U.S. patent application number 10/119118 was filed with the patent office on 2003-06-05 for stabilized oral pharmaceutical composition.
Invention is credited to Bauer, Juliane M., Brugger, Andrew M., Forbes, James C., Gao, Ping, Guido, Jane E., Hassan, Fred, Huang, Tiehua, Karim, Aziz, Robins, Russell H..
Application Number | 20030105144 10/119118 |
Document ID | / |
Family ID | 26962690 |
Filed Date | 2003-06-05 |
United States Patent
Application |
20030105144 |
Kind Code |
A1 |
Gao, Ping ; et al. |
June 5, 2003 |
Stabilized oral pharmaceutical composition
Abstract
An orally deliverable pharmaceutical composition is provided
comprising an aminosulfonyl-comprising drug, for example a
selective cyclooxygenase-2 inhibitory drug such as celecoxib, and a
solvent liquid comprising a polyethylene glycol and one or more
free radical-scavenging antioxidants. At least a substantial part
of the drug is in dissolved form in the solvent liquid. The
composition has rapid-onset properties and is useful in treatment
of cyclooxygenase-2 mediated conditions and disorders.
Inventors: |
Gao, Ping; (Portage, MI)
; Huang, Tiehua; (Kalamazoo, MI) ; Robins, Russell
H.; (Portage, MI) ; Bauer, Juliane M.;
(Portage, MI) ; Guido, Jane E.; (Vicksburg,
MI) ; Brugger, Andrew M.; (Libertyville, IL) ;
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: |
26962690 |
Appl. No.: |
10/119118 |
Filed: |
April 9, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60284589 |
Apr 17, 2001 |
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60357959 |
Feb 19, 2002 |
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Current U.S.
Class: |
514/357 ;
514/378; 514/406; 514/471; 514/602 |
Current CPC
Class: |
C07D 261/08 20130101;
A61K 47/22 20130101; A61K 31/415 20130101; A61K 9/4866 20130101;
A61K 47/12 20130101; A61K 47/60 20170801; A61K 31/42 20130101; A61P
29/00 20180101; A61K 47/02 20130101; A61P 25/06 20180101; C07D
231/12 20130101; A61P 43/00 20180101; A61K 47/38 20130101; A61K
9/4858 20130101; C07D 413/12 20130101; A61K 31/635 20130101; A61K
9/0019 20130101 |
Class at
Publication: |
514/357 ;
514/406; 514/378; 514/471; 514/602 |
International
Class: |
A61K 031/44; A61K
031/42; A61K 031/415; A61K 031/18; A61K 031/365 |
Claims
What is claimed is:
1. An orally deliverable pharmaceutical composition comprising (a)
a drug of low water solubility in a therapeutically and/or
prophylactically effective amount and (b) a solvent liquid that
comprises at least one pharmaceutically acceptable polyethylene
glycol and at least one pharmaceutically acceptable free
radical-scavenging antioxidant, wherein a substantial portion of
the drug is in dissolved or solubilized form in the solvent liquid,
and wherein the drug comprises an aminosulfonyl functional group
and/or is capable of reacting with a polyethylene glycol or with a
polyethylene glycol degradation product to form an addition
compound.
2. The composition of claim 1 wherein the drug is a selective
cyclooxygenase-2 inhibitory drug.
3. The composition of claim 2 wherein the selective
cyclooxygenase-2 inhibitory drug is a compound of formula 8where
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.
4. The composition of claim 3 wherein the five- to six-membered
ring is selected from the group consisting of cyclopentenone,
furanone, methylpyrazole, isoxazole and pyridine rings substituted
at no more than one position.
5. The composition of claim 2 wherein the drug is selected from the
group consisting of celecoxib, deracoxib, valdecoxib and
JTE-522.
6. The composition of claim 2 wherein the drug is celecoxib.
7. The composition of claim 2 wherein the drug is valdecoxib.
8. The composition of claim 2 that further comprises 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.
9. The composition of claim 2 that further comprises 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.
10. The composition of claim 9 wherein the alkylxanthine compound
is caffeine.
11. The composition of claim 1 wherein the polyethylene glycol has
an average molecular weight of about 100 to about 10,000.
12. The composition of claim 1 wherein the polyethylene glycol is
of liquid grade.
13. The composition of claim 1 wherein the at least one free
radical-scavenging antioxidant is present in the solvent liquid in
a total amount of about 0.01% to about 5% by weight of the
composition.
14. The composition of claim 1 wherein the at least one free
radical-scavenging antioxidant is present in the solvent liquid in
a total amount of about 0.01% to about 1% by weight of the
composition.
15. The composition of claim 1 wherein the at least one free
radical-scavenging antioxidant is selected from the group
consisting of vitamin E, ascorbic acid and salts thereof, butylated
hydroxyanisole, butylated hydroxytoluene, fumaric acid and salts
thereof, hypophosphorous acid, malic acid, alkyl gallates, sodium
thiosulfate, sodium sulfite, sodium bisulfite and sodium
metabisulfite.
16. The composition of claim 1 wherein the at least one free
radical-scavenging antioxidant is propyl gallate.
17. The composition of claim 1 wherein the at least one free
radical-scavenging antioxidant is vitamin E.
18. The composition of claim 1 wherein substantially all of the
drug present in the composition is in dissolved or solubilized
form.
19. The composition of claim 1 wherein the solvent liquid further
comprises a turbidity-decreasing polymer.
20. The composition of claim 19 wherein the at least one
turbidity-decreasing polymer is hydroxypropylmethylcellulose.
21. The composition of claim 1 wherein the solvent liquid further
comprises at least one pharmaceutically acceptable fatty acid and
at least one pharmaceutically acceptable organic amine.
22. The composition of claim 21 wherein the at least one fatty acid
is oleic acid.
23. The composition of claim 21 wherein the at least one organic
amine is a tertiary amine selected from the group consisting of
triethanolamine and dimethylaminoethanol.
24. The composition of claim 1 that comprises one or more discrete
dose units, wherein a therapeutically and/or prophylactically
effective amount of the drug is contained in one to a small
plurality of said dose units.
25. The composition of claim 24 wherein each dose unit is a
liquid-filled capsule having a capsule wall.
26. The composition of claim 25 wherein the capsule wall comprises
a turbidity-decreasing polymer.
27. The composition of claim 26 wherein the turbidity-decreasing
polymer is hydroxypropylmethylcellulose.
28. 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 2.
29. A method of analgesia comprising orally administering an
effective pain-relieving amount of a composition of claim 2 to a
subject in need of analgesia.
30. The method of claim 29 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.
31. The method of claim 29 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.
32. A method of use of a composition of claim 2 in manufacture of a
medicament useful for treating a medical condition or disorder in a
subject where treatment with a cyclooxygenase-2 inhibitor is
indicated.
Description
[0001] This application claims priority of U.S. provisional patent
application Serial No. 60/284,589 filed on Apr. 17, 2001, and of
U.S. provisional patent application Serial No. 60/357,959 filed on
Feb. 19, 2002.
