claim 42 wherein the selective
cyclooxygenase-2 inhibitory drug is selected from the group
consisting of celecoxib, deracoxib, valdecoxib, rofecoxib,
etoricoxib, 2-(3,5-difluorophenyl)-3-[4-
-(methylsulfonyl)phenyl]-2-cyclopenten-1-one,
(S)-6,8-dichloro-2-(trifluor- omethyl)-2H-1benzopyran-3-carboxylic
acid and 2-(3,4-difluorophenyl)-4-(3--
hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3-(2H)-pyridazinon-
e.
46. The composition of claim 45 wherein the selective
cyclooxygenase-2 inhibitory drug is celecoxib.
47. The composition of claim 46 that comprises one or more dose
units each comprising about 10 mg to about 1000 mg of
celecoxib.
48. The composition of claim 46 that comprises one or more dose
units each comprising about 50 mg to about 400 mg of celecoxib.
50. The composition of claim 45 wherein the drug is valdecoxib.
51. The composition of claim 37 wherein the cellulosic polymer is
selected from the group consisting of sodium
carboxymethylcellulose, hydroxypropylmethylcellulose,
methylcellulose, hydroxypropylcellulose, and ethylcellulose.
52. The composition of claim 37 wherein the cellulosic polymer is
hydroxypropylmethylcellulose.
53. The composition of claim 52 wherein the
hydroxypropylmethylcellulose has about 15% to about 35% methoxyl
substitution and about 3% to about 15% hydroxypropoxyl
substitution.
54. The composition of claim 52 wherein the
hydroxypropylmethylcellulose has about 19% to about 30% methoxyl
substitution and about 4% to about 12% hydroxypropoxyl
substitution.
55. The composition of claim 52 wherein the
hydroxypropylmethylcellulose has about 19% to about 24% methoxyl
substitution and about 7% to about 12% hydroxypropoxyl
substitution.
56. The composition of claim 42 further comprising a vasomodulator,
wherein the selective cyclooxygenase-2 inhibitory drug and the
vasomodulator are present in total and relative amounts effective
to relieve pain in headache or migraine.
57. The composition of claim 42 further comprising an alkylxanthine
compound, wherein the selective cyclooxygenase-2 inhibitory drug
and the alkylxanthine compound are present in total and relative
amounts effective to relieve pain in headache or migraine.
58. The composition of claim 57 wherein the alkylxanthine compound
is selected from the group consisting of caffeine, theophylline and
theobromine.
59. The composition of claim 58 wherein the alkylxanthine compound
is caffeine.
60. The composition of claim 37 wherein the cellulosic polymer is
present in the solvent liquid in an amount of about 1% to about 20%
by weight of the solvent liquid.
61. The composition of claim 37 wherein the cellulosic polymer is
present in the solvent liquid in an amount of about 1% to about 15%
by weight of the solvent liquid.
62. The composition of claim 37 that is an imbibable liquid.
63. The composition of claim 37 further comprising a water-soluble
capsule wall wherein the drug and solvent liquid are
encapsulated.
64. The composition of claim 63 wherein the cellulosic polymer is
present in the capsule wall in an amount of about 5% to about 100%
by weight of the wall.
65. The composition of claim 63 wherein the cellulosic polymer is
present in the capsule wall in an amount of about 15% to about 100%
by weight of the wall.
66. The composition of claim 37 wherein the solvent liquid
comprises a solvent selected from the group consisting of
pharmaceutically acceptable glycols and glycol ethers.
67. The composition of claim 66 wherein the solvent is polyethylene
glycol.
68. The composition of claim 67 wherein the polyethylene glycol has
an average molecular weight of about 100 to about 10,000.
69. The composition of claim 67 wherein the polyethylene glycol has
an average molecular weight of about 100 to about 1,000.
70. The composition of claim 67 wherein the polyethylene glycol has
an average molecular weight of about 375 to about 450.
71. The composition of claim 67 wherein the polyethylene glycol is
of liquid grade.
72. An orally deliverable pharmaceutical composition comprising a
drug of low water solubility in a high energy phase together with
one or more pharmaceutically acceptable excipients, encapsulated
within a capsule wall that comprises a turbidity-decreasing polymer
in an amount effective to substantially inhibit crystallization
and/or precipitation of the drug in simulated gastric fluid.
73. The composition of claim 72 wherein the drug is a selective
cyclooxygenase-2 inhibitory drug.
74. The composition of claim 73 wherein the selective
cyclooxygenase-2 inhibitory drug is selected from the group
consisting of celecoxib, deracoxib, valdecoxib, rofecoxib,
etoricoxib, 2-(3,5-difluorophenyl)-3-[4-
-(methylsulfonyl)phenyl]-2-cyclopenten-1-one,
(S)-6,8-dichloro-2-(trifluor- omethyl)-2H-1-benzopyran-3-carboxylic
acid and 2-(3,4-difluorophenyl)-4-(3-
-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3-(2H)-pyridazino-
ne.
75. The composition of claim 74 wherein the selective
cyclooxygenase-2 inhibitory drug is celecoxib.
76. The composition of claim 72 wherein said high energy phase is
an amorphous phase of the drug.
77. The composition of claim 72 wherein said high energy phase is a
salt of an acid or base form of the drug.
78. The composition of claim 72 wherein the turbidity-decreasing
polymer is a cellulosic polymer.
79. The composition of claim 78 wherein the cellulosic polymer is
selected from the group consisting of sodium
carboxymethylcellulose, hydroxypropylmethylcellulose,
methylcellulose, hydroxypropylcellulose, and ethylcellulose.
80. The composition of claim 78 wherein the cellulosic polymer is
hydroxypropylmethylcellulose.
81. The composition of claim 80 wherein the
hydroxypropylmethylcellulose has about 15% to about 35% methoxyl
substitution and about 3% to about 15% hydroxypropoxyl
substitution.
82. The composition of claim 80 wherein the
hydroxypropylmethylcellulose has about 19% to about 30% methoxyl
substitution and about 4% to about 12% hydroxypropoxyl
substitution.
83. The composition of claim 80 wherein the
hydroxypropylmethylcellulose has about 19% to about 24% methoxyl
substitution and about 7% to about 12% hydroxypropoxyl
substitution.
84. The composition of claim 72 wherein the turbidity-decreasing
polymer is present in the capsule wall in an amount of about 5% to
about 100% by weight of the wall.
85. The composition of claim 72 wherein the turbidity-decreasing
polymer is present in the capsule wall in an amount of about 15% to
about 100% by weight of the wall.
86. A method of treating a medical condition or disorder in a
subject where treatment with a cyclooxygenase-2 inhibitor is
indicated, comprising orally administering to the subject a
composition of claim 6, claim 42, or claim 73.
87. A method of analgesia comprising orally administering, to a
subject in need of analgesia, an effective pain-relieving amount of
a composition of claim 6, claim 42, or claim 73.
88. The method of claim 87 wherein the subject suffers from
headache or migraine and wherein there is further orally
administered to the subject a vasomodulator, the selective
cyclooxygenase-2 inhibitory drug and the vasomodulator being
administered in total and relative amounts effective to relieve
pain in the headache or migraine.
89. The method of claim 88 wherein the vasomodulator is
co-formulated with the selective cyclooxygenase-2 inhibitory
drug.
90. The method of claim 87 wherein the subject suffers from
headache or migraine and wherein there is further orally
administered to the subject an alkylxanthine compound, the
selective cyclooxygenase-2 inhibitory drug and the alkylxanthine
compound being administered in total and relative amounts effective
to relieve pain in the headache or migraine.
91. The method of claim 90 wherein the alkylxanthine compound is
co-formulated with the selective cyclooxygenase-2 inhibitory
drug.
92. The method of claim 91 wherein the alkylxanthine compound is
selected from the group consisting of caffeine, theophyline, and
theobromine.
93. The method of claim 91 wherein the alkylxanthine compound is
caffeine.
Description
[0001] This application claims priority of U.S. provisional
application Serial No. 60/262,555 filed on Jan. 18, 2001 and of
U.S. provisional application Serial No. 60/284,608 filed on Apr.
17, 2001.
FIELD OF THE INVENTION
[0002] The present invention relates to orally deliverable
pharmaceutical compositions that comprise a drug of low water
solubility, more particularly to such compositions where the drug
is in dissolved form.
BACKGROUND OF THE INVENTION
[0003] Liquid dosage forms, for example solutions suitable for oral
administration, have become an important method by which drugs are
delivered to subjects, particularly where rapid onset of
therapeutic effect is desired. As an alternative to directly
imbibable liquid formulations of a drug, it is also known to
encapsulate liquid formulations, for example in soft or hard
gelatin capsules, to provide a discrete dosage form.
[0004] Unfortunately, many useful drugs have low solubility in
water and, therefore, are difficult to formulate at convenient
concentrations as solutions in an aqueous vehicle. Even when a
suitable solvent is found as a vehicle for such a drug, there is
often a tendency, particularly for a crystalline drug of low water
solubility, to precipitate out of solution and/or crystallize when
the drug comes in contact with water, for example in the aqueous
environment of the gastrointestinal tract. Such precipitation
and/or re-crystallization can offset or reduce the potential rapid
onset benefits sought by formulating the drug as a solution.
[0005] It is known to provide liquid dosage forms, including
encapsulated liquid dosage forms, of poorly water-soluble drugs as
self-emulsifying formulations. These formulations are generally
designed to form an emulsion, in some cases a microemulsion, when
mixed with gastrointestinal fluid. Even with a self-emulsifying
formulation, however, certain drugs still have a tendency to
precipitate and/or crystallize in gastrointestinal fluid.
[0006] Accordingly there remains a need in the art for a means to
inhibit precipitation and/or crystallization in gastrointestinal
fluid of a poorly water-soluble drug, and in particular for such a
means that can be incorporated in a self-emulsifying liquid dosage
form.
[0007] An illustrative class of drugs for which this need is
apparent is the class of selective cyclooxygenase-2 (COX-2)
inhibitory drugs of low water solubility.
[0008] Numerous compounds have been reported having therapeutically
and/or prophylactically useful selective COX-2 inhibitory effect,
and have been disclosed as having utility in treatment or
prevention of specific COX-2 mediated disorders or of such
disorders in general. Among such compounds are a large number of
substituted pyrazolyl benzenesulfonamides as reported in U.S. Pat.
No. 5,466,823 to Talley et al., including for example the compound
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-
-1-yl]benzenesulfonamide, also referred to herein as celecoxib (I),
and the compound
4-[5-(3-fluoro-4-methoxyphenyl)-3-difluoromethyl)-11H-pyrazo-
l-1-yl]benzenesulfonamide, also referred to herein as deracoxib
(II). 1
[0009] Other compounds reported to have therapeutically and/or
prophylactically useful selective COX-2 inhibitory effect are
substituted isoxazolyl benzenesulfonamides as reported in U.S. Pat.
No. 5,633,272 to Talley et al., including the compound
4-[5-methyl-3-phenylisoxazol-4-yl]b- enzenesulfonamide, also
referred to herein as valdecoxib (III). 2
[0010] Still other compounds reported to have therapeutically
and/or prophylactically useful selective COX-2 inhibitory effect
are substituted (methylsulfonyl)phenyl furanones as reported in
U.S. Pat. No. 5,474,995 to Ducharme et al., including the compound
3-phenyl-4-[4-(methylsulfonyl)- phenyl]-5H-furan-2-one, also
referred to herein as rofecoxib (IV). 3
[0011] U.S. Pat. No. 5,981,576 to Belley et al. discloses a further
series of (methylsulfonyl)phenyl furanones said to be useful as
selective COX-2 inhibitory drugs, including
3-(1-cyclopropylmethoxy)-5,5-dimethyl-4-[4-(m-
ethylsulfonyl)phenyl]-5H-furan-2-one and
3-(1-cyclopropylethoxy)-5,5-dimet-
hyl-4-[4-(methylsulfonyl)phenyl]-5H-furan-2-one.
[0012] U.S. Pat. No. 5,861,419 to Dube et al. discloses substituted
pyridines said to be useful as selective COX-2 inhibitory drugs,
including for example the compound
5-chloro-3-(4-methylsulfonyl)phenyl-2--
(2-methyl-5-pyridinyl)pyridine, also referred to herein as
etoricoxib (V). 4
[0013] European Patent Application No. 0 863 134 discloses the
compound
2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one
said to be useful as a selective COX-2 inhibitory drug.
[0014] U.S. Pat. No. 6,034,256 to Carter et al. discloses a series
of benzopyrans said to be useful as selective COX-2 inhibitory
drugs, including the compound
(S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyr- an-3-carboxylic
acid (VI). 5
[0015] International Patent Publication No. WO 00/24719 discloses
substituted pyridazinones said to be useful as selective COX-2
inhibitory drugs, including the compound
2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methy-
l-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3-(2H)-pyridazinone.
[0016] A need for formulated compositions of selective COX-2
inhibitory drugs, particularly rapid-onset compositions of such
drugs, exists. Rapid-onset drug delivery systems can provide many
benefits over conventional dosage forms. Generally, rapid-onset
preparations provide a more immediate therapeutic effect than
standard dosage forms. For example, in the treatment of acute pain,
for example in headache or migraine, rapid-onset dosage forms would
be useful to provide fast pain relief.
[0017] Australian Patent Applications No. 200042711, No. 200043730
and No. 200043736 disclose compositions comprising a selective
COX-2 inhibitory drug, a 5HT.sub.1 receptor agonist and caffeine,
said to be useful for treating migraine.
[0018] U.S. Pat. No. 5,993,858 to Crison & Amidon discloses an
excipient formulation for increasing bioavailability of a poorly
water-soluble drug. The formulation is said to be
self-microemulsifying and to comprise an oil or other lipid
material, a surfactant and a hydrophilic co-surfactant. The choice
of surfactant is said to be less critical than the choice of
co-surfactant, which reportedly should have an HLB
(hydrophilic-lipophilic balance) number greater than 8. A preferred
example of such a co-surfactant is said to be Labrasol.TM. of
Gattefoss, identified as a product "comprised of medium-chain
triglycerides derived from coconut oil" having HLB of 14. A
formulation prepared containing 15 mg nifedipine in a size 1 (0.5
ml) capsule, i.e., at a concentration of 30 mg/ml, is described as
a "clear solution" at 70.degree. C. but a "semi-solid" at room
temperature.
[0019] Cited in above-referenced U.S. Pat. No. 5,993,858 is prior
work by Farah et al. in which a self-microemulsifying formulation
was investigated for improving in vitro dissolution of
indomethacin. The formulation of Farah et al. reportedly comprised
an oil phase material Gelucire.TM. of Gattefoss Corporation,
together with a polyethylene glycol capric/caprylic glyceride
product having HLB of 10, a propylene glycol laurate product having
HLB of 4, and diethylene glycol monoethyl ether.
[0020] Drugs of low water solubility are sometimes orally
administered in suspension in an imbibable aqueous liquid. For
example, a suspension of particulate celecoxib in a vehicle of
apple juice is disclosed in co-assigned International Patent
Publication No. WO 00/32189, incorporated herein by reference. Also
disclosed therein is a dilute solution of celecoxib in a mixture of
PEG-400 (polyethylene glycol having an average molecular weight of
about 400) and water in a 2:1 ratio by volume.
[0021] The suspension and solution compositions of WO 00/32189 are
indicated therein to have comparable bioavailability. However,
following oral administration to dogs, the time taken for blood
serum celecoxib concentration to reach a maximum level (T.sub.max)
was shorter for the solution composition than for the
suspension.
[0022] Above-cited U.S. Pat. No. 5,760,068 discloses that its
subject pyrazolyl benzenesulfonamide compounds, of which celecoxib
and deracoxib are examples, can be administered parenterally as
isotonic solutions in a range of solvents including polyethylene
glycol and propylene glycol. It is also disclosed therein that the
subject compounds can alternatively be present in a
controlled-release capsule or tablet formulation for oral
administration wherein, for example, such a compound is dispersed
in hydroxypropylmethylcellulose (HPMC).
