U.S. patent application number 11/487554 was filed with the patent office on 2006-11-16 for tablet formulation.
This patent application is currently assigned to Pharmacia & Upjohn Company. Invention is credited to Ashley H. Bates, E. John Lee, Alice C. Martino, Walter Morozowich.
Application Number | 20060257476 11/487554 |
Document ID | / |
Family ID | 22214517 |
Filed Date | 2006-11-16 |
United States Patent
Application |
20060257476 |
Kind Code |
A1 |
Martino; Alice C. ; et
al. |
November 16, 2006 |
Tablet formulation
Abstract
Disclosed is a non-sustained release pharmaceutical tablet
composition which comprises a rapidly precipitating drug in an
amount from about 5 to about 60% and at least one member selected
from the group consisting of a binder in an amount of from about 2
to about 25% and a superdisintegrant in an amount from about 6 to
about 40% where the rapidly precipitating drug, "binder" and
superdisintegrant are mixed and compressed into a tablet without
heating, solvent or grinding.
Inventors: |
Martino; Alice C.;
(Kalamazoo, MI) ; Bates; Ashley H.; (Sorrento,
AU) ; Morozowich; Walter; (Kalamazoo, MI) ;
Lee; E. John; (Kalamazoo, MI) |
Correspondence
Address: |
FLYNN, THIEL, BOUTELL & TANIS, P.C.
2026 RAMBLING ROAD
KALAMAZOO
MI
49008-1631
US
|
Assignee: |
Pharmacia & Upjohn
Company
|
Family ID: |
22214517 |
Appl. No.: |
11/487554 |
Filed: |
July 14, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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|
09656364 |
Sep 6, 2000 |
7108864 |
|
|
11487554 |
Jul 14, 2006 |
|
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|
09327135 |
Jun 7, 1999 |
6177101 |
|
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09656364 |
Sep 6, 2000 |
|
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60088960 |
Jun 11, 1998 |
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Current U.S.
Class: |
424/464 |
Current CPC
Class: |
A61K 31/496 20130101;
A61K 9/2054 20130101 |
Class at
Publication: |
424/464 |
International
Class: |
A61K 9/20 20060101
A61K009/20 |
Claims
1. A non-sustained release non-chewable tablet composition
comprising: (a) a rapidly precipitating drug which is a salt form
of a poorly soluble free acid or an anhydrous form of a poorly
soluble free base or an anhydrous form of a poorly soluble free
acid that is prone to supersaturation when introduced in water or
simulated physiological fluid at body temperature, and more than
90% of it precipitates out within 60 min after coming into contact
with said water or simulated physiological fluid at body
temperature, with the proviso that the drug is not delavirdine
mesylate, is the sole active pharmaceutical ingredient in said
composition and is present in an amount from about 5 to about 60%;
(b) a polymeric binder present in an amount of from 2 to about 25%;
(c) a superdisintegrant in an amount from about 6 to about 40%; and
(d) a lubricant present in an amount up to about 5%; and wherein
the rapidly precipitating drug, polymeric binder, superdisintegrant
and lubricant are mixed and compressed into a tablet without
heating, solvent or grinding.
2. A non-sustained release, non-chewable pharmaceutical tablet
composition according to claim 1 where the polymeric binder is
selected from the group consisting of: hydroxypropyl
methylcellulose, PVP, hydroxypropyl cellulose, methylcellulose,
hydroxyethylcellulose, carbopol, sodium carboxymethylcellulose.
3. A non-sustained release, non-chewable pharmaceutical tablet
composition according to claim 1 wherein the polymeric binder is
hydroxypropyl methylcellulose.
4. A non-sustained release, non-chewable pharmaceutical tablet
composition according to claim 1 wherein the polymeric binder is
PVP.
5. A non-sustained release, non-chewable pharmaceutical tablet
composition according to claim 1 where the polymeric binder is
present in the amount as follows for: hydroxypropyl methyl
cellulose of from about 5 to about 20%, PVP from about 2 to about
15%, hydroxypropyl cellulose from about 5 to about 20%,
methylcellulose from about 5 to about 20%, hydroxyethylcellulose
from about 5 to about 20%, carbopol from about 3 to about 20%,
sodium carboxymethylcellulose from about 3 to about 20%.
6. A non-sustained release, non-chewable pharmaceutical tablet
composition according to claim 1 where the superdisintegrant is
croscarmellose sodium, sodium starch glycolate or L-hydroxypropyl
cellulose.
7. A non-sustained release, non-chewable pharmaceutical tablet
composition according to claim 1 where the superdisintegrant is
present in an amount of from about 6 to about 35%.
8. A non-sustained release, non-chewable pharmaceutical tablet
composition according to claim 7 where the superdisintegrant is
present in an amount of from about 10 to about 30%.
9. A non-sustained release, non-chewable pharmaceutical tablet
composition according to claim 1 which contains microcrystalline
cellulose in an amount up to about 50%.
10. A non-sustained release, non-chewable pharmaceutical tablet
composition according to claim 9 where the microcrystalline
cellulose is selected from the group consisting of microcrystalline
cellulose coarse powder microcrystalline cellulose medium powder
and microcrystalline cellulose 200.