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] Several compounds having a molecular structure that
comprises an aminosulfonyl functional group (herein referred to as
aminosulfonyl-comprising compounds) have been reported as having
therapeutically and/or prophylactically useful selective
cyclooxygenase-2 (COX-2) inhibitory effects, 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. 5,760,068 to
Talley et al., including for example the compound
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonam-
ide, also referred to herein as celecoxib (I), and the compound
4-[5-(3-fluoro-4-methoxyphenyl)-3-difluoromethyl)-1H-pyrazol-1-yl]benzene-
sulfonamide, also referred to herein as deracoxib (II). 1
[0004] Other aminosulfonyl-comprising 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]benzenesulfonamide, also
referred to herein as valdecoxib (III). 2
[0005] 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 are
useful to provide fast pain relief.
[0006] 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.
[0007] 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
Gattefosse, 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.
[0008] 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, 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.
[0009] 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.
[0010] 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.
[0011] 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).
[0012] 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.
[0013] It is known to encapsulate liquid formulations, for example
in soft or hard gelatin capsules, to provide a discrete dosage
form.
[0014] Many aminosulfonyl-comprising selective COX-2 inhibitory
drugs, including celecoxib, deracoxib and valdecoxib, 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
such drugs for rapid-onset, oral administration. With respect to
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 such 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.
[0015] Moreover, the solvent should be selected not to chemically
interact with or degrade the drug. For solutions and/or suspensions
that are to be encapsulated as oral dosage forms, the solvent must
further be selected not to degrade, erode, or react with the
capsule wall material. Further, liquids that can easily migrate
through a capsule wall, e.g., water in an amount greater than about
5% by weight of the solution, and low molecular weight
water-soluble, volatile organic compounds such as alcohols,
ketones, acids, amines and esters, are generally unsuitable for
encapsulation.
[0016] Water-miscible, nonvolatile liquids such as polyethylene
glycols have been successfully used in encapsulated solution
formulations. Moreover, polyethylene glycols are also good solvents
for drugs of low water solubility because they are known to improve
aqueous drug solubility. For example, celecoxib, which has very low
solubility in water, is highly soluble (>300 mg/g) in a 2:1
mixture of PEG-400 and water.
[0017] However, we have now discovered that polyethylene glycol,
when used as a solvent for an aminosulfonyl-comprising drug such as
celecoxib, can result in drug instability. This problem presents
practical difficulties in forming a chemically stable solution of
an aminosulfonyl-comprising drug using polyethylene glycol (which,
as described above, can be otherwise advantageous) as a
solvent.
[0018] 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 conditions and disorders, and several
clinically important examples of such drugs comprise an
aminosulfonyl functional group. Therefore, if the problem of
chemical instability of the drug in polyethylene glycol solution
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
a chemically stable solution of an aminosulfonyl-comprising
selective COX-2 inhibitory drug having polyethylene glycol as a
solvent, if such a solution could be prepared.
SUMMARY OF THE INVENTION
[0019] There is now provided an orally deliverable pharmaceutical
composition comprising a drug of low water solubility and a solvent
liquid that comprises at least one pharmaceutically acceptable
polyethylene glycol and at least one pharmaceutically acceptable
free radical-scavenging antioxidant, wherein 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 wherein
the drug comprises an aminosulfonyl functional group and/or is
capable of reacting with a polyethylene glycol or polyethylene
glycol degradation product to form an addition compound.
[0020] The term "solvent liquid" herein encompasses all of the
components of the liquid medium in which a particular drug is
dissolved or solubilized including but not limited to one or more
solvents, co-solvents, antioxidants, crystallization inhibitors,
dispersants, surfactants, co-surfactants, sweeteners, flavoring
agents, colorants, etc.
[0021] 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.
[0022] 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".
[0023] In a presently preferred embodiment, the solution or
solution/suspension is encapsulated in one or more capsules that
release the drug by capsule wall breakdown within a short period of
time after entry into the gastrointestinal tract. In this
embodiment, the capsule wall optionally comprises a cellulosic
polymer component wherein hydroxyl groups are substituted by
methoxyl and/or hydroxypropoxyl groups, for example HPMC.
[0024] Compositions of the invention have been found to resolve the
problem of drug instability in a surprisingly effective manner.
Thus, for the first time, a poorly water-soluble drug that
comprises an aminosulfonyl functional group, and/or is capable of
reacting with a polyethylene glycol or polyethylene glycol
degradation product to form an addition compound, is presented in a
stable, concentrated solution formulation having a polyethylene
glycol as a solvent. Preferably such formulations are presented in
a dose form that is convenient for oral administration.
Formulations of the invention are particularly advantageous because
they are chemically stable, 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 thereby providing rapid onset of therapeutic
action.
[0025] 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.
[0026] 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.
[0027] 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.
[0028] 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.
[0029] 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.
[0030] 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 an aminosulfonyl-comprising
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, an
aminosulfonyl-comprising 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) an aminosulfonyl-comprising 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.
[0031] Other features of this invention will be in part apparent
and in part pointed out hereinafter.
DETAILED DESCRIPTION OF THE INVENTION
[0032] 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.
[0033] Aminosulfonyl-Comprising Drug
[0034] 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 that comprises an
aminosulfonyl functional group and/or is capable of reacting with a
polyethylene glycol or a polyethylene glycol degradation product to
form an addition compound. 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.
[0035] 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.
[0036] The term "aminosulfonyl functional group" herein refers to a
functional group having the following structure: 3
[0037] wherein the wavy line represents a bond by which the
functional group is attached to the rest of the drug molecule; and
R is hydrogen or a substituent that preserves ability of
polyethylene glycol or a polyethylene glycol degradation product to
react with the amino group adjacent to R to form an addition
compound. Illustrative examples of such substituents include
partially unsaturated heterocyclyl, heteroaryl, cycloalkenyl, aryl,
alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano, nitro,
carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyalkyl,
cyanoalkyl, hydroxyalkyl, hydroxyl, alkoxyalkyloxyalkyl,
haloalkylsulfonyloxy, carboxyalkoxyalkyl, cycloalkylalkyl, alkynyl,
heterocyclyloxy, alkylthio, cycloalkyl, heterocyclyl, cycloalkenyl,
aralkyl, heterocyclylalkyl, heteroarylcarbonyl, alkylthioalkyl,
areylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl,
arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl,
alkoxycarbonylalkyl, aminocarbonylalkyl, alkylaminocarbonyl,
N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl,
alkylaminocarbonylalkyl, alkylamino, N-arylamino, N-aralkylamino,
N-alkyl-N-aralkylamino, N-alkyl-Narylamino, Aminoalkyl,
alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl,
N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy,
aralkoxy, arylthio, aralkylthio, alkylsufinyl, alkylsulfonyl,
etc.