[0023] Above-cited U.S. Pat. No. 5,633,272 discloses that its
subject isoxazolyl benzenesulfonamides, of which valdecoxib is an
example, can be administered parenterally as isotonic solutions in
a range of solvents including polyethylene glycol and propylene
glycol. It is also disclosed therein that the subject compounds can
alternatively be present in a controlled-release capsule or tablet
formulation for oral administration wherein, for example, such a
compound is dispersed in HPMC.
[0024] Above-cited U.S. Pat. No. 5,474,995 discloses that its
subject (methylsulfonyl)phenyl furanones, of which rofecoxib is an
example, can be administered parenterally in an isotonic solution
in 1,3-butanediol. Also disclosed therein are oil-in-water
emulsions, syrups and elixirs for oral administration, formulated
with a sweetening agent such as propylene glycol, and aqueous
suspensions formulated with suspending agents including
methylcellulose and HPMC.
[0025] Above-cited U.S. Pat. No. 5,861,419 discloses that its
subject substituted pyridines, of which etoricoxib is an example,
can be administered parenterally in an isotonic solution in
1,3-butanediol. Also disclosed therein are oil-in-water emulsions,
syrups and elixirs for oral administration, formulated with a
sweetening agent such as propylene glycol, and aqueous suspensions
formulated with suspending agents including methylcellulose and
HPMC.
[0026] Many selective COX-2 inhibitory compounds, including
celecoxib, deracoxib, valdecoxib, rofecoxib and etoricoxib, have
low solubility in aqueous media. In addition, some, for example
celecoxib, have relatively high dose requirements. These properties
present practical problems in formulating concentrated solutions of
selective COX-2 inhibitory drugs for rapid-onset, oral
administration. With respect to such high dose, low solubility
drugs, the size of the capsule or volume of solution required to
provide a therapeutic dose becomes a limiting factor. For example,
a drug that has a solubility of 10 mg/ml in a given solvent and a
therapeutic dose of 400 mg/day would require ingestion of 40 ml of
solution. Such a volume can be inconvenient or unacceptable for
consumption in imbibable form; this volume also presents particular
problems where an encapsulated dosage form is desired because
capsules that contain more than about 1.0 ml to about 1.5 ml of
liquid are generally considered to be too large for comfortable
swallowing. Thus, where a solution is administered in capsule form,
multiple capsules would need to be ingested in order to provide the
required dose. To avoid such problems, a solvent must be selected
wherein the drug has relatively high solubility.
[0027] As described hereinbelow, treatment with selective COX-2
inhibitory drugs of low water solubility is indicated in a very
wide array of COX-2 mediated disorders and conditions. Therefore,
if the problem of precipitation or crystallization in
gastrointestinal fluid from a solution formulation, for example a
self-emulsifying formulation, could be overcome, a significant
advance would be realized in treatment of COX-2 mediated conditions
and disorders, particularly in treatment of acute disorders where
early relief from pain or other symptoms is desired. It would
represent an especially important advance in the art to provide an
effective method of treatment of acute pain, for example in
headache or migraine, using such a formulation.
SUMMARY OF THE INVENTION
[0028] There is now provided an orally deliverable pharmaceutical
composition comprising a drug of low water solubility, a solvent
liquid that comprises at least one pharmaceutically acceptable
solvent, and a turbidity-decreasing polymer. In a preferred
embodiment, the polymer is a cellulosic polymer having at least a
portion of substitutable hydroxyl groups substituted by methoxyl
and/or hydroxypropoxyl groups, wherein (a) a substantial portion,
for example at least about 15% by weight, of the drug is in
dissolved or solubilized form in the solvent liquid, and (b) the
polymer is present in an amount sufficient to substantially inhibit
crystallization and/or precipitation of the drug in simulated
gastric fluid.
[0029] Whether a given polymer is a "turbidity-decreasing polymer"
herein can be determined according to Test I described
hereinbelow.
[0030] The term "solvent liquid" herein encompasses all of the
components of the liquid medium in which a particular drug is
dissolved or solubilized, with the exception of a polymer component
as defined above. Thus the "solvent liquid" includes not only one
or more solvents but optionally additional excipients such as
co-solvents, surfactants, co-surfactants, antioxidants, sweeteners,
flavoring agents, colorants, etc.
[0031] In a presently preferred composition of the invention,
substantially all of the drug is in dissolved or solubilized form
in the solvent liquid and substantially none of the drug is in
solid particulate form. Such a composition is referred to herein as
a "solution". It is particularly preferred that the solution is
finely self-emulsifiable in simulated gastric fluid, as described
hereinbelow.
[0032] An alternative composition of the invention comprises, in
addition to a first portion of the drug in dissolved or solubilized
form, a second portion of the drug in particulate form dispersed in
the solvent liquid. In this embodiment, part of the drug is in
solution and part is in suspension. Such a composition is referred
to herein as a "solution/suspension".
[0033] "Simulated gastric fluid", abbreviated herein to "SGF", is
an aqueous solution of 0.01M hydrochloric acid and 0.15M sodium
chloride, having a pH of about 2.
[0034] In a presently preferred embodiment, the solution or
solution/suspension is encapsulated in one or more capsules having
a wall that breaks down in gastrointestinal fluid to release the
drug within a short period of time after entry into the
gastrointestinal tract.
[0035] The turbidity-decreasing polymer as defined herein is
sometimes herein referred to as a "crystallization inhibitor". This
crystallization inhibitor can be present (a) in solution or
suspension in the solvent liquid, and/or (b) as a component of a
capsule wall.
[0036] In one embodiment, there is provided an orally deliverable
pharmaceutical composition comprising a finely self-emulsifiable
liquid formulation of a drug of low water solubility, encapsulated
within a capsule wall that comprises a turbidity-decreasing
polymer, preferably a turbidity-decreasing cellulosic polymer
having at least a portion of substitutable hydroxyl groups
substituted by methoxyl and/or hydroxypropoxyl groups, in an amount
effective to substantially inhibit crystallization and/or
precipitation of the drug in simulated gastric fluid. Preferably
the capsule wall consists predominantly of a turbidity-decreasing
cellulosic polymer, for example HPMC.
[0037] This embodiment can be seen to be part of a broader
embodiment of the invention, according to which there is provided
an orally deliverable pharmaceutical composition comprising a drug
of low water solubility in a high energy phase together with one or
more pharmaceutically acceptable excipients, encapsulated within a
capsule wall that comprises a turbidity-decreasing polymer,
preferably a turbidity-decreasing cellulosic polymer having at
least a portion of substitutable hydroxyl groups substituted by
methoxyl and/or hydroxypropoxyl groups, in an amount effective to
substantially inhibit crystallization and/or precipitation of the
drug in simulated gastric fluid.
[0038] A "high energy phase" herein is any form of the drug,
including solids, salts of bases or acids, semi-solids and liquids,
that exhibits a more rapid dissolution rate and/or a greater
tendency for supersaturation in an aqueous medium than the most
thermodynamically stable crystalline form of the drug. Thus in this
embodiment, the drug can be in any high energy phase, for example
in a solid state particulate form other than the lowest energy
crystalline form (e.g., in amorphous form).
[0039] Compositions of the invention are illustratively useful
where the drug is a selective COX-2 inhibitory drug, and have been
found to resolve at least some of the difficulties alluded to above
in a surprisingly effective manner. Thus, according to the
invention, a drug of low water solubility is now presented in a
high energy phase, for example in a finely self-emulsifiable
solution formulation, with greatly reduced tendency to precipitate
and/or crystallize upon release into gastrointestinal fluid, as
indicated for example by in vitro release into SGF. Preferably such
formulations are presented in a dosage form that is convenient for
oral administration. Formulations of the invention are particularly
advantageous because they permit a high concentration of the drug,
are suitable for encapsulation and, following oral administration
thereof, can permit rapid absorption of the drug into the
bloodstream through inhibition of precipitation and/or
crystallization of the drug. By virtue of this rapid absorption,
formulations of the invention can provide rapid onset of
therapeutic action.
[0040] It can be theorized that a poorly water-soluble drug can
provide more rapid onset of therapeutic effect when orally
administered in solution, particularly a self-emulsifiable
solution, than in particulate form because the process of
dissolution in the gastrointestinal tract is not required. An even
greater advantage by comparison with a solid formulation such as a
tablet can be postulated because neither disintegration nor
dissolution is required in the case of the solution
composition.
[0041] Additionally, a drug administered in imbibable solution can
be available for absorption higher in the alimentary tract, for
example, in the mouth and esophagus, than one that becomes
available for absorption only upon disintegration of the carrier
formulation in the stomach or bowel.
[0042] A further advantage of liquid dosage forms such as imbibable
solutions and solution/suspensions for many subjects is that these
dosage forms are easy to swallow. A yet further advantage of
imbibable liquid dosage forms is that metering of doses is
continuously variable, providing infinite dose flexibility. The
benefits of ease of swallowing and dose flexibility are
particularly advantageous for infants, children and the
elderly.
[0043] When encapsulated, a solution or solution/suspension can
provide the subject with the beneficial rapid absorption
characteristics associated with liquid formulations in addition to
the convenience of a discrete, easy to swallow capsule form.
[0044] The highly concentrated solutions permitted by the present
invention are beneficial for several reasons. First, concentrated
solutions are less costly to package and easier to transport and
handle than dilute solutions. Second, concentrated solutions
provide flexibility in administration as they can be administered
with any desired degree of dilution. And third, concentrated drug
solutions, especially when encapsulated, do not require consumption
of large volumes of fluid, which can be uncomfortable for many
patient populations.
[0045] In one embodiment, a method of analgesia is provided
comprising orally administering, to a subject in need of analgesia,
an effective pain-relieving amount of a selective COX-2 inhibitory
drug composition of the invention. In another embodiment, a method
of treatment and/or prevention of headache or migraine is provided
comprising orally administering, to a subject in need of such
treatment or prevention, a selective COX-2 inhibitory drug
composition of the invention and a vasomodulator, for example a
methylxanthine, wherein the selective COX-2 inhibitory drug and the
vasomodulator are administered in effective pain-relieving total
and relative amounts. The selective COX-2 inhibitory drug and the
vasomodulator can be administered as components of separate
compositions or of a single composition. Such a single composition
comprising (a) a selective COX-2 inhibitory drug, formulated as
provided herein, and (b) a vasomodulator, is a further embodiment
of the invention. A presently preferred methylxanthine is
caffeine.
[0046] Other features of this invention will be in part apparent
and in part pointed out hereinafter.
BRIEF DESCRIPTION OF THE DRAWINGS
[0047] FIG. 1 shows in vitro dissolution behavior in SGF of
celecoxib compositions SF-1A, SF-1B, and SF-1C of Example 2.
[0048] FIG. 2 shows in vitro dissolution behavior in SGF of
celecoxib compositions SF-2A and SF-3B of the invention by
comparison with celecoxib composition SF-3A, all as described in
Example 3.
[0049] FIG. 3 shows in vitro dissolution behavior in SGF of
celecoxib composition SF-4A of the invention by comparison with
celecoxib composition SF4B, both as described in Example 4.
[0050] FIG. 4 shows in vivo bioavailability of celecoxib after oral
administration of celecoxib test compositions SF-5A and SF-7A of
the invention by comparison with celecoxib composition SF-6A, all
as described in Example 5, to fasting dogs.
[0051] FIG. 5 shows in vitro dissolution behavior of comparative
paclitaxel solution formulation SF-8 and of solution formulation
SF-9 of the invention, both as described in Example 7, in SGF.
DETAILED DESCRIPTION OF THE INVENTION
[0052] Novel pharmaceutical compositions according to the present
invention comprise one or more orally deliverable dose units. The
term "orally deliverable" herein means suitable for oral
administration. The term "oral administration" herein includes any
form of delivery of a therapeutic agent or a composition thereof to
a subject wherein the agent or composition is placed in the mouth
of the subject, whether or not the agent or composition is
swallowed. Thus "oral administration" includes buccal and
sublingual as well as esophageal administration. Absorption of the
agent can occur in any part or parts of the gastrointestinal tract
including the mouth, esophagus, stomach, duodenum, jejunum, ileum
and colon. The term "dose unit" herein means a portion of a
pharmaceutical composition that contains an amount of a therapeutic
agent suitable for a single oral administration to provide a
therapeutic effect. Typically one dose unit, or a small plurality
(up to about 4) of dose units, provides a sufficient amount of the
agent to result in the desired effect.
[0053] Drug of Low Water Solubility
[0054] Each dose unit or small plurality of dose units comprises,
in a therapeutically and/or prophylactically effective total
amount, a drug of low water solubility. A "drug of low water
solubility" or "poorly water solubility drug" herein refers to any
drug compound having a solubility in water, measured at 37.degree.
C., not greater than about 10 mg/ml, and preferably not greater
than about 1 mg/ml. It is contemplated that compositions of the
invention are especially advantageous for drugs having a solubility
in water, measured at 37.degree. C., not greater than about 0.1
mg/ml.
[0055] Solubility in water for many drugs can be readily determined
from standard pharmaceutical reference books, for example
[0056] The Merck Index, 11th ed., 1989 (published by Merck &
Co., Inc., Rahway, N.J.); the United States Pharmacopoeia, 24th ed.
(USP 24), 2000; The Extra Pharmacopoeia, 29th ed., 1989 (published
by Pharmaceutical Press, London); and the Physicians Desk Reference
(PDR), 2001 ed. published by Medical Economics Co., Montvale,
N.J.), each of which is individually incorporated herein by
reference.
[0057] For example, individual drugs of low solubility as defined
herein include those drugs categorized as "slightly soluble", "very
slightly soluble", "practically insoluble" and "insoluble" in USP
24, pp. 2254-2298; and those drugs categorized as requiring 100 ml
or more of water to dissolve 1 g of the drug, as listed in USP 24,
pp. 2299-2304.