[0038] Non-limiting illustrative examples of
aminosulfonyl-comprising drugs include ABT-751 of Eisai
(N-(2-((4-hydroxyphenyl)amino)-3-pyridyl)4-
-methoxybenzene-sulfonamide); alpiropride; amosulalol; amprenavir;
amsacrine; argatroban; asulacrine; azosemide; BAY-38-4766 of Bayer
(N-[4-[[[5-(dimethylamino)-1-naphthalenyl]sulfonyl]amino]phenyl]-3-hydrox-
y-2,2-dimethylpropanamide); bendroflumethiazide; BMS-193884 of
Bristol Myers Squibb
(N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-[1,1'-bipheny-
l]-2-sulfonamide); bosentan; bumetamide; celecoxib; chlorthalidone;
delavirdine; deracoxib; dofetilide; domitroban; dorzolamide;
dronedarone; E-7070 of Eisai
(N-(3-chloro-1H-indol-7-yl)-1,4-benzene-disulfonamide); EF-7412 of
Schwartz Pharma (N-3-[4-[4-(tetrahydro-1,3-dioxo-1H-pyrrolo[1,-
2-c]imidazol-2(3H)-yl)butyl]-1-piperazinyl]phenyl]ethanesulfonamide);
fenquizone; furosemide; glibenclamide; gliclazide; glimepiride;
glipentide; glipizide; gliquidone; glisolamide; GW-8510 of Glaxo
SmithKline
(4-[[(6,7-dihydro-7-oxo-8H-pyrrolo[2,3-g]benzothiazol-8-yliden-
e)methyl]amino]-N-2-pyridinylbenzenesulfonamide); GYKI-16638 of
Ivax
(N-[4-[2-[[2-(2,6-dimethoxyphenoxy)-1-methylethyl]methylamino]ethyl]pheny-
l]methanesulfonamide);HMR-1098 of Aventis
(5-chloro-2-methoxy-N-[2-[4-meth-
oxy-3-[[[(methylamino)thioxomethyl]amino]sulfonyl]phenyl]ethyl]benzamide);
hydrochlorothiazide; ibutilide; indapamide; IS-741 of Ishihara
(N-[2-[(ethylsulfonyl)
amino]-5-(trifluoromethyl)-3-pyridinyl]cyclohexane- carboxamide);
JTE-522 of Japan Tobacco (4-(4-cyclohexyl-2-methyl-5-oxazoly-
l)-2-fluorobenzenesulfonamide); KCB-328 of Chugai
(N-[3-amino-4-[2-[[2-(3,-
4-dimethoxyphenyl)ethyl]methylamino]ethoxy]phenyl]methanesulfonamide);
KT2-962 of Kotobuki (3-[4-[[(4-chlorophenyl)
sulfonyl]amino]butyl]-6-(1-m- ethylethyl)-1-azulene sulfonic acid);
levosulpiride; LY-295501
(N-[[(3,4-dichlorophenyl)amino]carbonyl]-2,3-dihydro-5-benzofuransulfonam-
ide) and LY-404187
(N-2-(4-(4-cyanophenyl)phenyl)propyl-2-propanesulfonami- de) of Eli
Lilly; metolazone; naratriptan; nimesulide; NS-49 of Nippon
((R)-N-[3-(2-amino-1-hydroxyethyl)-4-fluorophenyl]methanesulfonamide);
ONO-8711 of Ono
((5Z)-6-[(2R,3S)-3-[[[(4-chloro-2-methylphenyl)sulfonyl]a-
mino]methyl]bicyclo[2.2.2]oct-2-yl]-5-hexenoic acid); piretamide;
PNU-103657 of Pharmacia
(1-[5-methanesulfonamidoindol-2-ylcarbonyl]-4-(N--
methyl-N-(3-(2-methylpropyl)-2-pyridinyl)amino)piperidine);
polythiazide; ramatroban; RO-61-1790 of Hoffmann LaRoche
(N-[6-(2-hydroxyethoxy)-5-(2-m-
ethoxyphenoxy)-2-[2-(1H-tetrazol-5-yl)-4-pyridinyl]-4-pyrimidinyl]-5-methy-
l-2-pyridinesulfonamide); RPR-130737
(4-hydroxy-3-[2-oxo-3(S)-[5-(3-pyridy-
l)thiophen-2-ylsulfonamido]pyrrolidin-1-ylmethyl]benzamide) and
RPR-208707 of Aventis; S-18886
(3-[(6-(4-chlorophenylsulfonylamino)-2-methyl-5,6,7,8-
-tetrahydronaphth]-1-yl)propionic acid) and S-32080
(3-[6-(4-chlorophenylsulfonylamido)-2-propyl-3-(3-pyridyl-methyl)-5,6,7,8-
-tetrahydronaphthalen-1-yl]propionic acid) of Servier; S-36496 of
Kaken
(2-sulfonyl-[N-(4-chlorophenyl)sulfonylamino-butyl-N-[(4-cyclobutylthiazo-
l-2-yl)ethenylphenyl-3-yl-methyl]]aminobenzoic acid); sampatrilat;
SB-203208 of Glaxo SmithKline (L-phenylalanine, b-methyl-,
(4aR,6S,7R,7aS)-4-(aminocarbonyl)-7-[[[[[(2S,3S)-2-amino-3-methyl-1-oxope-
ntyl]amino]sulfonyl]acetyl]amino]-7-carboxy-2,4a,5,6,7,7a-hexahydro-2-meth-
yl-1H-cyclopenta[c]pyridin-6-yl ester, (bS)-); SE-170 of DuPont
(2-(5-amidino-1H-indol-3-yl)N-[2'-(aminosulfonyl)-3-bromo(1,1'-biphenyl)--
4-yl]acetamide); sivelestat; SJA-6017 of Senju
(N-(4-fluorophenylsulfonyl)- -L-valyl-L-leucinal); SM-19712 of
Sumitomo (4-chloro-N-[[(4-cyano-3-methyl-
-1-phenyl-1H-pyrazol-5-yl)amino]carbonyl]benzenesulfonamide);
sonepiprazole; sotalol; sulfadiazine; sulfaguanole; sulfasalazine;
sulpiride; sulprostone; sumatriptan; T-614 of Toyama
(N-[3-(formylamino)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]-methanesulfonam-
ide); T-138067
(2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenes-
ulfonamide) and T-900607
(2,3,4,5,6-pentafluoro-N-(3-ureido-4-methoxypheny-
l)benzenesulfonamide) of Tularik; TAK-661 of Takeda
(2,2-dimethyl-3-[[7-(1-methylethyl)[1,2,4]triazolo[1,5-b]pyridazin-6-yl]o-
xy]-1-propanesulfonamide); tamsulosin; tezosentan; tipranavir;
tirofiban; torasemide; trichloromethiazide; tripamide; valdecoxib;
veralipride; xipamide; Z-335 of Zeria
(2-[2-(4-chlorophenylsulfonylaminomethyl)indan-5- -yl]acetic acid);
zafirlukast; zonisamide; and salts thereof.
[0039] In a preferred embodiment, the aminosulfonyl-comprising drug
is a selective COX-2 inhibitory drug of low water solubility.
Suitable selective COX-2 inhibitory drugs are compounds having the
formula (IV): 4
[0040] wherein:
[0041] A is a substituent selected from partially unsaturated or
unsaturated heterocyclyl and partially unsaturated or unsaturated
carbocyclic rings, preferably a heterocyclyl group selected from
pyrazolyl, furanonyl, isoxazolyl, pyridinyl, cyclopentenonyl and
pyridazinonyl groups;
[0042] X is O, S or CH.sub.2;
[0043] n is 0 or 1;
[0044] R.sup.1 is at least one substituent selected from
heterocyclyl, cycloalkyl, cycloalkenyl and aryl, and is optionally
substituted at a substitutable position with one or more radicals
selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl,
hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino,
nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;
[0045] R.sup.2 is an NH.sub.2 group;
[0046] R.sup.3 is one or more radicals selected from hydrido, halo,
alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl,
heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl,
aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl,
heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl,
alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl,
alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl,
aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl,
aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl,
N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl,
alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino,
N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino,
aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl,
N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy,
aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl,
aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl,
arylsulfonyl and N-alkyl-N-arylaminosulfonyl, R.sup.3 being
optionally substituted at a substitutable position with one or more
radicals selected from alkyl, haloalkyl, cyano, carboxyl,
alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino,
alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo,
alkoxy and alkylthio; and
[0047] R.sup.4 is selected from hydrido and halo.
[0048] Particularly suitable selective COX-2 inhibitory drugs are
compounds having the formula (V): 5
[0049] where 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.
[0050] Illustratively, compositions of the invention are suitable
for celecoxib, deracoxib, valdecoxib and JTE-522, more particularly
celecoxib and valdecoxib.
[0051] The invention is illustrated herein with particular
reference to celecoxib, and it will be understood that any drug of
low water solubility that comprises an aminosulfonyl functional
group and/or is capable of reacting with a polyethylene glycol or a
polyethylene glycol degradation product to form an addition
compound can, if desired, be substituted in whole or in part for
celecoxib in compositions herein described.
[0052] 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, preferably
about 10 mg to about 400 mg, and more preferably about 100 mg to
about 200 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.
[0053] Where the subject is a child or a small animal (e.g., a
dog), for example, an amount of celecoxib relatively low in the
typical 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.
[0054] 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.
[0055] Form of Compositions of the Invention
[0056] 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.
[0057] 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.
[0058] A composition of the invention comprises an
aminosulfonyl-comprisin- g 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.
[0059] The solvent liquid comprises at least one pharmaceutically
acceptable polyethylene glycol as a solvent, at least one
pharmaceutically acceptable free radical-scavenging antioxidant 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, substances added
to mask or counteract a disagreeable taste or odor, flavors, dyes,
fragrances, preservatives, and substances added to improve
appearance of the composition.
[0060] 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.
[0061] 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.
[0062] 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 turbidity-decreasing
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.
[0063] 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. The
polyethylene glycol solvent, the free radical-scavenging
antioxidant and the other, optional, components of the solvent
liquid can be mixed first, prior to addition of the drug;
alternatively, the drug can be mixed with the solvent before
addition of other components. Order of addition is generally not
critical, but it is typically preferred to add the drug to the
solvent liquid after adding the antioxidant. 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.
[0064] A preferred embodiment of the invention is a composition
comprising a therapeutically effective amount of an
aminosulfonyl-comprising drug of low water solubility, for example
celecoxib or valdecoxib, substantially completely dissolved in a
solvent liquid comprising at least one pharmaceutically acceptable
polyethylene glycol and at least one pharmaceutically acceptable
free radical-scavenging antioxidant. 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).
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.
[0065] Solvent
[0066] Any pharmaceutically acceptable polyethylene glycol (PEG)
can be used as a solvent in a composition of the invention.
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): Industrial Solvents Handbook, 5th ed., Noyes
Data Corporation, Westwood, N.J., p. 392. A presently preferred PEG
has an average molecular weight of about 375 to about 450, as
exemplified by PEG-400.
[0067] As pointed out hereinabove, 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.
[0068] However, the present inventors encountered an unexpected
problem when celecoxib was formulated in dissolved or solubilized
form in PEG-400. During storage of a solution formulation of
celecoxib in PEG-400, one or more impurities were generated. These
impurities were 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 having chemical structures that
have now been determined and are disclosed hereinbelow. 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.
[0069] 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, has now been solved. According to the present
invention, presence of a free radical-scavenging antioxidant in the
solvent liquid greatly enhances chemical stability of the drug.
[0070] Free Radical-Scavenging Antioxidant
[0071] Certain drugs present in aqueous preparations are known to
be susceptible to oxidative degradation, particularly in the
presence of oxygen. Hydrogen peroxide, for example, is a known free
radical generator that can produce free radicals that interact with
drugs in such preparations so as to cause drug degradation.
Antioxidants have been used in the art to limit such
peroxide-mediated drug degradation. Generally, in such a situation,
antioxidants act by providing electrons and easily available
hydrogen atoms that are accepted more readily by the free radicals
than are those of the drug being protected. See Ansel et al.
(1995): Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th
Edition, page 117.
[0072] The problem faced by the present inventors differs from the
above situation in at least two ways. First, according to the
present problem it is believed that it is polyethylene glycol, not
the drug, that is directly degraded by free radicals. Second, there
is strong evidence to suggest that the degradation mechanism is not
dependent upon peroxide (i.e., the polyethylene glycol degradation
proceeds by an oxygen-independent mechanism).
[0073] Surprisingly, we have now discovered that the presence of a
small amount of a free-radical scavenging antioxidant in a
composition of the invention greatly improves chemical stability of
the drug. This finding is quite different from above-described
situations where antioxidants have previously been used to prevent
drug degradation. Without being bound by theory, it is believed
that a free radical-scavenging antioxidant inhibits, slows or
delays polyethylene glycol degradation, thereby limiting or
inhibiting chemical interaction between polyethylene glycol
degradation products and the drug.
[0074] Therefore, a composition of the present invention 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
thiosulfate, 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.
[0075] One or more free radical-scavenging antioxidants are 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 11%,
by weight of the composition.
[0076] Other Excipients
[0077] Compositions of the invention optionally contain
pharmaceutically acceptable excipients other than polyethylene
glycol and free radical-scavenging antioxidants. In the case of a
solution composition, for example, such excipients can include
co-solvents, sweeteners, crystallization inhibitors, 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.
[0078] 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
Gattefosse; propylene glycol fatty acid esters, for example
propylene glycol laurate; polyoxyethylene (35) castor oil, for
example Cremophorm 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.
[0079] 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 simulated gastric fluid. "Simulated gastric
fluid" and its abbreviation "SGF", as the term is used herein,
describes an aqueous solution of 0.01M hydrochloric acid and 0. 15M
sodium chloride, having a pH of about 2. 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.
[0080] Whether a composition is "finely self-emulsifiable" in SGF
as defined herein can illustratively be determined according to
Test I.
[0081] Test I:
[0082] 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.
[0083] B. The test liquid is mildly agitated at 75 rpm for 2
minutes using an orbital shaker, to permit emulsification.
[0084] 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.
[0085] 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.
[0086] 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).
[0087] F. A plot is prepared of number (i.e., unweighted) or volume
(i.e., weighted) of emulsion particles versus particle
diameter.
[0088] 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.
[0089] H. If Test I 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.
[0090] 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.
[0091] 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.
[0092] 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 I, at
least about 50%and 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.
[0093] 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.
[0094] 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.
[0095] In a solution composition of the invention, the drug, even
when finely emulsified, can, upon exposure to the aqueous
environment of the gastrointestinal tract, precipitate and
agglomerate in a solid, typically crystalline, particulate form.