[0058] Illustratively, suitable drugs of low water solubility
include, without limitation, drugs from the following classes:
abortifacients, ACE inhibitors, .alpha.- and .beta.-adrenergic
agonists, .alpha.- and .beta.-adrenergic blockers, adrenocortical
suppressants, adrenocorticotropic hormones, alcohol deterrents,
aldose reductase inhibitors, aldosterone antagonists, anabolics,
analgesics (including narcotic and non-narcotic analgesics),
androgens, angiotensin II receptor antagonists, anorexics,
antacids, anthelminthics, antiacne agents, antiallergics,
antialopecia agents, antiamebics, antiandrogens, antianginal
agents, antiarrhythmics, antiarteriosclerotics,
antiarthritic/antirheumatic agents (including selective COX-2
inhibitors), antiasthmatics, antibacterials, antibacterial
adjuncts, anticholinergics, anticoagulants, anticonvulsants,
antidepressants, antidiabetics, antidiarrheal agents,
antidiuretics, antidotes to poison, antidyskinetics,
antieczematics, antiemetics, antiestrogens, antifibrotics,
antiflatulents, antifungals, antiglaucoma agents,
antigonadotropins, antigout agents, antihistaminics,
antihyperactives, antihyperlipoproteinemics,
antihyperphosphatemics, antihypertensives, antihyperthyroid agents,
antihypotensives, antihypothyroid agents, anti-inflammatories,
antimalarials, antimanics, antimethemoglobinemics, antimigraine
agents, antimuscarinics, antimycobacterials, antineoplastic agents
and adjuncts, antineutropenics, antiosteoporotics, antipagetics,
antiparkinsonian agents, antipheochromocytoma agents,
antipneumocystis agents, antiprostatic hypertrophy agents,
antiprotozoals, antipruritics, antipsoriatics, antipsychotics,
antipyretics, antirickettsials, antiseborrheics,
antiseptics/disinfectants, antispasmodics, antisyphylitics,
antithrombocythemics, antithrombotics, antitussives,
antiulceratives, antiurolithics, antivenins, antiviral agents,
anxiolytics, aromatase inhibitors, astringents, benzodiazepine
antagonists, bone resorption inhibitors, bradycardic agents,
bradykinin antagonists, bronchodilators, calcium channel blockers,
calcium regulators, carbonic anhydrase inhibitors, cardiotonics,
CCK antagonists, chelating agents, cholelitholytic agents,
choleretics, cholinergics, cholinesterase inhibitors,
cholinesterase reactivators, CNS stimulants, contraceptives,
debriding agents, decongestants, depigmentors, dermatitis
herpetiformis suppressants, digestive aids, diuretics, dopamine
receptor agonists, dopamine receptor antagonists,
ectoparasiticides, emetics, enkephalinase inhibitors, enzymes,
enzyme cofactors, estrogens, expectorants, fibrinogen receptor
antagonists, fluoride supplements, gastric and pancreatic secretion
stimulants, gastric cytoprotectants, gastric proton pump
inhibitors, gastric secretion inhibitors, gastroprokinetics,
glucocorticoids, .alpha.-glucosidase inhibitors, gonad-stimulating
principles, growth hormone inhibitors, growth hormone releasing
factors, growth stimulants, hematinics, hematopoietics, hemolytics,
hemostatics, heparin antagonists, hepatic enzyme inducers,
hepatoprotectants, histamine H.sub.2 receptor antagonists, HIV
protease inhibitors, HMG CoA reductase inhibitors,
immunomodulators, immunosuppressants, insulin sensitizers, ion
exchange resins, keratolytics, lactation stimulating hormones,
laxatives/cathartics, leukotriene antagonists, LH-RH agonists,
lipotropics, 5-lipoxygenase inhibitors, lupus erythematosus
suppressants, matrix metalloproteinase inhibitors,
mineralocorticoids, miotics, monoamine oxidase inhibitors,
mucolytics, muscle relaxants, mydriatics, narcotic antagonists,
neuroprotectives, nootropics, ovarian hormones, oxytocics, pepsin
inhibitors, pigmentation agents, plasma volume expanders, potassium
channel activators/openers, progestogens, prolactin inhibitors,
prostaglandins, protease inhibitors, radio-pharmaceuticals,
5.alpha.-reductase inhibitors, respiratory stimulants, reverse
transcriptase inhibitors, sedatives/hypnotics, serenics, serotonin
noradrenaline reuptake inhibitors, serotonin receptor agonists,
serotonin receptor antagonists, serotonin uptake inhibitors,
somatostatin analogs, thrombolytics, thromboxane A.sub.2 receptor
antagonists, thyroid hormones, thyrotropic hormones, tocolytics,
topoisomerase I and II inhibitors, uricosurics, vasomodulators
including vasodilators and vasoconstrictors, vasoprotectants,
xanthine oxidase inhibitors, and combinations thereof.
[0059] Non-limiting illustrative examples of suitable drugs of low
water solubility include, for example, acetohexamide,
acetylsalicylic acid, alclofenac, allopurinol, atropine,
benzthiazide, carprofen, celecoxib, chlordiazepoxide,
chlorpromazine, clonidine, codeine, codeine phosphate, codeine
sulfate, deracoxib, diacerein, diclofenac, diltiazem, estradiol,
etodolac, etoposide, etoricoxib, fenbufen, fenclofenac, fenprofen,
fentiazac, flurbiprofen, griseofulvin, haloperidol, ibuprofen,
indomethacin, indoprofen, ketoprofen, lorazepam,
medroxyprogesterone acetate, megestrol, methoxsalen,
methylprednisone, morphine, morphine sulfate, naproxen,
nicergoline, nifedipine, niflumic, oxaprozin, oxazepam,
oxyphenbutazone, paclitaxel, phenindione, phenobarbital, piroxicam,
pirprofen, prednisolone, prednisone, procaine, progesterone,
pyrimethamine, rofecoxib, sulfadiazine, sulfamerazine,
sulfisoxazole, sulindac, suprofen, temazepam, tiaprofenic acid,
tilomisole, tolmetic, valdecoxib, etc.
[0060] The amount of drug incorporated in a dosage form of the
invention can be selected according to known principles of
pharmacy. A therapeutically effective amount of drug is
specifically contemplated. The term "therapeutically and/or
prophylactically effective amount" as used herein refers to an
amount of drug that is sufficient to elicit the required or desired
therapeutic and/or prophylactic response. Typically, the drug will
be present in a total amount of about 1% to about 75% by weight of
the composition.
[0061] In a particularly preferred embodiment, the drug is a
selective COX-2 inhibitory drug of low water solubility. Any such
selective COX-2 inhibitory drug known in the art can be used,
including without limitation compounds disclosed in the patents and
publications listed below, each of which is individually
incorporated herein by reference.
[0062] U.S. Pat. No. 5,344,991 to Reitz & Li.
[0063] U.S. Pat. No. 5,380,738 to Norman et al.
[0064] U.S. Pat. No. 5,393,790 to Reitz et al.
[0065] U.S. Pat. No. 5,401,765 to Lee.
[0066] U.S. Pat. No. 5,418,254 to Huang & Reitz.
[0067] U.S. Pat. No. 5,420,343 to Koszyk & Weier.
[0068] U.S. Pat. No. 5,434,178 to Talley & Rogier.
[0069] U.S. Pat. No. 5,436,265 to Black et al.
[0070] Above-cited U.S. Pat. No. 5,466,823.
[0071] Above-cited U.S. Pat. No. 5,474,995.
[0072] U.S. Pat. No. 5,475,018 to Lee & Bertenshaw.
[0073] U.S. Pat. No. 5,486,534 to Lee et al.
[0074] U.S. Pat. No. 5,510,368 to Lau et al.
[0075] U.S. Pat. No. 5,521,213 to Prasit et al.
[0076] U.S. Pat. No. 5,536,752 to Ducharme et al.
[0077] U.S. Pat. No. 5,543,297 to Cromlish et al.
[0078] U.S. Pat. No. 5,547,975 to Talley et al.
[0079] U.S. Pat. No. 5,550,142 to Ducharme et al.
[0080] U.S. Pat. No. 5,552,422 to Gauthier et al.
[0081] U.S. Pat. No. 5,585,504 to Desmond et al.
[0082] U.S. Pat. No. 5,593,992 to Adams et al.
[0083] U.S. Pat. No. 5,596,008 to Lee.
[0084] U.S. Pat. No. 5,604,253 to Lau et al.
[0085] U.S. Pat. No. 5,604,260 to Guay & Li.
[0086] U.S. Pat. No. 5,616,458 to Lipsky et al.
[0087] U.S. Pat. No. 5,616,601 to Khanna et al.
[0088] U.S. Pat. No. 5,620,999 to Weier et al.
[0089] Above-cited U.S. Pat. No. 5,633,272.
[0090] U.S. Pat. No. 5,639,780 to Lau et al.
[0091] U.S. Pat. No. 5,643,933 to Talley et al.
[0092] U.S. Pat. No. 5,658,903 to Adams et al.
[0093] U.S. Pat. No. 5,668,161 to Talley et al.
[0094] U.S. Pat. No. 5,670,510 to Huang & Reitz.
[0095] U.S. Pat. No. 5,677,318 to Lau.
[0096] U.S. Pat. No. 5,681,842 to Dellaria & Gane.
[0097] U.S. Pat. No. 5,686,460 to Nicola et al.
[0098] U.S. Pat. No. 5,686,470 to Weier et al.
[0099] U.S. Pat. No. 5,696,143 to Talley et al.
[0100] U.S. Pat. No. 5,710,140 to Ducharme et al.
[0101] U.S. Pat. No. 5,716,955 to Adams et al.
[0102] U.S. Pat. No. 5,723,485 to Gungor & Teulon.
[0103] U.S. Pat. No. 5,739,166 to Reitz et al.
[0104] U.S. Pat. No. 5,741,798 to Lazer et al.
[0105] U.S. Pat. No. 5,756,499 to Adams et al.
[0106] U.S. Pat. No. 5,756,529 to Isakson & Talley.
[0107] U.S. Pat. No. 5,776,967 to Kreft et al.
[0108] U.S. Pat. No. 5,783,597 to Beers & Wachter.
[0109] U.S. Pat. No. 5,789,413 to Black et al.
[0110] U.S. Pat. No. 5,807,873 to Nicola & Teulon.
[0111] U.S. Pat. No. 5,817,700 to Dube et al.
[0112] U.S. Pat. No. 5,830,911 to Failli et al.
[0113] U.S. Pat. No. 5,849,943 to Atkinson & Wang.
[0114] U.S. Pat. No. 5,859,036 to Sartori et al.
[0115] Above-cited U.S. Pat. No. 5,861,419.
[0116] U.S. Pat. No. 5,866,596 to Sartori & Teulon.
[0117] U.S. Pat. No. 5,869,524 to Failli.
[0118] U.S. Pat. No. 5,869,660 to Adams et al.
[0119] U.S. Pat. No. 5,883,267 to Rossen et al.
[0120] U.S. Pat. No. 5,892,053 to Zhi et al.
[0121] U.S. Pat. No. 5,922,742 to Black et al.
[0122] U.S. Pat. No. 5,929,076 to Adams & Garigipati.
[0123] U.S. Pat. No. 5,932,598 to Talley et al.
[0124] U.S. Pat. No. 5,935,990 to Khanna et al.
[0125] U.S. Pat. No. 5,945,539 to Haruta et al.
[0126] U.S. Pat. No. 5,958,978 to Yamazaki et al.
[0127] U.S. Pat. No. 5,968,958 to Guay et al.
[0128] U.S. Pat. No. 5,972,950 to Nicolai & Teulon.
[0129] U.S. Pat. No. 5,973,191 to Marnett & Kalgutkar.
[0130] Above-cited U.S. Pat. No. 5,981,576.
[0131] U.S. Pat. No. 5,994,381 to Haruta et al.
[0132] U.S. Pat. No. 6,002,014 to Haruta et al.
[0133] U.S. Pat. No. 6,004,960 to Li et al.
[0134] U.S. Pat. No. 6,005,000 to Hopper et al
[0135] U.S. Pat. No. 6,020,343 to Belley et al.
[0136] U.S. Pat. No. 6,020,347 to DeLaszlo & Hagmann.
[0137] Above-cited U.S. Pat. No. 6,034,256.
[0138] U.S. Pat. No. 6,040,319 to Corley et al.
[0139] U.S. Pat. No. 6,040,450 to Davies et al.
[0140] U.S. Pat. No. 6,046,208 to Adams et al.
[0141] U.S. Pat. No. 6,046,217 to Friesen et al.
[0142] U.S. Pat. No. 6,057,319 to Black et al.
[0143] U.S. Pat. No. 6,063,804 to De Nanteuil et al.
[0144] U.S. Pat. No. 6,063,807 to Chabrier de Lassauniere &
Broquet.
[0145] U.S. Pat. No. 6,071,954 to LeBlanc et al.
[0146] U.S. Pat. No. 6,077,868 to Cook et al.
[0147] U.S. Pat. No. 6,077,869 to Sui & Wachter.
[0148] U.S. Pat. No. 6,083,969 to Ferro et al.
[0149] U.S. Pat. No. 6,096,753 to Spohr et al.
[0150] U.S. Pat. No. 6,133,292 to Wang et al.
[0151] International Patent Publication No. WO 94/15932.
[0152] International Patent Publication No. WO 96/19469.
[0153] International Patent Publication No. WO 96/26921.
[0154] International Patent Publication No. WO 96/31509.
[0155] International Patent Publication No. WO 96/36623.
[0156] International Patent Publication No. WO 96/38418.
[0157] International Patent Publication No. WO 97/03953.
[0158] International Patent Publication No. WO 97/10840.
[0159] International Patent Publication No. WO 97/13755.
[0160] International Patent Publication No. WO 97/13767.
[0161] International Patent Publication No. WO 97/25048.
[0162] International Patent Publication No. WO 97/30030.
[0163] International Patent Publication No. WO 97/34882.
[0164] International Patent Publication No. WO 97/46524.
[0165] International Patent Publication No. WO 98/04527.
[0166] International Patent Publication No. WO 98/06708.
[0167] International Patent Publication No. WO 98/07425.
[0168] International Patent Publication No. WO 98/17292.
[0169] International Patent Publication No. WO 98/21195.
[0170] International Patent Publication No. WO 98/22457.
[0171] International Patent Publication No. WO 98/32732.
[0172] International Patent Publication No. WO 98/41516.
[0173] International Patent Publication No. WO 98/43966.
[0174] International Patent Publication No. WO 98/45294.
[0175] International Patent Publication No. WO 98/47871.
[0176] International Patent Publication No. WO 99/01130.
[0177] International Patent Publication No. WO 99/01131.
[0178] International Patent Publication No. WO 99/01452.
[0179] International Patent Publication No. WO 99/01455.
[0180] International Patent Publication No. WO 99/10331.
[0181] International Patent Publication No. WO 99/10332.
[0182] International Patent Publication No. WO 99/11605.
[0183] International Patent Publication No. WO 99/12930.
[0184] International Patent Publication No. WO 99/14195.
[0185] International Patent Publication No. WO 99/14205.
[0186] International Patent Publication No. WO 99/15505.
[0187] International Patent Publication No. WO 99/23087.
[0188] International Patent Publication No. WO 99/24404.
[0189] International Patent Publication No. WO 99/25695.
[0190] International Patent Publication No. WO 99/35130.
[0191] International Patent Publication No. WO 99/61016.
[0192] International Patent Publication No. WO 99/61436.
[0193] International Patent Publication No. WO 99/62884.
[0194] International Patent Publication No. WO 99/64415.
[0195] International Patent Publication No. WO 00/01380.
[0196] International Patent Publication No. WO 00/08024.
[0197] International Patent Publication No. WO 00/10993.
[0198] International Patent Publication No. WO 00/13684.
[0199] International Patent Publication No. WO 00/18741.
[0200] International Patent Publication No. WO 00/18753.
[0201] International Patent Publication No. WO 00/23426.
[0202] Above-cited International Patent Publication No. WO
00/24719.
[0203] International Patent Publication No. WO 00/26216.
[0204] International Patent Publication No. WO 00/31072.
[0205] International Patent Publication No. WO 00/40087.
[0206] International Patent Publication No. WO 00/56348.
[0207] European Patent Application No. 0 799 823.
[0208] European Patent Application No. 0 846 689.
[0209] Above-cited European Patent Application No. 0 863 134.
[0210] European Patent Application No. 0 985 666.
[0211] Compositions of the invention are especially useful for
compounds having the formula (VIII): 6
[0212] where R.sup.3 is a methyl or amino group, R.sup.4 is
hydrogen or a C.sub.1-4 alkyl or alkoxy group, X is N or CR.sup.5
where R.sup.5 is hydrogen or halogen, and Y and Z are independently
carbon or nitrogen atoms defining adjacent atoms of a five- to
six-membered ring that is unsubstituted or substituted at one or
more positions with oxo, halo, methyl or halomethyl groups.
Preferred such five- to six-membered rings are cyclopentenone,
furanone, methylpyrazole, isoxazole and pyridine rings substituted
at no more than one position.
[0213] Illustratively, celecoxib, deracoxib, valdecoxib, rofecoxib,
etoricoxib,
2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclope-
nten-1-one,
(S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxy- lic
acid and
2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(-
methylsulfonyl)phenyl]-3-(2H)-pyridazinone, more particularly
celecoxib, valdecoxib, rofecoxib and etoricoxib, and still more
particularly celecoxib and valdecoxib, are useful in the method and
composition of the invention.
[0214] The invention is illustrated herein with particular
reference to celecoxib, and it will be understood that any other
selective COX-2 inhibitory drug of low solubility in water can, if
desired, be substituted in whole or in part for celecoxib in
compositions herein described. For example, compositions of the
invention are suitable for formulation of valdecoxib, alone or in
combination with celecoxib.
[0215] Where the drug is celecoxib, the composition typically
comprises celecoxib in a therapeutically and/or prophylactically
effective total amount of about 10 mg to about 1000 mg per dose
unit. Where the drug is a selective COX-2 inhibitory drug other
than celecoxib, the amount of the drug per dose unit is
therapeutically equivalent to about 10 mg to about 1000 mg of
celecoxib.