Such precipitation and/or crystallization can adversely impact any
rapid-onset benefits obtained by administering a drug in dissolved
form, because a drug that has reverted to a crystalline form must
undergo the process of dissolution prior to absorption.
[0096] Therefore, preferred compositions further comprise a
crystallization inhibitor, also referred to herein as a
turbidity-decreasing polymer. 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 preferably
comprise a turbidity-decreasing polymer. The polymer can be a
cellulosic or non-cellulosic polymer and is preferably
substantially water-soluble.
[0097] 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 II.
[0098] Test II:
[0099] 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.
[0100] B. A volume of water or buffered solution with a fixed pH is
placed in a first vessel and maintained at room temperature.
[0101] 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.
[0102] 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.
[0103] 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.
[0104] 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;
[0105] 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.
[0106] A technician performing Test II 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 II 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.
[0107] 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.
[0108] 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.
[0109] 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.
[0110] 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.
[0111] Surprisingly, it has been found that the crystallization
inhibitor need not be a component of the solvent liquid.
Optionally, 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 HPMC. The capsule wall can even
consist predominantly of HPMC.
[0112] If present, 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 III, 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.
[0113] Test III:
[0114] 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.
[0115] B. The mixture is maintained at a constant temperature of
about 37.degree. C. and is stirred using type II paddles (U.S. Pat.
No. 24) at a rate of 75 rpm for a period of 4 hours.
[0116] 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 Versaporm
membrane.
[0117] D. Filtrate is collected in a vessel.
[0118] E. Drug concentration in the filtrate is measured using high
performance liquid chromatography (HPLC).
[0119] 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.
[0120] 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.
[0121] 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. Generally, the crystallization
inhibitor, if present, and the 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.
[0122] 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.
[0123] 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.
[0124] 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
Gattefosse), 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 Gattefosse), sodium lauryl sulfate, sorbitan
monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan
monostearate, tyloxapol, and mixtures thereof.
[0125] 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.
[0126] Solution/Suspension Compositions
[0127] 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.
[0128] Therefore, according to this embodiment a composition is
provided comprising a therapeutically effective amount of a poorly
water-soluble aminosulfonyl-comprising drug, in part dissolved and
in part dispersed in a solvent liquid that comprises at least one
pharmaceutically acceptable polyethylene glycol and at least one
pharmaceutically acceptable free radical-scavenging antioxidant. In
this embodiment, part of the drug is in solution and part is in
suspension.
[0129] 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 aminosulfonyl-comprising 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.
[0130] 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.
[0131] 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.
[0132] 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.
[0133] 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.
[0134] Compositions of this embodiment can optionally comprise
additional excipients such as crystallization inhibitors,
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.
[0135] 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.
[0136] 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, BPMC, 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.
[0137] 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.
[0138] Discrete Dosage Forms
[0139] 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.
[0140] 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.
[0141] In a presently preferred embodiment, a crystallization
inhibitor, 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.
[0142] 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.
[0143] Test IV:
[0144] 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.
[0145] B. The mixture is maintained at a constant temperature of
about 37.degree. C. and is stirred using type II paddles (U.S. Pat.
No. 24) at a rate of 75 rpm for a period of 4 hours.
[0146] 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.
[0147] D. Filtrate is collected in a vessel.
[0148] E. Drug concentration in the filtrate is measured using high
performance liquid chromatography (HPLC).
[0149] 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.
[0150] 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.
[0151] 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.
[0152] 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.
[0153] 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.
[0154] 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.
[0155] 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.
[0156] 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.
[0157] U.S. Pat. No. 4,250,997 to Bodenmann et al.
[0158] U.S. Pat. No. 5,264,223 to Yamamoto et al.
[0159] U.S. Pat. No. 5,756,123 to Yamamoto et al.
[0160] International Patent Publication No. WO 96/05812.
[0161] International Patent Publication No. WO 97/35537.
[0162] International Patent Publication No. WO 00/18377.
[0163] International Patent Publication No. WO 00/27367.
[0164] International Patent Publication No. WO 00/28976.
[0165] International Patent Publication No. WO 01/03676.
[0166] European Patent Application No.0 211 079.
[0167] European Patent Application No. 0 919 228.
[0168] European Patent Application No. 1 029 539.
[0169] Non-limiting illustrative examples of suitable
HPMC-comprising capsules include XGel.TM. capsules of Bioprogress
and Qualicaps.TM. of Shionogi.
[0170] Imbibable Dosage Forms
[0171] 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, and 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.
[0172] 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.
[0173] Utility of Compositions that Comprise a Selective COX-2
Inhibitory Drug
[0174] In a preferred embodiment, compositions of the invention
comprise an aminosulfonyl-comprising 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.
[0175] 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.
[0176] Such compositions are also useful in treatment of asthma,
bronchitis, menstrual cramps, preterm labor, tendinitis, bursitis,
allergic neuritis, cytomegalovirus infectivity, apoptosis including
HIV-induced apoptosis, lumbago, liver disease including hepatitis,
skin-related conditions such as psoriasis, eczema, acne, bums,
dermatitis and ultraviolet radiation damage including sunburn, and
post-operative inflammation including that following ophthalmic
surgery such as cataract surgery or refractive surgery.
[0177] Such compositions are useful to treat gastrointestinal
conditions such as inflammatory bowel disease, Crohn's disease,
gastritis, irritable bowel syndrome and ulcerative colitis.
[0178] 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.
[0179] 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.
[0180] 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.
[0181] 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.
[0182] Such compositions are useful in treatment of allergic
rhinitis, respiratory distress syndrome, endotoxin shock syndrome
and liver disease.
[0183] 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.
[0184] 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.
[0185] 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.
[0186] 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.
[0187] 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.
[0188] 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.
[0189] 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.
[0190] 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.
[0191] 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.
[0192] 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.
[0193] For selective COX-2 inhibitory drugs other than celecoxib,
appropriate doses can be selected by reference to the patent
literature cited hereinabove.
[0194] 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.
[0195] 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.
[0196] 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.
[0197] 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, lomoxicam, 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").
[0198] 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.
[0199] 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.
[0200] 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.
[0201] 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.
[0202] 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.
[0203] 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.
[0204] 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
[0205] Six celecoxib solution formulations SF-1 to SF-6 were
prepared having components as shown in Table 1. In each case the
solvent liquid consisted of PEG-400, either alone (SF-1) or
together with at least one free radical-scavenging antioxidant
(SF-2 to SF-6). Celecoxib was present in solution at a
concentration of 50 mg/g in all formulations. Antioxidant amounts
are shown as % weight/weight.
1TABLE 1 Composition of celecoxib solution formulations SF-1 to
SF-6 Formulation Components SF-1 Celecoxib, PEG-400 SF-2 Celecoxib,
PEG-400, 0.1% vitamin E SF-3 Celecoxib, PEG-400, 0.1% BHA SF-4
Celecoxib, PEG-400, 0.1% BHT SF-5 Celecoxib, PEG-400, 0.1% propyl
gallate SF-6 Celecoxib, PEG-400, 0.05% BHA, 0.05% BHT
Example 2
[0206] A gradient HPLC assay was used to determine impurities in
celecoxib solution formulations SF-1 to SF-6 of Example 1 after
storage at various temperatures for different periods of time.