[0216] It will be understood that a therapeutically and/or
prophylactically effective amount of a drug for a subject is
dependent inter alia on the body weight of the subject. A "subject"
herein to which a therapeutic agent or composition thereof can be
administered includes a human patient of either sex and of any age,
and also includes any nonhuman animal, particularly a domestic or
companion animal, illustratively a cat, dog or horse.
[0217] Where the subject is a child or a small animal (e.g., a
dog), for example, an amount of celecoxib relatively low in the
preferred range of about 10 mg to about 1000 mg is likely to be
consistent with therapeutic effectiveness. Where the subject is an
adult human or a large animal (e.g., a horse), therapeutic
effectiveness is likely to require dose units containing a
relatively greater amount of celecoxib. For an adult human, a
therapeutically effective amount of celecoxib per dose unit in a
composition of the present invention is typically about 50 mg to
about 400 mg. Especially preferred amounts of celecoxib per dose
unit are about 100 mg to about 200 mg, for example about 100 mg or
about 200 mg.
[0218] For other selective COX-2 inhibitory drugs, an amount of the
drug per dose unit can be in a range known to be therapeutically
effective for such drugs. Preferably, the amount per dose unit is
in a range providing therapeutic equivalence to celecoxib in the
dose ranges indicated immediately above.
[0219] Form of Compositions of the Invention
[0220] Compositions of the present invention are preferably in the
form of a concentrated solution that may or may not be encapsulated
as a discrete article. If encapsulated, preferably a single such
article or a small plurality (up to about 10, more preferably no
more than about 4) of such articles is sufficient to provide the
daily dose. Alternatively, compositions of the present invention
are in the form of a concentrated imbibable liquid. The phrase
"imbibable liquid" is used herein to refer to an unencapsulated
substantially homogeneous flowable mass, such as a solution or
solution/suspension, administered orally and swallowed in liquid
form and from which single dose units are measurably removable. The
term "substantially homogeneous" with reference to a pharmaceutical
composition that comprises several components means that the
components are sufficiently mixed such that individual components
are not present as discrete layers and do not form concentration
gradients within the composition.
[0221] A particular dose unit can be selected to accommodate the
desired frequency of administration used to achieve a specified
daily dose. For example, a daily dosage amount of 400 mg can be
accommodated by administration of one 200 mg dose unit, or two 100
mg dose units, twice a day. The amount of the composition that is
administered and the dosage regimen for treating the condition or
disorder will depend on a variety of factors, including the age,
weight, sex and medical condition of the subject, the nature and
severity of the condition or disorder, the route and frequency of
administration, and the particular drug selected, and thus may vary
widely. It is contemplated, however, that for most purposes a
once-a-day or twice-a-day administration regimen provides the
desired therapeutic efficacy.
[0222] A composition of the invention comprises a drug of low water
solubility, at least a portion of which is in dissolved or
solubilized form in a solvent liquid suitable for oral
administration.
[0223] The solvent liquid comprises at least one pharmaceutically
acceptable solvent and optionally one or more additional
components, including pharmaceutically acceptable excipients. The
term "excipient" herein means any substance, not itself a
therapeutic agent, used as a carrier or vehicle for delivery of a
therapeutic agent to a subject or added to a pharmaceutical
composition to improve its handling, storage, disintegration,
dispersion, dissolution, release or organoleptic properties or to
permit or facilitate formation of a dose unit of the composition
into a discrete article such as a capsule suitable for oral
administration. Excipients can include, by way of illustration and
not limitation, diluents, disintegrants, dispersants, binding
agents, adhesives, wetting agents, lubricants, glidants,
crystallization inhibitors, stabilizers, antioxidants, substances
added to mask or counteract a disagreeable taste or odor, flavors,
dyes, fragrances, preservatives, and substances added to improve
appearance of the composition.
[0224] Such optional additional components should be physically and
chemically compatible with the other ingredients of the composition
and should not be deleterious to the recipient. Importantly, some
of the above-listed classes of excipients overlap each other.
Compositions of the present invention can be adapted for
administration by any suitable oral route by selection of
appropriate solvent liquid components and a dosage of the drug
effective for the treatment intended. Accordingly, components
employed in the solvent liquid can themselves be solids,
semi-solids, liquids, or combinations thereof.
[0225] An imbibable composition of the invention can be in the form
of, for example, a solution, a solution/suspension, an elixir, a
syrup, or any other liquid form reasonably adapted for oral
administration. Such compositions can also comprise excipients
selected from, for example, emulsifying and suspending agents,
sweetening and flavoring agents, surfactants and
co-surfactants.
[0226] Alternatively, as described in detail below, a composition
of the present invention can be prepared in the form of discrete
unit dose articles, for example, capsules having a wall that
illustratively comprises gelatin and/or a cellulosic polymer such
as HPMC, each capsule containing a liquid composition comprising a
predetermined amount of drug in a solvent liquid. The liquid
composition within the capsule is released by breakdown of the wall
on contact with gastrointestinal fluid. The particular mechanism of
capsule wall breakdown is not important and can include such
mechanisms as erosion, degradation, dissolution, etc.
[0227] Compositions of the invention can be prepared by any
suitable method of pharmacy that includes the step of bringing into
association the drug and the components of the solvent liquid. In
general, celecoxib compositions of the invention are prepared by
uniformly and intimately admixing celecoxib with a solvent liquid
in such a way that at least a portion, preferably substantially
all, of the celecoxib is dissolved or solubilized in the solvent
liquid; and then, if desired, encapsulating the resulting solution
or solution/suspension, for example in hard or soft capsules.
[0228] A preferred embodiment of the invention is a composition
comprising a therapeutically effective amount of a drug of low
water solubility, for example celecoxib or valdecoxib,
substantially completely dissolved in a solvent liquid comprising
at least one pharmaceutically acceptable solvent. In this
embodiment, substantially no part of the drug is present in solid
particulate form. Compositions of this embodiment can be formulated
either in an imbibable or discrete dosage form (e.g.,
encapsulated). Such compositions further comprise a crystallization
inhibitor as more fully described below, the crystallization
inhibitor being present in the solvent liquid and/or as a component
of a capsule wall. Preferably, concentrated solutions of this
embodiment have a drug concentration of about 10% to about 75%,
more preferably about 20% to about 75%, by weight of the
composition.
[0229] Solvent
[0230] A preferred solvent is a glycol or glycol ether. Suitable
glycol ethers include those conforming to formula (IX):
R.sup.1--O--((CH.sub.2).sub.mO).sub.n--R.sup.2 (IX)
[0231] wherein R.sup.1 and R.sup.2 are independently hydrogen or
C.sub.1-6 alkyl, C.sub.1-6 alkenyl, phenyl or benzyl groups, but no
more than one of R.sup.1 and R.sup.2 is hydrogen; m is an integer
of 2 to about 5; and n is an integer of 1 to about 20. It is
preferred that one of R.sup.1 and R.sup.2 is a C.sub.1-4 alkyl
group and the other is hydrogen or a C.sub.1-4 alkyl group; more
preferably at least one of R.sup.1 and R.sup.2 is a methyl or ethyl
group. It is preferred that m is 2. It is preferred that n is an
integer of 1 to about 4, more preferably 2.
[0232] Glycol ethers used as solvents in compositions of the
present invention typically have a molecular weight of about 75 to
about 1000, preferably about 75 to about 500, and more preferably
about 100 to about 300. Importantly, the glycol ethers used in
compositions of the present invention must be pharmaceutically
acceptable and must meet all other conditions prescribed
herein.
[0233] Non-limiting examples of glycol ethers that may be used in
compositions of the present invention include ethylene glycol
monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol
monoethyl ether, ethylene glycol diethyl ether, ethylene glycol
monobutyl ether, ethylene glycol dibutyl ether, ethylene glycol
monophenyl ether, ethylene glycol monobenzyl ether, ethylene glycol
butylphenyl ether, ethylene glycol terpinyl ether, diethylene
glycol monomethyl ether, diethylene glycol dimethyl ether,
diethylene glycol monoethyl ether, diethylene glycol diethyl ether,
diethylene glycol divinyl ether, ethylene glycol monobutyl ether,
diethylene glycol dibutyl ether, diethylene glycol monoisobutyl
ether, triethylene glycol dimethyl ether, triethylene glycol
monoethyl ether, triethylene glycol monobutyl ether, tetraethylene
glycol dimethyl ether, and mixtures thereof. See for example Flick
(1998): Industrial Solvents Handbook, 5th ed., Noyes Data
Corporation, Westwood, N.J. A particularly suitable glycol ether
solvent is diethylene glycol monoethyl ether, sometimes referred to
in the art as DGME or ethoxydiglycol. It is available for example
under the trademark Transcutol.TM. of Gattefoss Corporation.
[0234] Glycols suitable as solvents in compositions of the present
invention include propylene glycol, 1,3-butanediol and polyethylene
glycols. A presently preferred solvent is polyethylene glycol
(PEG).
[0235] Any pharmaceutically acceptable PEG can be used. Preferably,
the PEG has an average molecular weight of about 100 to about
10,000, and more preferably about 100 to about 1,000. Still more
preferably, the PEG is of liquid grade. Non-limiting examples of
PEGs that can be used in solvent liquids of this invention include
PEG-200, PEG-350, PEG-400, PEG-540 and PEG-600. See for example
Flick (1998), op. cit., p. 392. A presently preferred PEG has an
average molecular weight of about 375 to about 450, as exemplified
by PEG-400.
[0236] PEGs such as PEG-400 have many desirable properties as
solvents for poorly water-soluble drugs. In the case of celecoxib,
for example, the drug can be dissolved or solubilized at a very
high concentration in PEG-400, enabling formulation of a
therapeutically effective dose in a very small volume of solvent
liquid. This is especially important where the resulting solution
is to be encapsulated, as capsules of a size convenient for
swallowing can be prepared containing a therapeutically effective
dose even of a drug such as celecoxib having a relatively high dose
requirement for efficacy.
[0237] However, a solution composition of a poorly water-soluble
drug in a solvent such as PEG exhibits a strong tendency for the
drug to crystallize or precipitate when diluted in an aqueous
medium such as that found in the gastrointestinal tract. This
problem can be studied by adding such a composition, whether
encapsulated or not, to SGF in an in vitro test. According to the
present invention, a surprisingly effective solution to this
problem has been found through use of a crystallization
inhibitor.
[0238] Crystallization Inhibitor
[0239] We have discovered that certain polymers can substantially
inhibit precipitation and/or crystallization of a poorly
water-soluble drug, when a solution of the drug in a substantially
non-aqueous solvent is exposed to SGF. Accordingly, compositions of
the present invention comprise a crystallization inhibitor
comprising at least one polymer. The polymer can be a cellulosic or
non-cellulosic polymer and is preferably substantially
water-soluble.
[0240] It will be understood that certain polymers are more
effective at inhibiting precipitation and/or crystallization of a
selected poorly water soluble drug than others, and that not all
polymers inhibit precipitation and/or crystallization as described
herein of every poorly water-soluble drug. Whether a particular
polymer is useful as a crystallization inhibitor for a particular
poorly water soluble drug according to the present invention can be
readily determined by one of ordinary skill in the art, for example
according to Test I.
[0241] Test I:
[0242] A. A suitable amount of the drug is dissolved in a solvent
(e.g., ethanol, dimethyl sulfoxide or, where the drug is an acid or
base, water) to obtain a concentrated drug solution.
[0243] B. A volume of water or buffered solution with a fixed pH is
placed in a first vessel and maintained at room temperature.
[0244] C. An aliquot of the concentrated drug solution is added to
the contents of the first vessel to obtain a first sample solution
having a desired target drug concentration. The drug concentration
selected should be one which produces substantial precipitation and
consequently higher apparent absorbance (i.e., turbidity) than a
saturated solution having no such precipitation.
[0245] D. A test polymer is selected and, in a second vessel, the
polymer is dissolved in water or a buffered solution with a fixed
pH (identical in composition, pH and volume to that used in step C)
in an amount sufficient to form a 0.25%-2% w/w polymer
solution.
[0246] E. To form a second sample solution, an aliquot of the
concentrated drug solution prepared in step A is added to the
polymer solution in the second vessel to form a sample solution
having a final drug concentration equal to that of the first sample
solution.
[0247] F. At 60 minutes after preparation of both sample solutions,
apparent absorbance (i.e., turbidity) of each sample solution is
measured using light having a wavelength of 650 nm;
[0248] G. If the turbidity of the second sample solution is less
than the turbidity of the first sample solution, the test polymer
is deemed to be a "turbidity-decreasing polymer" and is useful as a
crystallization inhibitor for the test drug.
[0249] A technician performing Test I will readily find a suitable
polymer concentration for the test within the polymer concentration
range provided above, by routine experimentation. In a particularly
preferred embodiment, a concentration of the polymer is selected
such that when Test I is performed, the apparent absorbance of the
second sample solution is not greater than about 50% of the
apparent absorbance of the first sample solution.
[0250] In another embodiment, compositions of the invention
comprise a crystallization inhibitor comprising at least one
cellulosic polymer. Preferred cellulosic polymers are selected from
HPMC, methylcellulose, ethylcellulose, sodium
carboxymethylcellulose and hydroxypropylcellulose. More preferably,
the at least one cellulosic polymer is selected from cellulosic
polymers having at least a portion of substitutable hydroxyl groups
substituted with methoxyl and/or hydroxypropoxyl groups. Still more
preferably, the at least one cellulosic polymer is HPMC.
[0251] HPMC useful as a crystallization inhibitor according to the
invention preferably has a viscosity, 2% in water, of about 100 to
about 20,000 cP. HPMCs vary in the degree of substitution of
available hydroxyl groups on the cellulosic backbone by methoxyl
groups and by hydroxypropoxyl groups. With increasing
hydroxypropoxyl substitution, the resulting HPMC becomes more
hydrophilic in nature. It is preferred to use HPMC having about 15%
to about 35%, more preferably about 19% to about 30%, and most
preferably about 19% to about 24%, methoxyl substitution, and
having about 3% to about 15%, more preferably about 4% to about
12%, and most preferably about 7% to about 12%, hydroxypropoxyl
substitution.
[0252] Suitable HPMCs that are relatively hydrophilic in nature are
illustratively available under the brand names Methocel.TM. of Dow
Chemical Co. and Metolose.TM. of Shin-Etsu Chemical Co.
[0253] An illustrative presently preferred HPMC is one with
substitution type 2208, denoting about 19% to about 24% methoxyl
substitution and about 7% to about 12% hydroxypropoxyl
substitution, and with a nominal viscosity, 2% in water, of about
4000 cP.
[0254] Surprisingly, it has been found that the crystallization
inhibitor need not be a component of the solvent liquid.
Optionally, as described below, a crystallization inhibitor such as
HPMC can be a component of a capsule wall wherein a solution
composition of the invention is encapsulated. In one embodiment,
substantially no HPMC or other crystallization inhibitor is present
in the solvent liquid but the capsule wall comprises a
crystallization inhibitor such as HPMC. The capsule wall can even
consist predominantly of such a crystallization inhibitor.
[0255] The crystallization inhibitor is preferably present in a
total amount sufficient to substantially inhibit drug
crystallization and/or precipitation upon dilution of the
composition in SGF. An amount sufficient to "substantially inhibit
drug crystallization and/or precipitation" herein means an amount
sufficient to prevent, slow, inhibit or delay precipitation of drug
from solution and/or to prevent, slow, inhibit or delay formation
of crystalline drug particles from dissolved drug particles. For
practical purposes, whether an amount of crystallization inhibitor
in a given test composition is sufficient to substantially inhibit
drug crystallization and/or precipitation can be determined
according to Test II, which can also be used to determine whether a
particular polymer component is useful as a crystallization
inhibitor in a particular composition of the invention.
[0256] Test II:
[0257] A. A volume of a test composition, either in unencapsulated
or encapsulated form, having a polymer component is placed in a
volume of SGF to form a mixture having a fixed ratio of about 1 g
to about 2 g of the composition per 100 ml of SGF.
[0258] B. The mixture is maintained at a constant temperature of
about 37.degree. C. and is stirred using type II paddles (USP 24)
at a rate of 75 rpm for a period of 4 hours.
[0259] C. At one or more time-points after at least about 15
minutes of stirring but before about 4 hours of stirring, an
aliquot of the mixture is drawn and filtered, for example through a
non-sterile Acrodisc.TM. syringe filter with a 0.8 .mu.m
Versapor.TM. membrane.
[0260] D. Filtrate is collected in a vessel.
[0261] E. Drug concentration in the filtrate is measured using high
performance liquid chromatography (HPLC).
[0262] F. The test is repeated identically with a comparative
composition that is substantially similar to the test composition
except that it lacks the polymer component. Where the polymer
component in the test composition is present in the solvent liquid,
it is replaced in the comparative composition by polyethylene
glycol solvent. Where the polymer component in the test composition
is present in a capsule wall, it is replaced in the comparative
composition with gelatin.
[0263] G. If the drug concentration in the filtrate resulting from
the test composition is greater than that in the filtrate resulting
from the comparative composition, the polymer component present in
the test composition is deemed to substantially inhibit
crystallization and/or precipitation of the drug in SGF.
[0264] A crystallization inhibitor such as HPMC, when present in
the solvent liquid, is generally present in a total amount of about
1% to about 20%, preferably about 1% to about 15%, and most
preferably about 1% to about 10%, by weight of the solvent liquid.
Typically, the higher the drug concentration in the composition,
the more of the cellulosic polymer will be required to provide a
crystallization-inhibiting effect. In general, the cellulosic
polymer and drug are present in a ratio of about 1:100 to about
1:1, preferably about 1:50 to about 1:1 and more preferably about
1:25 to about 1:1, by weight.
[0265] Use of a crystallization inhibitor as provided herein can in
some situations permit a reduction in the amount of surfactant in a
solution composition, particularly in a self-emulsifying solution
composition. This can be beneficial because of undesirable
side-effects of certain surfactants when administered orally in
large amounts. Such side-effects include irritation of the
gastrointestinal tract, foaming, which can lead to gas entrapment,
and, in some cases, anaphylactoid reactions that can be
life-threatening.
[0266] Other Excipients
[0267] Compositions of the invention optionally contain
pharmaceutically acceptable excipients other than a solvent and a
crystallization inhibitor. In the case of a solution composition,
for example, such excipients can include co-solvents, sweeteners,
antioxidants, preservatives, dispersants, emulsifying agents, etc.
Through selection and combination of excipients, compositions can
be provided exhibiting improved performance with respect to drug
concentration, dissolution, dispersion, emulsification, efficacy,
flavor, patient compliance and other properties.
[0268] A composition, particularly a solution composition, of the
invention optionally comprises one or more pharmaceutically
acceptable co-solvents. Non-limiting examples of suitable
co-solvents include additional glycols, alcohols, for example
ethanol and n-butanol; oleic and linoleic acid triglycerides, for
example soybean oil; caprylic/capric triglycerides, for example
Miglyol.TM. 812 of Huls; caprylic/capric mono- and diglycerides,
for example Capmul.TM. MCM of Abitec; polyoxyethylene
caprylic/capric glycerides such as polyoxyethylene (8)
caprylic/capric mono- and diglycerides, for example Labrasol.TM. of
Gattefoss; propylene glycol fatty acid esters, for example
propylene glycol laurate; polyoxyethylene (35) castor oil, for
example Cremophor.TM. EL of BASF; polyoxyethylene glyceryl
trioleate, for example Tagat.TM. TO of Goldschmidt; lower alkyl
esters of fatty acids, for example ethyl butyrate, ethyl caprylate
and ethyl oleate; and water.
[0269] A composition, particularly a solution composition, of the
invention optionally comprises a pharmaceutically acceptable fatty
acid and a pharmaceutically acceptable organic amine (also referred
to herein as a "fatty acid/organic amine pair") in total and
relative amounts such that the composition is finely
self-emulsifiable in SGF. Without being bound by theory, it is
believed that a fatty acid/organic amine pair, when present in a
composition of the invention, promotes formation of charged
fine-emulsion droplets upon exposure of the composition to an
aqueous medium such as SGF.
[0270] Whether a composition is "finely self-emulsifiable" in SGF
as defined herein can illustratively be determined according to
Test III.
[0271] Test III:
[0272] A. A 400 .mu.l aliquot of a test composition is placed into
a screw-top, side-arm vessel containing 20 ml SGF (maintained at
37.degree. C. throughout the test) to form a test liquid.
[0273] B. The test liquid is mildly agitated at 75 rpm for 2
minutes using an orbital shaker, to permit emulsification.
[0274] C. A 5-50 .mu.l aliquot of the test liquid is withdrawn
through the side-arm using a pipette and is discharged from the
pipette into a sampling vessel.
[0275] D. A pump (e.g., model RHOCKC-LF, Fluid Metering Inc.,
Syosset, N.Y.) is used to pull the test liquid from the sampling
vessel through a combination scattering/obscuration sensor (e.g.,
LE400-0.5, Particle Sizing Systems, Santa Barbara, Calif.) at a
rate of 1 ml/minute for a period of 1 minute.
[0276] E. Emulsion particles are counted individually by light
scattering in the size (i.e., diameter) range from 0.5 to 1 .mu.m
and by light obscuration in the size range above 1 .mu.m, using the
vendor's software (e.g., Version 1.59).
[0277] F. A plot is prepared of number (i.e., unweighted) or volume
(i.e., weighted) of emulsion particles versus particle
diameter.
[0278] G. Integration of the plot, accounting for all dilutions, is
performed to estimate total number or volume of emulsion particles
present in the test liquid large enough to be detected by the
sensor.
[0279] H. If Test III results in about 25% or more, by volume, of
emulsion particles having a diameter of 1 .mu.m or less, the test
composition is deemed to be finely self-emulsifiable.
[0280] Preferred fatty acids have a saturated or unsaturated
C.sub.6-24 carbon chain. Non-limiting examples of suitable fatty
acids include oleic acid, octanoic acid, caproic acid, caprylic
acid, capric acid, eleostearic acid, lauric acid, myristic acid,
palmitic acid, stearic acid, icosanoic acid, elaidic acid, linoleic
acid, linolenic acid, eicosapentaenoic acid and docosahexaenoic
acid. Oleic acid is an especially preferred fatty acid.
[0281] Preferred organic amines have a C.sub.2-8 carbon chain with
one or two amine groups. More preferably, organic amines can be
selected from C.sub.2-8 alkyl amines, alkylene diamines, alkanol
amines, alkylalkanol amines, glycol ether amines and aryl amines.
Non-limiting examples of suitable organic amines include
monoethanolamine, diethanolamine, triethanolamine,
dimethylaminoethanol, tromethamine, etc. Particularly preferred
organic amines are tertiary amines, for example triethanolamine and
dimethylaminoethanol.
[0282] Preferably, if present, a fatty acid/organic amine pair is
selected (as to both type and amount of each component) such that
when a composition of the invention is subjected to Test II, at
least about 50%, more preferably at least about 75%, by volume of
the emulsion particles counted have a diameter of about 1 .mu.m or
less. It is especially preferred that a substantial portion by
volume of the emulsion particles counted, more preferably at least
about 75%, still more preferably at least about 85%, and most
preferably at least about 90%, have a diameter of about 0.5 .mu.m
or less.
[0283] A preferred mole ratio of fatty acid to amine group(s) in
the organic amine is about 5:1 to about 1:100, more preferably
about 3:1 to about 1:50, and still more preferably about 2:1 to
about 1:10, for example about 1:1. Preferably, if present, the
fatty acid and organic amine are collectively present in an amount
of about 1% to about 50%, more preferably about 2% to about 30%,
and still more preferably about 5% to about 15%, by weight of the
composition.
[0284] It is believed, without being bound by theory, that a finely
self-emulsifiable solution composition of the invention,
particularly one having a fatty acid/organic amine pair as
described above, will provide the drug in a form that is especially
rapidly absorbable in the gastrointestinal tract.
[0285] When certain poorly water-soluble drugs are formulated in
dissolved or solubilized form in PEG, it has been found that
impurities can be generated during storage. For example, in the
case of a celecoxib solution composition in PEG-400, the impurities
have been traced to reaction of the celecoxib not with PEG-400
itself but with a breakdown product of PEG-400. Without being bound
by theory, it is believed that the breakdown product that reacts
with celecoxib is ethylene oxide. Products of the reaction include
addition compounds. It is contemplated that any drug compound
having an aminosulfonyl functional group has a potential to react
with a polyethylene glycol breakdown product in a similar way.
[0286] The problem of chemical instability of such a drug in a
polyethylene glycol solvent, or indeed of any drug that can react
with polyethylene glycol or a breakdown product thereof to form an
addition compound, can be overcome by including a free
radical-scavenging antioxidant in the solvent liquid.
[0287] Therefore, a composition of the present invention optionally
further comprises at least one pharmaceutically acceptable free
radical-scavenging antioxidant. A free radical-scavenging
antioxidant is to be contrasted with a "non-free radical-scavenging
antioxidant", i.e., an antioxidant that does not possess free
radical-scavenging properties. Non-limiting illustrative examples
of suitable free radical-scavenging antioxidants include
.alpha.-tocopherol (vitamin E), ascorbic acid (vitamin C) and salts
thereof including sodium ascorbate and ascorbic acid palmitate,
butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),
fumaric acid and salts thereof, hypophosphorous acid, malic acid,
alkyl gallates, for example propyl gallate, octyl gallate and
lauryl gallate, sodium sulfite, sodium bisulfite and sodium
metabisulfite. Preferred free radical-scavenging antioxidants are
alkyl gallates, vitamin E, BHA and BHT. More preferably the at
least one free radical-scavenging antioxidant is propyl
gallate.
[0288] One or more free radical-scavenging antioxidants are
optionally present in compositions of the invention in a total
amount effective to substantially reduce formation of an addition
compound, typically in a total amount of about 0.01% to about 5%,
preferably about 0.01% to about 2.5%, and more preferably about
0.01% to about 1%, by weight of the composition.
[0289] A composition of the invention optionally comprises one or
more pharmaceutically acceptable sweeteners. Non-limiting examples
of suitable sweeteners include mannitol, propylene glycol, sodium
saccharin, acesulfame K, neotame and aspartame. Alternatively or in
addition, a viscous sweetener such as sorbitol solution, syrup
(sucrose solution) or high-fructose corn syrup can be used and, in
addition to sweetening effects, can also be useful to increase
viscosity and to retard sedimentation. Use of sweeteners is
especially advantageous in imbibable compositions of the invention,
as these can be tasted by the subject prior to swallowing. An
encapsulated composition does not typically interact with the
organs of taste in the mouth and use of a sweetener is normally
unnecessary.
[0290] A composition of the invention optionally comprises one or
more pharmaceutically acceptable preservatives other than free
radical-scavenging antioxidants. Non-limiting examples of suitable
preservatives include benzalkonium chloride, benzethonium chloride,
benzyl alcohol, chlorobutanol, phenol, phenylethyl alcohol,
phenylmercuric nitrate, thimerosal, etc.
[0291] A composition of the invention optionally comprises one or
more pharmaceutically acceptable wetting agents. Surfactants,
hydrophilic polymers and certain clays can be useful as wetting
agents to aid in dissolution and/or dispersion of a hydrophobic
drug such as celecoxib. Non-limiting examples of suitable
surfactants include benzalkonium chloride, benzethonium chloride,
cetylpyridinium chloride, dioctyl sodium sulfosuccinate, nonoxynol
9, nonoxynol 10, octoxynol 9, poloxamers, polyoxyethylene (8)
caprylic/capric mono- and diglycerides (e.g., Labrasol.TM. of
Gattefoss), polyoxyethylene (35) castor oil, polyoxyethylene (20)
cetostearyl ether, polyoxyethylene (40) hydrogenated castor oil,
polyoxyethylene (10) oleyl ether, polyoxyethylene (40) stearate,
polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80
(e.g., Tween.TM. 80 of ICI), propylene glycol laurate (e.g.,
Lauroglycol.TM. of Gattefoss), sodium lauryl sulfate, sorbitan
monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan
monostearate, tyloxapol, and mixtures thereof.
[0292] Additionally, compositions of the invention optionally
comprise one or more pharmaceutically acceptable buffering agents,
flavoring agents, colorants, stabilizers and/or thickeners. Buffers
can be used to control pH of a formulation and can thereby modulate
drug solubility. Flavoring agents can enhance patient compliance by
making the composition more palatable, particularly in the case of
an imbibable composition, and colorants can provide a product with
a more aesthetic and/or distinctive appearance. Non-limiting
examples of suitable colorants include D&C Red No. 33, FD&C
Red No. 3, FD&C Red No. 40, D&C Yellow No. 10, and C Yellow
No. 6.
[0293] Solution/Suspension Compositions
[0294] In one embodiment, the solvent liquid, depending on the
particular components present therein, is suitable to maintain a
first portion of drug in solution to provide a therapeutically
effective rapid-onset dose while also maintaining a second portion
of the drug undissolved but in suspension. The suspended portion
typically provides less immediate release of the drug and so can
extend the duration of therapeutic effect, although such extended
duration is not a requirement of this embodiment of the
invention.
[0295] Therefore, according to this embodiment a composition is
provided comprising a therapeutically effective amount of a poorly
water-soluble drug, in part dissolved and in part dispersed in a
solvent liquid that comprises at least one pharmaceutically
acceptable solvent. In this embodiment, part of the drug is in
solution and part is in suspension. The composition further
comprises a crystallization inhibitor as described above, the
crystallization inhibitor being present in the solvent liquid
and/or as a component of a capsule wall.
[0296] Preferably, the components of the solvent liquid are
selected such that at least about 15% by weight of the drug is in
dissolved or solubilized form in the solvent liquid. One way of
modifying a solvent liquid to increase the amount of the poorly
water soluble drug in suspension as opposed to solution is to add
water in an amount necessary to give the required reduction in
solubility of the drug in the solvent liquid.
[0297] Depending on the relative importance of rapid onset and
sustained action for the indication for which the drug is being
administered, the relative proportions of dissolved and suspended
drug can be varied significantly. For example, for acute pain
indications, about 50% of the drug can be in solution and about 50%
of the drug can be dispersed in particulate form. Alternatively,
for indications demanding longer acting therapeutic effectiveness,
illustratively about 20% of the drug can be in solution and about
80% of the drug can be dispersed in particulate form.
[0298] The particulate form of the drug can be generated
mechanically, for example by milling or grinding, or by
precipitation from solution. Particles formed directly from such
processes are described herein as "primary particles" and can
agglomerate to form secondary aggregate particles. The term
"particle size" as used herein refers to size, in the longest
dimension, of primary particles, unless the context demands
otherwise. Particle size is believed to be an important parameter
affecting the clinical effectiveness of celecoxib and other drugs
of low water solubility.
[0299] Particle size can be expressed as the percentage of total
particles that have a diameter smaller than a given reference
diameter. For example, a useful parameter is "D.sub.90 particle
size". By definition, in a batch of a drug that has a D.sub.90
particle size of 60 .mu.m, 90% of the particles, by volume, have a
diameter less than 60 .mu.m. For practical purposes a determination
of D.sub.90 based on 90% by weight rather than by volume is
generally suitable.
[0300] Compositions of this embodiment preferably have a
distribution of suspended drug particle sizes such that D.sub.90 of
the particles, in their longest dimension, is about 0.5 .mu.m to
about 200 .mu.m, preferably about 0.5 .mu.m to about 75 .mu.m, and
more preferably about 0.5 .mu.m to about 25 .mu.m. For example,
where the drug is celecoxib, a decrease in particle size in
accordance with this embodiment of the invention generally improves
drug bioavailability. In addition or alternatively, suspended
celecoxib particles in a composition of the invention preferably
have a mean particle size less than about 10 .mu.m, more preferably
about 0.1 .mu.m to about 10 .mu.m, and most preferably about 0.5
.mu.m to about 5 .mu.m, for example about 1 .mu.m.