Solution formulation samples were drawn and were dissolved in
methanol to obtain a celecoxib concentration of about 0.4 to about
0.5 mg/ml prior to injection. Chromatographic conditions were as
follows: (a) flow rate: 1 ml/min.; (b) detection: UV 254 nm; (c)
injection volume: 10 .mu.l; (d) column: 5 .mu.m Supercosil, LC-DP,
250.times.4.6 mm; (e) column temperature: 40.degree. C.; (f) mobile
phase A: 10 mM NH.sub.4AC or KH.sub.2PO.sub.4, pH 3; (g) mobile
phase B: 100% acetonitrile; (h) running time: 45 minutes. Data are
shown in Tables 2 and 3.
2TABLE 2 Impurity level (%) in formulations SF-1 to SF-5 following
storage days stored at 70.degree. C. Formulation 9 14 16 20 28 33
35 90 SF-1 2.9 3.7 7.6 12.6 SF-2 0.02 0.02 0.02 2.8 SF-3 0.02 0.02
0.02 0.09 SF-4 0.03 0.04 0.06 0.30 SF-5 ND ND ND 0.15 ND = None
detected
[0207]
3TABLE 3 Impurity level (%) in formulations SF-1, SF-2, SF-5 and
SF-6 following storage at different temperatures Temperature
Formulation Days 50.degree. C. 40.degree. C. 25.degree. C.
4.degree. C. SF-1 0 0.00 0.00 0.00 0.00 7 0.09 21 4.12 0.11 0.00 31
6.25 0.00 74 7.83 5.40 0.08 0.00 131 7.85 6.87 0.44 0.00 SF-2 0
0.00 0.00 0.00 0.00 7 0.00 21 0.02 0.00 0.00 31 0.01 0.00 74 0.06
0.02 0.00 0.00 131 0.07 0.01 0.00 0.00 SF-5 0 0.00 0.00 0.00 0.00 7
0.02 21 0.05 0.03 0.02 31 0.05 0.00 74 0.15 0.11 0.03 0.00 131 0.20
0.09 0.02 0.00 SF-6 0 0.00 0.00 0.00 0.00 7 0.00 21 0.01 0.01 0.00
31 0.01 0.00 74 0.03 0.02 0.01 0.00 131 0.06 0.01 0.00 0.00
[0208] The data in Tables 2 and 3 indicate that the presence of a
small amount of a free radical-scavenging antioxidant such as
vitamin E, butyl gallate, BHA or BHT greatly improves chemical
stability of celecoxib dissolved in PEG-400 by comparison with
compositions comprising no such antioxidant.
Example 3
[0209] Solution formulation SF-1 of Example 1 was bubbled with
ethylene oxide, a putative source of free radicals, for 15 minutes,
and was then stored at 70.degree. C. for 10 days. After storage,
the formulation was analyzed for the presence of impurities.
Addition compounds detected therein were isolated by
reversed-phase, semi-preparative HPLC. A 20.times.250 mm Kromasil
C18 column was employed with either an isocratic or a gradient,
acetonitrile-aqueous trifluoroacetic acid mobile phase. Detection
was accomplished at 254 nm. Pooled fractions containing individual
addition compounds, herein referred to as Peak 1, Peak 2 and Peak 3
addition compounds, were concentrated, desalted and reduced in
chemical noise-causing components by trapping on a 7.times.300 mm
Hamilton PRP-1 column. The eluent from the trapping column
containing the individual addition compounds was freeze-dried to
yield the final isolates. Peak 1 addition compound was 99% pure and
Peak 2 addition compound was >99% pure by analytical HPLC. Peak
3 addition compound was 81% pure by analytical HPLC.
[0210] Analytical HPLC was also used to collect analytical scale
peak cuts for mass spectrometric analysis on a PE Sciex Q-Star
Qq-TOF mass spectrometer. Survey and product ion scans, as well as
high resolution mass measurements for empirical formula
determination were acquired in .mu.ESI (micro-electrospray
ionization) mode. High resolution mass spectral information on Peak
1 and Peak 2 addition compounds were obtained on a Finnigan
MAT-900ST mass spectrometer operating in .mu.ESI mode. Accurate
mass measurement for Peak 1 addition compound was carried out by
linear E-scan peak matching at a resolution of 7,400 (m/Am 10%
valley definition) using the reference ions from PEG-400,
(C.sub.2H.sub.4O).sub.9H.sub.2ONa at 437.23627 and
(C.sub.2H.sub.4O).sub.10H.sub.2ONa at 481.26248 daltons,
respectively, to match against the sample pseudo-molecular ion.
Accurate mass measurement for Peak 2 addition compound was carried
out by linear E-scan peak matching at a resolution of 7,100 (m/Am
10% valley definition) using the reference ions from PEG-400
(C.sub.2H.sub.4O).sub.8H.sub.2ONa at 393.21005 and
(C.sub.2H.sub.4O).sub.9H.sub.2ONa at 437.23627 daltons,
respectively, to match against the sample pseudo-molecular ion.
[0211] NMR samples were prepared in a nitrogen glove box and
dissolved in 150 .mu.l dimethyl sulfoxide-d.sub.6. Data were
acquired on a Varian INOVA 400 NMR spectrometer operating at a
proton frequency of 399.80 MHz, and equipped with a Nalorac inverse
geometry, micro-gradient probe. Experiments were used directly from
the vendor's standard library with no modifications.
[0212] Peak 1
[0213] Celecoxib and Peak 1 addition compound were individually
mounted on gold-coated microscope slides for IR and Raman analyses.
Micro-IR specular reflectance data were collected from
4000.fwdarw.650 cm.sup.-1 at 4-cm.sup.-1 resolution on a Nicolet
760 spectrometer equipped with a liquid nitrogen cooled MCT
detector. Sensitivity, expressed as instrument gain, was 8. Data
were processed as a Fourier transform utilizing a Happ-Genzel
apodization function and plotted as % transmittance vs. frequency.
The final spectra were the sum of 200 individual scans. Micro-Raman
data were collected from 3700.fwdarw.100 cm.sup.-1 on a Nicolet 960
FT-Raman spectrometer, equipped with a liquid nitrogen cooled
germanium detector. Sensitivity, expressed as instrument gain, was
64. Data were processed as a Fourier transform utilizing a
Happ-Genzel apodization function and plotted as absorbance vs.
frequency. The final spectra were the sum of 10,000 individual
scans.