[0301] Compositions of this embodiment can optionally comprise
additional excipients such as dispersants, co-solvents, sweeteners,
preservatives, emulsifying agents, etc., as described above.
Further, compositions of this embodiment can be formulated either
in imbibable or discrete dosage form.
[0302] Additionally, certain excipients such as suspending agents,
thickening agents and flocculating agents can be particularly
useful where suspended drug particles are desired, for example in
solution/suspension compositions. Through selection and combination
of excipients, solution/suspension compositions can be provided
exhibiting improved performance with respect to drug concentration,
physical stability, efficacy, flavor, and overall patient
compliance.
[0303] Solution/suspension compositions of the invention optionally
comprise one or more pharmaceutically acceptable suspending agents.
Suspending agents are used to impart increased viscosity and retard
sedimentation. Suspending agents are of various classes including
cellulose derivatives, clays, natural gums, synthetic gums and
miscellaneous agents. Non-limiting examples of suspending agents
that can be used in compositions of the present invention include
acacia, agar, alginic acid, aluminum monostearate, attapulgite,
bentonite, carboxymethylcellulose calcium, carboxymethylcellulose
sodium, carrageenan, carbomer, for example carbomer 910, dextrin,
ethylmethylcellulose, gelatin, guar gum, HPMC, methylcellulose,
ethylcellulose, ethylhydroxyethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose, kaolin, magnesium aluminum silicate,
microcrystalline cellulose, microcrystalline cellulose with
carboxymethylcellulose sodium, powdered cellulose, silica gel,
colloidal silicon dioxide, locust bean gum, pectin, sodium
alginate, propylene glycol alginate, tamarind gum, tragacanth,
xanthan gum, povidone, veegum, glycyrrhizin, pregelatinized starch,
sodium starch glycolate and mixtures thereof.
[0304] In certain circumstances, it can be desirable to use
flocculating agents in solution/suspension compositions of the
invention. Flocculating agents enable particles to link together in
loose aggregates or flocs and include surfactants, hydrophilic
polymers, clays and electrolytes. Non-limiting examples of suitable
flocculating agents include sodium lauryl sulfate, docusate sodium,
benzalkonium chloride, cetylpyridinium chloride, polysorbate 80,
sorbitan monolaurate, carboxymethylcellulose sodium, xanthan gum,
tragacanth, methylcellulose, PEG, magnesium aluminum silicate,
attapulgite, bentonite, potassium dihydrogen phosphate, aluminum
chloride, sodium chloride and mixtures thereof.
[0305] Discrete Dosage Forms
[0306] It has been found that the demands of a rapid-onset
formulation are met surprisingly well by a preparation containing a
solution or solution/suspension of the present invention
encapsulated as a discrete dosage unit article. Therefore, another
embodiment of the present invention is a concentrated composition,
either a solution or solution/suspension, wherein the composition
is formulated as one or more discrete dose units, for example soft
or hard capsules.
[0307] Any suitable encapsulation material, for example gelatin or
HPMC, can be used. As indicated hereinabove, HPMC can be an
advantageous material for use in the capsule wall because it can
act as a crystallization inhibitor upon exposure of the composition
to gastrointestinal fluid. A polymer component such as HPMC is
"present in the capsule wall" or is a "capsule wall component" as
described herein if the polymer is (a) dispersed or mixed together
with any other capsule wall component(s), (b) the only capsule wall
component, or (c) present as a coating on the outside or inside of
the capsule wall.
[0308] In a presently preferred embodiment, a polymer, preferably a
polymer having methoxyl and/or hydroxypropoxyl substitution as
described hereinabove, and more preferably HPMC, is present in the
capsule wall in a total amount of about 5% to substantially 100%,
and preferably about 15% to substantially 100%, by weight of the
wall.
[0309] The crystallization inhibitor is preferably present in the
wall in a total amount sufficient to substantially inhibit drug
crystallization and/or precipitation upon dissolution, dilution
and/or degradation of the composition in SGF. For practical
purposes, whether an amount of crystallization inhibitor present in
the wall of a given test composition is sufficient to substantially
inhibit drug crystallization and/or precipitation can be determined
according to Test IV, which can also be used to determine whether a
particular polymer component is useful as a crystallization
inhibitor when present in the capsule wall of a particular
composition of the invention.
[0310] Test IV:
[0311] A. A volume of a solution or solution/suspension as
described herein above is enclosed in a capsule comprising a test
polymer to form a test composition, and is placed in a volume of
SGF to form a mixture having a fixed ratio of about 1 g to about 2
g of the composition per 100 ml of SGF.
[0312] B. The mixture is maintained at a constant temperature of
about 37.degree. C. and is stirred using type II paddles (USP 24)
at a rate of 75 rpm for a period of 4 hours.
[0313] C. At one or more time-points after at least about 15
minutes of stirring but before about 4 hours of stirring, an
aliquot of the mixture is drawn and filtered, for example through a
non-sterile Acrodisc.TM. syringe filter with a 0.8 .mu.m
Versapor.TM. membrane.
[0314] D. Filtrate is collected in a vessel.
[0315] E. Drug concentration in the filtrate is measured using high
performance liquid chromatography (HPLC).
[0316] F. The test is repeated identically with a comparative
composition comprising a solution or solution/suspension that is
substantially similar to the solution or solution/suspension used
in Step A but which is enclosed in a capsule comprising no
crystallization inhibitor (i.e. comprises no polymer or, if a
polymer is present, it is a polymer such as gelatin which does not
inhibit crystallization and/or precipitation). The polymer
component is replaced in the capsule enclosing the comparative
composition with gelatin.
[0317] G. If the drug concentration in the filtrate resulting from
the test composition is greater than that in the filtrate resulting
from the comparative composition, the polymer component present in
the capsule wall of the test composition is deemed to be present in
an amount sufficient to substantially inhibit crystallization
and/or precipitation of the drug in SGF.
[0318] In addition to one or more such crystallization inhibitors,
a suitable capsule wall can comprise any additional component
useful in the art such as gelatin, starch, carrageenan, sodium
alginate, plasticizers, potassium chloride, coloring agents, etc. A
suitable capsule herein may have a hard or soft wall.
[0319] Where a crystallization-inhibiting polymer is present as a
capsule wall component, the solution or solution/suspension
contained therein can additionally, but optionally, comprise a
further amount of a crystallization inhibitor.
[0320] Preferably, one to about six, more preferably one to about
four, and still more preferably one or two of such discrete dosage
units per day provides a therapeutically effective dose of the
drug.
[0321] Compositions of this embodiment are preferably formulated
such that each discrete dosage unit contains about 0.3 ml to about
1.5 ml, more preferably about 0.3 ml to about 1 ml, for example
about 0.8 ml or about 0.9 ml, of solution or
solution/suspension.
[0322] Concentrated solutions or solutions/suspensions can be
encapsulated by any method known in the art including the plate
process, vacuum process, or the rotary die process. See, for
example, Ansel et al. (1995) in Pharmaceutical Dosage Forms and
Drug Delivery Systems, 6th ed., Williams & Wilkins, Baltimore,
Md., pp. 176-182. By the rotary die process, liquid encapsulation
material, for example gelatin, flowing from an overhead tank is
formed into two continuous ribbons by a rotary die machine and
brought together by twin rotating dies. Simultaneously, metered
fill material is injected between ribbons at the same moment that
the dies form pockets of the ribbons. These pockets of
fill-containing encapsulation material are then sealed by pressure
and heat, and the capsules are served from the machine.
[0323] Soft capsules can be manufactured in different shapes
including round, oval, oblong, and tube-shape, among others.
Additionally, by using two different ribbon colors, two-tone
capsules can be produced.
[0324] Capsules that comprise HPMC are known in the art and can be
prepared, sealed and/or coated, by way of non-limiting
illustration, according to processes disclosed in the patents and
publications listed below, each of which is individually
incorporated herein by reference.
[0325] U.S. Pat. No. 4,250,997 to Bodemnann et al.
[0326] U.S. Pat. No. 5,264,223 to Yamamoto et al.
[0327] U.S. Pat. No. 5,756,123 to Yamamoto et al.
[0328] International Patent Publication No. WO 96/05812.
[0329] International Patent Publication No. WO 97/35537.
[0330] International Patent Publication No. WO 00/18377.
[0331] International Patent Publication No. WO 00/27367.
[0332] International Patent Publication No. WO 00/28976.
[0333] International Patent Publication No. WO 01/03676.
[0334] European Patent Application No. 0 211 079.
[0335] European Patent Application No. 0 919 228.
[0336] European Patent Application No. 1 029 539.
[0337] Non-limiting illustrative examples of suitable
HPMC-comprising capsules include XGel.TM. capsules of Bioprogress
and Qualicaps.TM. of Shionogi.
[0338] Imbibable Dosage Forms
[0339] Another embodiment of the present invention is a
concentrated composition, either a concentrated solution or a
concentrated solution/suspension, that can be directly imbibed or
diluted with inert diluents and/or other carriers and imbibed; such
compositions of the invention, whether diluted or not, are referred
to for convenience herein as "imbibable compositions". Imbibable
compositions can be prepared by any suitable method of pharmacy
that includes the steps of bringing into association the drug of
low water solubility, illustratively celecoxib, the solvent liquid
and the crystallization inhibitor. As there is no capsule wall in
this embodiment, the crystallization inhibitor must be present in
the solvent liquid. Where the drug is celecoxib, compositions of
this embodiment preferably contain about 40 mg/ml to about 750
mg/ml, more preferably about 50 mg/ml to about 500 mg/ml, still
more preferably about 50 mg/ml to about 350 mg/ml, and most
preferably, about 100 mg/ml to about 300 mg/ml, for example about
200 mg/ml, of celecoxib.
[0340] In a further embodiment, solutions or solution/suspensions
of the invention are provided that are required to be diluted to
provide a dilution suitable for direct, imbibable administration.
In this embodiment, solutions or solution/suspensions of the
present invention are added, in a therapeutically effective dosage
amount, to about 1 ml to about 20 ml of an inert liquid. Preferably
solutions or solution/suspensions of the present invention are
added to about 2 ml to about 15 ml, and more preferably to about 5
ml to about 10 ml, of inert liquid. The term "inert liquid" as used
herein refers to pharmaceutically acceptable, preferably palatable
liquid carriers. Such carriers are typically aqueous. Examples
include water, fruit juices, carbonated beverages, etc.
[0341] Drug in High Energy Phase
[0342] Low energy, hydrophobic crystalline solids, due to their
highly organized, lattice-like structures, typically require a
significant amount of energy for dissolution. The energy required
for a drug molecule to escape from a crystal, for example, is
greater than is required for the same drug molecule to escape from
a non-crystalline, amorphous form or from a higher energy
crystalline polymorph. Therefore, a drug in a high energy phase can
be more readily absorbed from the gastrointestinal tract into the
blood stream than the same drug in a low energy crystalline state.
Importantly, however, over time and upon contact with aqueous
fluid, for example SGF, drugs in a high energy phase tend to revert
to a steady state of low energy, for example to a stable, low
energy crystalline state.
[0343] Therefore, another embodiment of the invention provides an
orally deliverable pharmaceutical composition comprising a drug of
low water solubility in a high energy phase together with one or
more pharmaceutically acceptable excipients, encapsulated within a
capsule wall that comprises a a cellulosic polymer having at least
a portion of substitutable hydroxyl groups substituted by methoxyl
and/or hydroxypropoxyl groups, in an amount effective to
substantially inhibit crystallization and/or precipitation of the
drug in simulated gastric fluid.
[0344] Whether a capsule comprises a methoxyl- and/or
hydroxypropoxyl-substituted cellulosic polymer in an amount
effective to substantially inhibit drug crystallization and/or
precipitation can be determined according to Test II, described
above.
[0345] Utility of Compositions that Comprise a Selective COX-2
Inhibitory Drug
[0346] In a preferred embodiment, compositions of the invention
comprise a selective COX-2 inhibitory drug of low water solubility.
Compositions of this embodiment are useful in treatment and
prevention of a very wide range of disorders mediated by COX-2,
including but not restricted to disorders characterized by
inflammation, pain and/or fever. Such compositions are especially
useful as anti-inflammatory agents, such as in treatment of
arthritis, with the additional benefit of having significantly less
harmful side effects than compositions of conventional nonsteroidal
anti-inflammatory drugs (NSAIDs) that lack selectivity for COX-2
over COX-1. In particular, such compositions have reduced potential
for gastrointestinal toxicity and gastrointestinal irritation
including upper gastrointestinal ulceration and bleeding, reduced
potential for renal side effects such as reduction in renal
function leading to fluid retention and exacerbation of
hypertension, reduced effect on bleeding times including inhibition
of platelet function, and possibly a lessened ability to induce
asthma attacks in aspirin-sensitive asthmatic subjects, by
comparison with compositions of conventional NSAIDs. Thus
compositions of the invention comprising a selective COX-2
inhibitory drug are particularly useful as an alternative to
conventional NSAIDs where such NSAIDs are contraindicated, for
example in patients with peptic ulcers, gastritis, regional
enteritis, ulcerative colitis, diverticulitis or with a recurrent
history of gastrointestinal lesions; gastrointestinal bleeding,
coagulation disorders including anemia such as hypoprothrombinemia,
hemophilia or other bleeding problems; kidney disease; or in
patients prior to surgery or patients taking anticoagulants.
[0347] Such compositions are useful to treat a variety of arthritic
disorders, including but not limited to rheumatoid arthritis,
spondyloarthropathies, gouty arthritis, osteoarthritis, systemic
lupus erythematosus and juvenile arthritis.
[0348] Such compositions are also useful in treatment of asthma,
bronchitis, menstrual cramps, preterm labor, tendinitis, bursitis,
allergic neuritis, cytomegalovirus infectivity, apoptosis including
HUV-induced apoptosis, lumbago, liver disease including hepatitis,
skin-related conditions such as psoriasis, eczema, acne, burns,
dermatitis and ultraviolet radiation damage including sunburn, and
post-operative inflammation including that following ophthalmic
surgery such as cataract surgery or refractive surgery.
[0349] Such compositions are useful to treat gastrointestinal
conditions such as inflammatory bowel disease, Crohn's disease,
gastritis, irritable bowel syndrome and ulcerative colitis.
[0350] Such compositions are useful in treating inflammation in
such diseases as migraine headaches, periarteritis nodosa,
thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma,
rheumatic fever, type I diabetes, neuromuscular junction disease
including myasthenia gravis, white matter disease including
multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's
syndrome, polymyositis, gingivitis, nephritis, hypersensitivity,
swelling occurring after injury including brain edema, myocardial
ischemia, and the like.
[0351] Such compositions are useful in treatment of ophthalmic
diseases, such as retinitis, conjunctivitis, retinopathies,
uveitis, ocular photophobia, and of acute injury to the eye
tissue.
[0352] Such compositions are useful in treatment of pulmonary
inflammation, such as that associated with viral infections and
cystic fibrosis, and in bone resorption such as that associated
with osteoporosis.
[0353] Such compositions are useful for treatment of certain
central nervous system disorders, such as cortical dementias
including Alzheimer's disease, neurodegeneration, and central
nervous system damage resulting from stroke, ischemia and trauma.
The term "treatment" in the present context includes partial or
total inhibition of dementias, including Alzheimer's disease,
vascular dementia, multi-infarct dementia, pre-senile dementia,
alcoholic dementia and senile dementia.
[0354] Such compositions are useful in treatment of allergic
rhinitis, respiratory distress syndrome, endotoxin shock syndrome
and liver disease.
[0355] Such compositions are useful in treatment of pain, including
but not limited to postoperative pain, dental pain, muscular pain,
and pain resulting from cancer. For example, such compositions are
useful for relief of pain, fever and inflammation in a variety of
conditions including rheumatic fever, influenza and other viral
infections including common cold, low back and neck pain,
dysmenorrhea, headache, toothache, sprains and strains, myositis,
neuralgia, synovitis, arthritis, including rheumatoid arthritis,
degenerative joint diseases (osteoarthritis), gout and ankylosing
spondylitis, bursitis, bums, and trauma following surgical and
dental procedures.
[0356] Such compositions are useful for treating and preventing
inflammation-related cardiovascular disorders, including vascular
diseases, coronary artery disease, aneurysm, vascular rejection,
arteriosclerosis, atherosclerosis including cardiac transplant
atherosclerosis, myocardial infarction, embolism, stroke,
thrombosis including venous thrombosis, angina including unstable
angina, coronary plaque inflammation, bacterial-induced
inflammation including Chlamydia-induced inflammation, viral
induced inflammation, and inflammation associated with surgical
procedures such as vascular grafting including coronary artery
bypass surgery, revascularization procedures including angioplasty,
stent placement, endarterectomy, or other invasive procedures
involving arteries, veins and capillaries.
[0357] Such compositions are useful in treatment of
angiogenesis-related disorders in a subject, for example to inhibit
tumor angiogenesis. Such compositions are useful in treatment of
neoplasia, including metastasis; ophthalmological conditions such
as corneal graft rejection, ocular neovascularization, retinal
neovascularization including neovascularization following injury or
infection, diabetic retinopathy, macular degeneration, retrolental
fibroplasia and neovascular glaucoma; ulcerative diseases such as
gastric ulcer; pathological, but non-malignant, conditions such as
hemangiomas, including infantile hemangiomas, angiofibroma of the
nasopharynx and avascular necrosis of bone; and disorders of the
female reproductive system such as endometriosis.
[0358] Such compositions are useful in prevention and treatment of
benign and malignant tumors and neoplasia including cancer, such as
colorectal cancer, brain cancer, bone cancer, epithelial
cell-derived neoplasia (epithelial carcinoma) such as basal cell
carcinoma, adenocarcinoma, gastrointestinal cancer such as lip
cancer, mouth cancer, esophageal cancer, small bowel cancer,
stomach cancer, colon cancer, liver cancer, bladder cancer,
pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast
cancer, skin cancer such as squamous cell and basal cell cancers,
prostate cancer, renal cell carcinoma, and other known cancers that
effect epithelial cells throughout the body. Neoplasias for which
compositions of the invention are contemplated to be particularly
useful are gastrointestinal cancer, Barrett's esophagus, liver
cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate
cancer, cervical cancer, lung cancer, breast cancer and skin
cancer. Such compositions can also be used to treat fibrosis that
occurs with radiation therapy. Such compositions can be used to
treat subjects having adenomatous polyps, including those with
familial adenomatous polyposis (FAP). Additionally, such
compositions can be used to prevent polyps from forming in patients
at risk of FAP.
[0359] Such compositions inhibit prostanoid-induced smooth muscle
contraction by inhibiting synthesis of contractile prostanoids and
hence can be of use in treatment of dysmenorrhea, premature labor,
asthma and eosinophil-related disorders. They also can be of use
for decreasing bone loss particularly in postmenopausal women
(i.e., treatment of osteoporosis), and for treatment of
glaucoma.
[0360] Because of the rapid onset of therapeutic effect that can be
exhibited by compositions of the invention, these compositions have
particular advantages over prior formulations for treatment of
acute COX-2 mediated disorders, especially for relief of pain, for
example in headache, including sinus headache and migraine.
[0361] Preferred uses for compositions of the present invention are
for treatment of rheumatoid arthritis and osteoarthritis, for pain
management generally (particularly post-oral surgery pain,
post-general surgery pain, post-orthopedic surgery pain, and acute
flares of osteoarthritis), for prevention and treatment of headache
and migraine, for treatment of Alzheimer's disease, and for colon
cancer chemoprevention.
[0362] For treatment of rheumatoid arthritis or osteoarthritis,
such compositions of the invention can be used to provide a daily
dosage of celecoxib of about 50 mg to about 1000 mg, preferably
about 100 mg to about 600 mg, more preferably about 150 mg to about
500 mg, still more preferably about 175 mg to about 400 mg, for
example about 200 mg. A daily dose of celecoxib of about 0.7 to
about 13 mg/kg body weight, preferably about 1.3 to about 8 mg/kg
body weight, more preferably about 2 to about 6.7 mg/kg body
weight, and still more preferably about 2.3 to about 5.3 mg/kg body
weight, for example about 2.7 mg/kg body weight, is generally
appropriate when administered in a composition of the invention.
The daily dose can be administered in one to about four doses per
day, preferably one or two doses per day.
[0363] For treatment of Alzheimer's disease or cancer, such
compositions of the invention can be used to provide a daily dosage
of celecoxib of about 50 mg to about 1000 mg, preferably about 100
mg to about 800 mg, more preferably about 150 mg to about 600 mg,
and still more preferably about 175 mg to about 400 mg, for example
about 400 mg. A daily dose of about 0.7 to about 13 mg/kg body
weight, preferably about 1.3 to about 10.7 mg/kg body weight, more
preferably about 2 to about 8 mg/kg body weight, and still more
preferably about 2.3 to about 5.3 mg/kg body weight, for example
about 5.3 mg/kg body weight, is generally appropriate when
administered in a composition of the invention. The daily dose can
be administered in one to about four doses per day, preferably one
or two doses per day.
[0364] For pain management generally and specifically for treatment
and prevention of headache and migraine, such compositions of the
invention can be used to provide a daily dosage of celecoxib of
about 50 mg to about 1000 mg, preferably about 100 mg to about 600
mg, more preferably about 150 mg to about 500 mg, and still more
preferably about 175 mg to about 400 mg, for example about 200 mg.
A daily dose of celecoxib of about 0.7 to about 13 mg/kg body
weight, preferably about 1.3 to about 8 mg/kg body weight, more
preferably about 2 to about 6.7 mg/kg body weight, and still more
preferably about 2.3 to about 5.3 mg/kg body weight, for example
about 2.7 mg/kg body weight, is generally appropriate when
administered in a composition of the invention. The daily dose can
be administered in one to about four doses per day. Administration
at a rate of one 50 mg dose unit four times a day, one 100 mg dose
unit or two 50 mg dose units twice a day or one 200 mg dose unit,
two 100 mg dose units or four 50 mg dose units once a day is
preferred.
[0365] For selective COX-2 inhibitory drugs other than celecoxib,
appropriate doses can be selected by reference to the patent
literature cited hereinabove.
[0366] Besides being useful for human treatment, such compositions
of the invention are useful for veterinary treatment of companion
animals, exotic animals, farm animals, and the like, particularly
mammals. More particularly, such compositions of the invention are
useful for treatment of COX-2 mediated disorders in horses, dogs
and cats.
[0367] This embodiment of the invention is further directed to a
therapeutic method of treating a condition or disorder where
treatment with a COX-2 inhibitory drug is indicated, the method
comprising oral administration of a composition of the invention to
a subject in need thereof. The dosage regimen to prevent, give
relief from, or ameliorate the condition or disorder preferably
corresponds to once-a-day or twice-a-day treatment, but can be
modified in accordance with a variety of factors. These include the
type, age, weight, sex, diet and medical condition of the subject
and the nature and severity of the disorder. Thus, the dosage
regimen actually employed can vary widely and can therefore deviate
from the preferred dosage regimens set forth above.
[0368] Initial treatment can begin with a dose regimen as indicated
above. Treatment is generally continued as necessary over a period
of several weeks to several months or years until the condition or
disorder has been controlled or eliminated. Subjects undergoing
treatment with a composition of the invention can be routinely
monitored by any of the methods well known in the art to determine
effectiveness of therapy. Continuous analysis of data from such
monitoring permits modification of the treatment regimen during
therapy so that optimally effective doses are administered at any
point in time, and so that the duration of treatment can be
determined. In this way, the treatment regimen and dosing schedule
can be rationally modified over the course of therapy so that the
lowest amount of the composition exhibiting satisfactory
effectiveness is administered, and so that administration is
continued only for so long as is necessary to successfully treat
the condition or disorder.
[0369] Compositions of the present embodiment can be used in
combination therapies with opioids and other analgesics, including
narcotic analgesics, Mu receptor antagonists, Kappa receptor
antagonists, non-narcotic (i.e. non-addictive) analgesics,
monoamine uptake inhibitors, adenosine regulating agents,
cannabinoid derivatives, Substance P antagonists, neurokinin-1
receptor antagonists and sodium channel blockers, among others.
Preferred combination therapies comprise use of a composition of
the invention with one or more compounds selected from aceclofenac,
acemetacin, e-acetamidocaproic acid, acetaminophen, acetaminosalol,
acetanilide, acetylsalicylic acid (aspirin), S-adenosylmethionine,
alclofenac, alfentanil, allylprodine, alminoprofen, aloxiprin,
alphaprodine, aluminum bis(acetylsalicylate), amfenac,
aminochlorthenoxazin, 3-amino-4-hydroxybutyric acid,
2-amino-4-picoline, aminopropylon, aminopyrine, amixetrine,
ammonium salicylate, ampiroxicam, amtolmetin guacil, anileridine,
antipyrine, antipyrine salicylate, antrafenine, apazone, bendazac,
benorylate, benoxaprofen, benzpiperylon, benzydamine,
benzylmorphine, bermoprofen, bezitramide, .alpha.-bisabolol,
bromfenac, p-bromoacetanilide, 5-bromosalicylic acid acetate,
bromosaligenin, bucetin, bucloxic acid, bucolome, bufexamac,
bumadizon, buprenorphine, butacetin, butibufen, butophanol, calcium
acetylsalicylate, carbamazepine, carbiphene, carprofen, carsalam,
chlorobutanol, chlorthenoxazin, choline salicylate, cinchophen,
cinmetacin, ciramadol, clidanac, clometacin, clonitazene, clonixin,
clopirac, clove, codeine, codeine methyl bromide, codeine
phosphate, codeine sulfate, cropropamide, crotethamide,
desomorphine, dexoxadrol, dextromoramide, dezocine, diampromide,
diclofenac sodium, difenamizole, difenpiramide, diflunisal,
dihydrocodeine, dihydrocodeinone enol acetate, dihydromorphine,
dihydroxyaluminum acetylsalicylate, dimenoxadol, dimepheptanol,
dimethylthiambutene, dioxaphetyl butyrate, dipipanone, diprocetyl,
dipyrone, ditazol, droxicam, emorfazone, enfenamic acid, epirizole,
eptazocine, etersalate, ethenzamide, ethoheptazine, ethoxazene,
ethylmethylthiambutene, ethylmorphine, etodolac, etofenamate,
etonitazene, eugenol, felbinac, fenbufen, fenclozic acid, fendosal,
fenoprofen, fentanyl, fentiazac, fepradinol, feprazone,
floctafenine, flufenamic acid, flunoxaprofen, fluoresone,
flupirtine, fluproquazone, flurbiprofen, fosfosal, gentisic acid,
glafenine, glucametacin, glycol salicylate, guaiazulene,
hydrocodone, hydromorphone, hydroxypethidine, ibufenac, ibuprofen,
ibuproxam, imidazole salicylate, indomethacin, indoprofen,
isofezolac, isoladol, isomethadone, isonixin, isoxepac, isoxicam,
ketobemidone, ketoprofen, ketorolac, p-lactophenetide, lefetamine,
levorphanol, lofentanil, lonazolac, lornoxicam, loxoprofen, lysine
acetylsalicylate, magnesium acetylsalicylate, meclofenamic acid,
mefenamic acid, meperidine, meptazinol, mesalamine, metazocine,
methadone hydrochloride, methotrimeprazine, metiazinic acid,
metofoline, metopon, mofebutazone, mofezolac, morazone, morphine,
morphine hydrochloride, morphine sulfate, morpholine salicylate,
myrophine, nabumetone, nalbuphine, 1-naphthyl salicylate, naproxen,
narceine, nefopam, nicomorphine, nifenazone, niflumic acid,
nimesulide, 5'-nitro-2'-propoxyacetanilide, norlevorphanol,
normethadone, normorphine, norpipanone, olsalazine, opium,
oxaceprol, oxametacine, oxaprozin, oxycodone, oxymorphone,
oxyphenbutazone, papaveretum, paranyline, parsalmide, pentazocine,
perisoxal, phenacetin, phenadoxone, phenazocine, phenazopyridine
hydrochloride, phenocoll, phenoperidine, phenopyrazone, phenyl
acetylsalicylate, phenylbutazone, phenyl salicylate, phenyramidol,
piketoprofen, piminodine, pipebuzone, piperylone, piprofen,
pirazolac, piritramide, piroxicam, pranoprofen, proglumetacin,
proheptazine, promedol, propacetamol, propiram, propoxyphene,
propyphenazone, proquazone, protizinic acid, ramifenazone,
remifentanil, rimazolium metilsulfate, salacetamide, salicin,
salicylamide, salicylamide o-acetic acid, salicylsulfuric acid,
salsalte, salverine, simetride, sodium salicylate, sufentanil,
sulfasalazine, sulindac, superoxide dismutase, suprofen,
suxibuzone, talniflumate, tenidap, tenoxicam, terofenamate,
tetrandrine, thiazolinobutazone, tiaprofenic acid, tiaramide,
tilidine, tinoridine, tolfenamic acid, tolmetin, tramadol,
tropesin, viminol, xenbucin, ximoprofen, zaltoprofen and zomepirac
(see The Merck Index, 12th Edition (1996), Therapeutic Category and
Biological Activity Index, lists therein headed "Analgesic",
"Anti-inflammatory" and "Antipyretic").
[0370] Particularly preferred combination therapies comprise use of
a composition of this embodiment with an opioid compound, more
particularly where the opioid compound is codeine, meperidine,
morphine or a derivative thereof.
[0371] The compound to be administered in combination with a
selective COX-2 inhibitory drug can be formulated separately from
the drug or co-formulated with the drug in a composition of the
invention. Where a selective COX-2 inhibitory drug is co-formulated
with a second drug, for example an opioid drug, the second drug can
be formulated in immediate-release, rapid-onset, sustained-release
or dual-release form.
[0372] In an embodiment of the invention, particularly where the
COX-2 mediated condition is headache or migraine, the present
selective COX-2 inhibitory drug composition is administered in
combination therapy with a vasomodulator, preferably a xanthine
derivative having vasomodulatory effect, more preferably an
alkylxanthine compound.
[0373] Combination therapies wherein an alkylxanthine compound is
co-administered with a selective COX-2 inhibitory drug composition
as provided herein are embraced by the present embodiment of the
invention whether or not the alkylxanthine is a vasomodulator and
whether or not the therapeutic effectiveness of the combination is
to any degree attributable to a vasomodulatory effect. The term
"alkylxanthine" herein embraces xanthine derivatives having one or
more C.sub.1-4 alkyl, preferably methyl, substituents, and
pharmaceutically acceptable salts of such xanthine derivatives.
Dimethylxanthines and trimethylxanthines, including caffeine,
theobromine and theophylline, are especially preferred. Most
preferably, the alkylxanthine compound is caffeine.
[0374] The total and relative dosage amounts of the selective COX-2
inhibitory drug and of the vasomodulator or alkylxanthine are
selected to be therapeutically and/or prophylactically effective
for relief of pain associated with the headache or migraine.
Suitable dosage amounts will depend on the particular selective
COX-2 inhibitory drug and the particular vasomodulator or
alkylxanthine selected. For example, in a combination therapy with
celecoxib and caffeine, typically the celecoxib will be
administered in a daily dosage amount of about 50 mg to about 1000
mg, preferably about 100 mg to about 600 mg, and the caffeine in a
daily dosage amount of about 1 mg to about 500 mg, preferably about
10 mg to about 400 mg, more preferably about 20 mg to about 300
mg.