[0214] The molecular weight of Peak 1 addition compound was found
to be 469 daltons, 88 daltons heavier than celecoxib and indicative
of addition of two ethanolic moieties. The molecular weight was
confirmed by high resolution peak matching, of an analytical peak
cut, as 469.12831 daltons, within 0.2 ppm of theory for
C.sub.21H.sub.22F.sub.3N.sub.3O.sub- .4S. The accurate mass of Peak
1 addition compound, less the ionizing proton, was measured as
469.12826 daltons. The empirical formula for best fit using the
valence rules was C.sub.21H.sub.22F.sub.3N.sub.3O.sub.4S and within
0.1 ppm in mass from theory, thus confirming the molecular weight
of this product. Peak 1 addition compound is believed to be
N,N-bis(2-hydroxyethyl)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyra-
zol-1-yl]benzenesulfonamide, having the structure (V): 6
[0215] NMR analysis of Peak 1 addition compound produced similar
data to those for the bulk drug. A major difference existed in the
absence of the --SO.sub.2NH.sub.2 protons, and the inclusion of
resonances consistent with the presence of two --CH.sub.2CH.sub.2OH
functionalities. The methylene protons and carbons exhibited
distinct chemical shifts that are consistent with the proposed
structure.
[0216] The IR and Raman spectra of celecoxib and Peak 1 addition
compound are very similar, indicating that the bulk of the
structure is the same as that of celecoxib. Several spectral
differences, however, between the two molecules are evident. The
two N--H stretching vibrations in the spectrum of celecoxib at 3236
and 3342 cm.sup.-1 are missing in the data for Peak 1 addition
compound, indicating the amino group present in celecoxib is not
present in Peak 1 addition compound. The N--H vibrations in the IR
spectrum for celecoxib are replaced by an intense, broad absorbance
centered at 3430 cm.sup.-1 in the analogous data for Peak 1
addition compound. This broad band is typical of an O--H stretch,
but is much too intense to result from a single hydroxyl group,
indicating that Peak 1 addition compound possesses at least two OH
groups, in place of the NH.sub.2 group present in celecoxib.
Another major spectral difference between the vibrational spectra
for celecoxib and Peak 1 addition compound are the presence of
Raman C--H stretching vibrational bands for Peak 1 addition
compound at 2967 and 2991 cm.sup.-1 that are not present in the
analogous data for celecoxib. These differences indicate the
presence of additional CH.sub.2 groups in the addition compound,
compared to celecoxib. Both the IR and Raman data are consistent
with the proposed structure.
[0217] The compound having the structure (V) is believed to be new
and is useful as an analytical marker, for example in detecting
stability of celecoxib in pharmaceutical compositions where the
celecoxib is or has been exposed to polyethylene glycol or ethylene
oxide, and/or as a selective cyclooxygenase-2 inhibitory drug or a
pro-drug thereof.
[0218] Peak 2
[0219] The molecular weight of Peak 2 addition compound was found
to be 425 daltons, 44 daltons heavier than celecoxib and indicative
of the addition of one ethanolic moiety. The molecular weight was
confirmed by high resolution peak matching, of an analytical peak
cut, as 425.10239 daltons, within 0.9 ppm of theory for
C.sub.19H.sub.18F.sub.3N.sub.3O.sub- .3S. The accurate mass of Peak
2 addition compound, less the ionizing proton, was measured as
425.10168 daltons. The empirical formula for best fit using the
valence rules was C.sub.19H.sub.18F.sub.3N.sub.3O.sub.3S and within
1.0 ppm in mass from theory, thus confirming the molecular weight
of this compound. Peak 2 addition compound is believed to be
N-(2-hydroxyethyl)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
-yl]benzenesulfonamide, having the structure (VI): 7
[0220] The NMR data for Peak 2 addition compound were similar to
those for Peak 1 addition compound in that this isolate also
exhibited the --CH.sub.2CH.sub.2OH functionality, but proton
integrations identified the presence of only one ethanol
substituent. The presence of an --NH-- group was also apparent in
the proton spectrum. The proton and carbon chemical shifts were in
accordance with the proposed structure.
[0221] The compound having the structure (VI) is believed to be new
and is useful as an analytical marker, for example in detecting
stability of celecoxib in pharmaceutical compositions where the
celecoxib is or has been exposed to polyethylene glycol or ethylene
oxide, and/or as a selective cyclooxygenase-2 inhibitory drug
and/or a pro-drug thereof.
[0222] Peak 3
[0223] Peak 3 addition compound was present in insufficient
concentration for an adequate isolate to be obtained for
spectroscopic analysis.
Example 4
[0224] Three celecoxib (10 mg/g) solutions (with methanol as
solvent), one containing no peroxide (S1), one containing 150 ppm
hydrogen peroxide (S2), and one containing 150 ppm t-butyl-peroxide
(S3), were prepared. HPLC analysis, as described in Example 2, was
performed to determine the presence or absence of impurities
following storage at different temperatures for various periods of
time (Table 4).
4TABLE 4 Chemical stability of celecoxib solutions S1-S3 Total
impurity level (%) Solution Time 4.degree. C. 25.degree. C.
59.degree. C. S1 0 0.15 0.15 0.15 1 week 0.15 0.15 0.54 2 weeks
0.14 1.57 3 weeks, then 3 days at 70.degree. C. 2.40 S2 0 0.15 0.15
0.15 1 week 0.15 0.15 0.46 2 weeks 0.14 0.94 3 weeks, then 3 days
at 70.degree. C. 1.60 S3 0 0.15 0.15 0.15 1 week 0.15 0.15 0.33 2
weeks 0.13 0.92 3 weeks, then 3 days at 70.degree. C. 2.00
[0225] These data indicate that the presence of hydrogen peroxide
or t-butyl-peroxide at a concentration of 150 ppm does not affect
celecoxib stability in methanol. These data are consistent with the
conclusion that chemical instability in a system comprising an
aminosulfonyl-comprising drug, for example celecoxib, and a
polyethylene glycol, is not peroxide-mediated.
Example 5
[0226] Two celecoxib solution formulations, SF-7, and SF-8, and two
vehicle (placebo) solution formulations, SF-9 and SF-10, were
prepared having components shown in Table 5.
5TABLE 5 Composition (mg) of solution formulations SF-7 to SF-10
Component SF-7 SF-8 SF-9 SF-10 Celecoxib 200 200 Water USP 26 26 26
26 HPMC (E5) 38 38 Ethanol 113 100 113 100 PEG-400 271 322 271 322
Polyvinylpyrrolidone 47 47 47 47 Polysorbate 80 217 217 217 217
Tromethamine 26 26 26 26 Oleic acid 61 61 61 61 Propyl gallate NF 1
1 1 1 Total 1000 1000 800 800
[0227] After storage for 90 days at different temperatures, the
fraction of the initial 1 mg/g propyl gallate remaining in each
formulation was measured via gradient HPLC. Sample of all
formulations were dissolved in methanol to obtain a suitable
concentration prior to injection. Chromatographic conditions were
as follows: (a) flow rate: 1 ml/min.; (b) detection: UV 254 nm; (c)
injection volume: 15 .mu.l; (d) column: 3.5 .mu.m Zorbax XBD-C8,
50.times.4.6 mm; (e) column temperature: 25.degree. C.; (f) mobile
phase A: 0.1% TFA in water; (g) mobile phase B: 0.1% TFA in
acetonitrile; (h) running time: 16 minutes. Data are shown in Table
6.