[0375] The vasomodulator or alkylxanthine component of the
combination therapy can be administered in any suitable dosage form
by any suitable route, preferably orally. The vasomodulator or
alkylxanthine can optionally be coformulated with the selective
COX-2 inhibitory drug in a single oral dosage form. Thus a solution
or solution/suspension formulation of the invention optionally
comprises both an aminosulfonyl-comprising selective COX-2
inhibitory drug and a vasomodulator or alkylxanthine such as
caffeine, in total and relative amounts consistent with the dosage
amounts set out hereinabove.
[0376] The phrase "in total and relative amounts effective to
relieve pain", with respect to amounts of a selective COX-2
inhibitory drug and a vasomodulator or alkylxanthine in a
composition of the present embodiment, means that these amounts are
such that (a) together these components are effective to relieve
pain, and (b) each component is or would be capable of contribution
to a pain-relieving effect if the other component is or were not
present in so great an amount as to obviate such contribution.
EXAMPLES
Example 1
[0377] Several polymers were tested as potential crystallization
inhibitors for celecoxib and valdecoxib according to Test I
described hereinabove. Polymers tested include polyvinylpyrrolidone
(PVP), MW 10,000, 29,000 and 55,000; sodium carboxymethylcellulose
(Na CMC), MW 250,000; dextran (MW 65,000); hydroxypropylcellulose
(HPC), MW 80,000; ethylcellulose A15; hydroxypropylmethylcellulose
(HPMC) E15; and polyethylene glycol (PEG), MW 8,000 and 20,000).
Glycerin, a non-polymer, was also tested for comparative purposes.
In each case, the solvent used to prepare the concentrated drug
solution was ethanol and the buffered solution used in step B of
Test I comprised pH 7 phosphate buffer. The sample solution in each
case contained 2.5% ethanol derived from the concentrated drug
solution.
[0378] As is shown in Table 1, where a high concentration (250
.mu.g/ml) of celecoxib which, in the absence of polymer produced
substantial precipitation (turbidity of 0.376), was tested, PVP
10,000, PVP 29,000, PVP 55,000, Na CMC 250,000, HPC 80,000,
ethylcellulose A15 and HPMC E15 all reduced turbidity of respective
sample solutions. Where a lower concentration of celecoxib (125
.mu.g/ml), which produced somewhat less precipitation (turbidity of
0.146) in the absence of polymer, was tested, PVP 10,000, PVP
29,000, PVP 55,000, Na CMC 250,000, HPC 80,000, ethylcellulose A15
and HPMC E15 all reduced turbidity of respective sample solutions.
Two lower concentrations (62.5 and 31.3 .mu.g/ml) of celecoxib were
also tested but did not produce enough precipitation in the absence
of polymer to adequately perform Test I. In general, background
noise in the turbidity reading accounts for a signal of about
0.03.
[0379] Testing of valdecoxib, a drug of slightly higher solubility
than celecoxib, at the low concentrations of 125, 62.5 and 31.3
.mu.g/ml did not produce enough precipitation in the absence of
polymer to adequately perform Test I. However, at 250 .mu.g/ml of
valdecoxib where a turbidity reading of 0.185 was observed in the
absence of polymer, PVP 29,000, PVP 55,000, Na CMC 250,000, HPC
80,000, ethylcellulose A15 and HPMC E15 reduced turbidity of
respective sample solutions.
1TABLE 1 Test I results for celecoxib and valdecoxib with several
polymers Absorbance at four drug Polymer concentrations (.mu.g/ml)
Drug (0.5% w/w) 250 125 62.5 31.3 Celecoxib PVP 10,000 0.2 0.072
0.041 0.035 Celecoxib PVP 29,000 0.118 0.064 0.037 0.031 Celecoxib
PVP 55,000 0.105 0.048 0.049 0.04 Celecoxib Na CMC 250,000 0.148
0.083 0.078 0.046 Celecoxib Dextran 65,000 0.379 0.266 0.076 0.033
Celecoxib HPC 80,000 0.11 0.05 0.038 0.034 Celecoxib Ethylcellulose
A15 0.085 0.06 0.039 0.041 Celecoxib HPMC E15 0.093 0.049 0.039
0.037 Celecoxib PEG 8,000 0.485 0.308 0.169 0.031 Celecoxib PEG
20,000 0.654 0.342 0.16 0.039 Celecoxib Glycerin 0.41 0.184 0.07
0.038 Celecoxib None 0.376 0.146 0.069 0.036 Valdecoxib PVP 10,000
0.321 0.032 0.034 0.032 Valdecoxib PVP 29,000 0.183 0.032 0.03 0.03
Valdecoxib PVP 55,000 0.162 0.032 0.031 0.032 Valdecoxib Na CMC
250,000 0.174 0.09 0.036 0.03 Valdecoxib Dextran 65,000 0.289 0.033
0.031 0.03 Valdecoxib HPC 80,000 0.093 0.046 0.032 0.031 Valdecoxib
Ethylcellulose A15 0.052 0.033 0.033 0.033 Valdecoxib HPMC E15
0.064 0.034 0.034 0.032 Valdecoxib PEG 8,000 0.345 0.03 0.03 0.03
Valdecoxib PEG 20,000 0.433 0.031 0.031 0.031 Valdecoxib Glycerin
0.229 0.029 0.028 0.03 Valdecoxib None 0.185 0.029 0.029 0.031
Example 2
[0380] A celecoxib solution formulation SF-1 was prepared as shown
in Table 2.
2TABLE 2 Composition (mg/g) of celecoxib solution formulation SF-1
Component SF-1 Celecoxib 200 PEG-400 300 Polysorbate 80 270 Oleic
acid 70 Tromethamine 30 Water 30 Absolute ethanol 100 Total
1000
[0381] Three different test compositions, SF-1A, SF-1B and SF-1C,
were prepared using SF-1. Test composition SF-1A consisted of 0.8 g
SF-1 in unencapsulated, imbibable form. Test composition SF-1B
consisted of 0.8 g SF-1 encapsulated in a hard gelatin capsule
(Capsugel) and test composition SF-1C consisted of 0.8 g SF-1
encapsulated in a 100 mg hard HPMC capsule (Shionogi).
[0382] An in vitro test was conducted, at a fixed dilution of 1 g
SF-1per 50 ml SGF, to evaluate dissolution behavior of celecoxib in
the above three test compositions in a limited volume of SGF
maintained at 37.degree. C. Test composition SF-1A was dissolved in
SGF which already contained 0.2% pre-dissolved HPMC. Test
compositions SF-1B and SF-1C were individually dissolved in SGF
containing no pre-dissolved HPMC. A constant stirring rate of 75
rpm was applied using type II paddles (USP 24). Any solid drug that
precipitated in SGF was removed by filtration through a non-sterile
Acrodisc.TM. syringe filter with a 0.8 .mu.m Versapor.TM. membrane.
Drug concentration in the SGF was determined by HPLC as a function
of time, reflecting the amount of drug remaining in a dissolved or
solubilized state (either existing as free drug in solution or
partitioning into emulsion droplets).
[0383] Remarkably, the results, shown in FIG. 1, indicate that upon
dissolution in SGF, the presence of HPMC (either pre-dissolved in
SGF as in test composition SF-1A or derived from the HPMC capsule
wall as in test composition SF-1C) effectively maintained a
supersaturated solution of celecoxib (approximately 2-3 mg/ml) for
at least 5 hours. In contrast, in the absence of HPMC (test
composition SF-1B), celecoxib concentration was much lower
(approximately 0.35 mg/ml) due to drug crystallization and
precipitation.
Example 3
[0384] Two celecoxib solution formulations, SF-2 and SF-3, were
prepared as shown in Table 3.
3TABLE 3 Composition (mg/g) of celecoxib solution formulations SF-2
and SF-3 Component SF-2 SF-3 Celecoxib 200 200 Water USP 26 26 HPMC
(E5) 38 -- Ethanol 113 100 PEG-400 271 322 Polyvinylpyrrolidone 47
47 Polysorbate 80 217 217 Tromethamine 26 26 Oleic acid 61 61
Propyl gallate NF 1 1 Total 1000 1000
[0385] Three test compositions were prepared as follows. Test
composition SF-2A consisted of 1 g SF-2 (which already contained 38
mg/ml HPMC) in a hard gelatin capsule (Capsugel); comparative test
composition SF-3A consisted of 1 g SF-3 (containing no HPMC) in a
hard gelatin capsule (Capsugel); and test composition SF-3B
consisted of 1 g SF-3 (containing no HPMC) in a 100 mg HPMC capsule
(Shionogi).
[0386] An in vitro dissolution test was conducted as described in
Example 2 (except at dilution of 1 g of test composition per 100 ml
SGF, and in no case was HPMC pre-dissolved in SGF). Data, shown in
FIG. 2, indicate that rapid precipitation of celecoxib occurred
when gelatin capsules were used and the solution formulation
contained no HPMC (SF-3A) while a supersaturated celecoxib solution
(1-1.2 mg/ml) was achieved with either HPMC suspended in the
solution formulation itself (SF-2A) or with HPMC present in the
capsule wall but not in the solution formulation (SF-3B).
Example 4
[0387] A celecoxib solution formulation (SF-4) was prepared having
components as shown in Table 4.
4TABLE 4 Composition (mg/g) of celecoxib solution formulation SF-4
Component SF-4 Celecoxib 200 PEG-400 442 Polysorbate 80 252 Oleic
acid 80 Dimethylethanolamine 26 Total 1000
[0388] Two test compositions were prepared as follows. Test
composition SF-4A consisted of 1 g SF-4 in a 100 mg HPMC capsule
(Shionogi) and comparative test composition SF-4B consisted of 1 g
SF-4 in a hard gelatin capsule (Capsugel).
[0389] An in vitro dissolution test was conducted as in Example 3.
The results, shown in FIG. 3, indicate that a supersaturated
celecoxib solution (approximately 1.5 mg/ml after 4 hours) was
achieved when HPMC was present in the capsule wall (SF-4A) while
rapid precipitation of celecoxib occurred when no HPMC was present
in the capsule wall (SF-4B).
EXAMPLE 5
[0390] Three celecoxib solution formulations SF-5 to SF-7 were
prepared having components as shown in Table 5.
5TABLE 5 Composition (mg/g) of celecoxib solution formulations SF-5
to SF-7 Component SF-5 SF-6 SF-7 Celecoxib 200 200 200 PEG-400 300
300 288 Polysorbate 80 270 270 232 Dehydrated alcohol 100 100 120
Oleic acid 70 70 65 Tromethamine 30 30 27.5 Water 30 30 27.5 HPMC
(E5) -- -- 40 Total 1000 1000 1000
[0391] Aliquots (1 g) of SF-5 were individually loaded into each of
several 100 mg HPMC capsules (Shionogi) to form test composition
SF-5A, and 1 g aliquots of SF-6 and SF-7 were individually loaded
into each of several hard gelatin capsules (Capsugel) to form
comparative test composition SF-6A and test composition SF-7A
respectively.
[0392] In vivo bioavailability of celecoxib after administration of
test compositions SF-5A, SF-6A and SF-7A was evaluated in fasting
dogs in a three-way cross-over design. Each of 6 dogs received a
test composition in an amount providing a celecoxib dose of 10
mg/kg. Blood serum celecoxib concentrations were measured by HPLC
at baseline and at 0.5, 0.75, 1.0, 1.5, 2, 3, 5, 8, and 24 hours
after administration. C.sub.max (maximum blood serum concentration)
and AUC (area under the curve, a measure of total bioavailability)
were calculated from the data in accordance with standard procedure
in the art. As shown in FIG. 4, the presence of HPMC as a component
of the solution formulation of SF-7A or as a capsule wall component
of SF-5A resulted in a higher C.sub.max and greater AUC than that
observed with comparative composition SF-6A that contained no
HPMC.
Example 6
[0393] A celecoxib suspension formulation was prepared for
comparative purposes as follows:
[0394] (a) 5.0 g Tween.TM. 80 (polysorbate 80) was placed in a
volumetric flask;
[0395] (b) ethanol was added (to 100 ml) to form a mixture and the
mixture was swirled to form a uniform solution;
[0396] (c) 5 ml of the uniform solution was transferred to a fresh
100 ml bottle containing 200 mg celecoxib to form a pre-mix;
[0397] (d) 75 ml apple juice was added to the premix to form an
intermediate celecoxib suspension; and
[0398] (e) the intermediate celecoxib suspension was left to stand
for 5 minutes, and was then shaken to form a celecoxib
suspension.
[0399] Bioavailability parameters resulting from administration of
test composition SF-2A of Example 3, in comparison with the
comparative celecoxib suspension composition of Example 6 and with
a commercial celecoxib (Celebrex.RTM. of Pharmacia) 200 mg capsule,
to human subjects were evaluated in a 24-subject, randomized, four
period, balanced, crossover study. A fourth composition, not
relevant to the present invention, was also included in the study
but is not reported here. Study duration was approximately 15 days
and subjects were randomly given one of each of the four dosage
forms on days 1, 5, 9 and 12; administration of each dose was
preceded by an 8 hour fasting period and was accompanied by 180 ml
of water. Plasma blood levels for each subject were measured at
pre-dose and at 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 12
and 24 hours after dosage administration. C.sub.max and AUC were
calculated from the data in accordance with standard procedure in
the art. As shown in Table 6, ingestion of test composition SF-2A
resulted in a C.sub.max more than 2.5 times greater than resulted
from ingestion of the comparative celecoxib suspension or the
commercial celecoxib capsule. Ingestion of test composition SF-2A
also resulted in an AUC 43% greater than, and a T.sub.max
substantially similar to, that resulting from ingestion of the
comparative celecoxib suspension.
6TABLE 6 In vivo bioavailability of celecoxib in human subjects
Commercial Comparative Test composition Parameter capsule
suspension SF-2A C.sub.max (ng/ml) 621 804 2061 T.sub.max (hr) 2.15
0.97 1.03 AUG (ng/ml)*hr 5060 4892 7593
Example 7
[0400] Two paclitaxel solution formulations, comparative
formulation SF-8 and solution formulation SF-9 of the invention
were prepared as shown in Table 7.
7TABLE 7 Composition (mg/g) of paclitaxel solution formulations
SF-8 and SF-9 Component SF-8 SF-9 Paclitaxel 60 60 PEG-400 160 150
Cremophor .TM. EL 420 400 Absolute ethanol 160 150 HPMC (E5) -- 50
Glyceryl dioleate 200 190 Total 1000 1000
[0401] Formulations SF-8 and SF-9 were individually evaluated in
duplicate in an in vitro dissolution experiment as described in
Example 2, at a 1 in 50 dilution. Data, shown in FIG. 5, indicate
that rapid precipitation of paclitaxel occurred in both duplicate
tests of solution formulation SF-8 that contained no HPMC, while a
supersaturated paclitaxel solution was achieved in both duplicate
tests when HPMC was present in the solution formulation (SF-9).
Example 8
[0402] Two paclitaxel solution formulations, SF-10 and SF-11, were
prepared as shown in Table 8. Oral bioavailability (in vivo) of
formulations SF-10 and SF-11 were evaluated in male Sprague-Dawley
rats (n=8). All formulations were orally dosed at 10 mg/kg.
8TABLE 8 Composition (mg/g) of paclitaxel solution formulations
SF-10 and SF-11 Component SF-10 SF-11 Paclitaxel 57 62.5 Absolute
ethanol 151.5 156.25 PEG 400 151.5 156.25 Cremophor .RTM. EL 400
417 Glyceryl dioleate 190 208 HPMC E5 50 -- Total 1000 1000
[0403] As shown in Table 9, oral administration of solution
formulation SF-10 resulted in a C.sub.max more than 20-fold greater
than resulted from administration of comparative solution
formulation SF-11 and a higher AUC than resulted from
administration of comparative solution formulation SF-11.
Administration of solution formulation SF-10 also resulted in a
T.sub.max substantially similar to that resulting from
administration of solution formulation SF-11.
9TABLE 9 In vivo bioavailability of paclitaxel in male
Sprague-Dawley Rats Parameter SF-10 SF-11 C.sub.max (ng/ml) 277
13.1 T.sub.max (hr) 0.63 0.42 AUC (ng/ml)*hr 329 26.8
* * * * *