6TABLE 6 Loss of propyl gallate in solution formulations SF-7 to
SF-10 after storage for 90 days Propyl gallate (% of theoretical)
remaining Temperature (.degree. C.) SF-7 SF-8 SF-9 SF-10 4 87 104
108 126 25 42 74 36 66 40 10 33 10 24 50 0 13 0 19 70 0 0 0 7
[0228] These data indicate that, in formulations comprising an
aminosulfonyl-comprising drug (celecoxib in the present example)
and in those without such a drug, propyl gallate is consumed at a
substantially equal rate over 90 days. Moreover, the rate of
consumption is temperature dependent with increasing rate as
temperature increases. These results suggest that the free
radical-scavenging antioxidant is consumed via a non drug-mediated
mechanism, and support the present theory that drug stabilization
results from an interaction between polyethylene glycol degradation
products and the free radical-scavenging antioxidant.
Example 6
[0229] A celecoxib solution formulation, SF-11, was prepared having
the composition shown in Table 7.
7TABLE 7 Composition (mg/g) of celecoxib solution formulation SF-11
Component SF-11 Celecoxib 200 Water USP 26 HPMC (E5) 38 Ethanol 113
PEG 400 271 PVP 47 Polysorbate 80 217 Tromethamine 26 Oleic acid 61
Propyl gallate NF 1 Total 1000
[0230] One gram of formulation SF-11 was individually placed into
each of several hard gelatin capsules (Capsugel) to form Test
Composition 1.
[0231] A celecoxib suspension for comparative purposes was prepared
as follows:
[0232] A. Tween.TM. 80, 5.0 g, was placed in a volumetric
flask.
[0233] B. Ethanol was added (to 100 ml) to form a mixture and the
mixture was swirled to form a uniform solution.
[0234] C. A 5 ml aliquot of the uniform solution was transferred to
a fresh 100 ml bottle containing 200 mg celecoxib, to form a
premix.
[0235] D. Apple juice, 75 ml, was added to the premix to form an
intermediate celecoxib suspension.
[0236] E. The intermediate celecoxib suspension was left to stand
for 5 minutes, and was then shaken to form a celecoxib suspension
for comparative purposes.
[0237] Bioavailability parameters resulting from administration of
Test Composition 1, in comparison with the comparative celecoxib
suspension composition of Example 5 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 8,
ingestion of Test Composition 1 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 1 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.
8TABLE 8 In vivo bioavailability of celecoxib in human subjects
Commercial Comparative Test composition Parameter capsule
suspension 1 C.sub.max (ng/ml) 621 804 2061 T.sub.max (hr) 2.15
0.97 1.03 AUC (ng/ml)*hr 5060 4892 7593
Example 7
[0238] Two celecoxib solution formulations, SF-12 and SF-13, and
two placebo solution formulations, P-2 and P-3, were prepared
having compositions shown in Table 9.
9TABLE 9 Composition (mg) of celecoxib solution formulations SF-12
and SF-13 and placebo solution formulations P-2 and P-3 Component
SF-12 SF-13 P-2 P-3 Celecoxib 100 200 -- -- Water USP 13 26 15.1
30.2 HPMC (E5) 19 38 22.1 44.2 Ethanol 56.5 113 65.7 131.4 PEG 400
135.5 271 157.5 315 PVP 23.5 47 27.3 54.6 Polysorbate 80 108.5 217
126.1 252.3 Tromethamine 13 26 15.1 30.2 Oleic acid 30.5 61 35.5
70.9 Propyl gallate NF 0.5 1 0.6 1.2 Total 500 1000 465 930
[0239] Amounts of 500 mg and 1000 mg of solution formulations SF-12
and SF-13 respectively were individually placed into each of
several soft gelatin capsules to form Test Compositions 2 (100 mg
celecoxib) and 3 (200 mg celecoxib), respectively. Test Composition
4 consisted of two capsules of Test Composition 3 resulting in a
400 mg celecoxib dose. Placebo solution formulations P-2 and P-3
were filled into soft capsules corresponding in size with those
containing solution formulations SF-12 and SF-13, respectively, to
form Placebo Composition 2 and Placebo Composition 3.
[0240] A randomized, double-blind, active and placebo controlled,
single-dose parallel group study was performed in order to assess
the analgesic efficacy of Test Compositions 2, 3 and 4 in
comparison with appropriate and visually matching placebo, in a
human post-oral surgery pain model.
[0241] Post-surgical patients (after extraction of two or more
impacted third molars requiring bone removal) who reported moderate
or severe post-oral surgery pain on a categorical pain scale (CPS;
0=no pain, 1=mild pain, 2=moderate pain, and 3=severe pain), and a
baseline pain intensity .gtoreq.50 mm on a visual analog scale
(VAS; whereby patient locates a sliding bar representing his or her
level of pain on a 100 mm horizontal scale with the left edge (0
mm) marked "no pain" and the right edge (100 mm) marked "worst
pain") within 6 hours after completion of surgery were selected and
randomized for study.
[0242] Each patient was randomized to one of four treatment groups
(approximately 55 per group) and, 6 hours after completion of
surgery, received the study medication assigned to his or her group
from both Bottle A and Bottle B as shown in the medication schedule
found in Table 10. Two additional compositions, not illustrative of
the present invention, were also included in the study but are not
reported here.
10TABLE 10 Schedule of study medication given to patients in
treatment groups 1-4 Treatment Group Bottle A (1 capsule) Bottle B
(2 capsules) 1. (Placebo) 1 .times. Placebo Composition 2 2 .times.
Placebo Composition 3 2. (Test 1 .times. Test Composition 2 2
.times. Placebo Composition 3 composition 2) 3. (Test 1 .times.
Placebo Composition 2 1 .times. Placebo Composition 3 composition
3) and 1 .times. Test Composition 3 4. (Test 1 .times. Placebo
Composition 2 2 .times. Test Composition 3 composition 4)
[0243] Pain was assessed at baseline (0 hour), 0.25, 0.50. 0.75,
1.0, 1.25, 1.50, 1.75, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, and
24 hours after administration of study medication. Each patient
individually determined and recorded time to perceptible pain
relief and time to meaningful pain relief, using two
stopwatches.
[0244] Time to onset of analgesia was then calculated for each
patient by performing a time-to-event analysis combining data from
patient's stopwatch assessments of time to perceptible and
meaningful pain relief. Baseline pain intensity for each group is
shown in Table 11. Median time to onset of analgesia is shown in
Table 12.
11TABLE 11 Baseline pain intensity Test Test Test Pain Scale
Composition 2 Composition 3 Composition 4 CPS (%) Moderate 56 56 57
Severe 44 44 43 VAS 0 to 100 mm Mean 73.29 72.78 73.86
[0245] These data show that patients in each test group had
comparable baseline pain intensity.
12TABLE 12 Median time to onset of analgesia Treatment Time (min)
Placebo >1440 Test Composition 2 31 Test Composition 3 28 Test
Composition 4 31
[0246] As determined in a similar pain study reported in
International Patent Publication No. WO 01/91750, incorporated
herein by reference, 200 mg Celebrex.RTM. capsules exhibit a median
time to onset of analgesia of 41 minutes. The data in Table 12 show
that patients taking Test Compositions 2, 3 or 4 experienced a
relatively fast median time to onset of analgesia of 31 minutes or
less.
* * * * *