11. A non-sustained release, non-chewable pharmaceutical tablet
composition according to claim 9 where the microcrystalline
cellulose is microcrystalline cellulose N.F. coarse powder.
12. A non-sustained release, non-chewable pharmaceutical tablet
composition according to claim 9 where the microcrystalline
cellulose is present in an amount of from about 10 to about
40%.
13. A non-sustained release, non-chewable pharmaceutical tablet
composition according to claim 1 which contains lactose in an
amount up to about 80%.
14. A non-sustained release, non-chewable pharmaceutical tablet
composition according to claim 13 where the lactose is selected
from the group consisting of lactose monohydrate spray process
standard, lactose monohydrate, lactate anhydrous, lactose
dihydrate, DMV lactose.
15. A non-sustained release, non-chewable pharmaceutical tablet
composition according to claim 13 where the lactose is N.F.
monohydrate spray process standard lactose.
16. A non-sustained release, non-chewable pharmaceutical tablet
composition according to claim 13 where the lactose is present in
an amount of from about 5 to about 20%.
17. A non-sustained release, non-chewable pharmaceutical tablet
composition according to claim 1 which contains a flow agent in an
amount up to 5%.
18. A non-sustained release, non-chewable pharmaceutical tablet
composition according to claim 17 where the flow agent is selected
from the group consisting of colloidal silicon dioxide and
talc.
19. A non-sustained release, non-chewable pharmaceutical tablet
composition according to claim 17 where the flow agent is colloidal
silicon dioxide N.F.
20. A non-sustained release, non-chewable pharmaceutical tablet
composition according to claim 17 where the flow agent is present
in an amount from 0.25 to about 2%.
21. A non-sustained release, non-chewable pharmaceutical tablet
composition according to claim 1 where the lubricant is selected
from the group consisting of magnesium stearate and stearic
acid.
22. A non-sustained release, non-chewable pharmaceutical tablet
composition according to claim 21 where the lubricant is magnesium
stearate.
23. A non-sustained release, non-chewable pharmaceutical tablet
composition according to claim 1 where the lubricant is present in
the amount of 0.25 to about 2%.
24. A non-sustained release, non-chewable pharmaceutical tablet
composition according to claim 1 where the rapidly precipitating
drug is present in an amount of from about 10 to about 40%.
25. A non-sustained release, non-chewable tablet composition
according to claim 3, wherein the polymeric binder is hydroxypropyl
methylcellulose of from about 5 to about 20%.
26. A non-sustained release, non-chewable tablet composition
according to claim 1, wherein the mixing is accomplished in a high
shear mixer.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a division of Ser. No. 09/656,364, filed Sep. 6,
2000, which is a continuation of Ser. No. 09/327,135, filed Jun. 7,
1999, now U.S. Pat. No. 6,177,101, which claims the benefit of Ser.
No. 60/088,960, filed Jun. 11, 1998.
FIELD OF THE INVENTION
[0002] The present invention is a tablet formulation which reduces
the rate of precipitation of a rapidly precipitating drug and
improves dissolution.
DESCRIPTION OF THE RELATED ART
[0003] U.S. Pat. No. 5,563,142 (Example 105) discloses
delavirdine.
[0004] International Publication WO 95/28398 based on PCT patent
application PCT/US95/02166 discloses delavirdine mesylate in two
crystal forms "S" and "T".
[0005] U.S. Pat. No. 5,358,941 discloses a compressed tablet
formulation comprising about 0.5 to 40% active ingredient, about
10-80% anhydrous lactose, about 5 to 50% by weight of
microcrystalline cellulose, about 0.5 to 10% by weight of
croscarmellose sodium and about 0.1 to 5% magnesium stearate. The
pharmaceutical tablet formulation of the present invention does not
require lactose.
[0006] Patent EP 283925 discloses utilization of solvent-based
polymers under action of high shearing forces so that precipitation
is divided into smallest particles to purify resorbable polyester
products. The claimed invention does not co-precipitate polymers in
any solvent system with the rapidly precipitating drug prior to
formulation with other ingredients, but relies only on close
proximity of the dry binder or superdisintegrant with the rapidly
precipitating drug in a conventional compressed tablet dosage
form.
[0007] International Journal of Pharmaceutics, 154, 59-66 (1997)
discloses the utilization of HPMC, HPC and PVP in a liquid system
at various polymer ratios with intent to delay precipitation.
Methods discussed include preparation of solid dispersions either
by the co-precipitation method of grinding method to improve
dissolution properties. The claimed invention utilizes conventional
direct compression method of tablet formulation and does not
utilize any solid dispersion techniques such as co-precipitation
via solvent use or grinding to achieve co-precipitation.
[0008] The Handbook of Drug Excipients, 2.sup.nd. Ed., edited by A.
Wade and P. J. Weller, 1994, page 141, and many other
pharmaceutical references, describe the common use of
superdisintegrants such as croscarmellose sodium are used to aid
tablet disintegration typically in the amount of 1-2% and not more
than 5% of the formulation. Higher amounts are not used or
recommended due to gelation of the croscarmellose sodium forming a
loose matrix which is known to impede dissolution of many drug
compounds. The present invention uses greater than 6%
croscarmellose sodium.
[0009] The Handbook of Drug Excipients, 2.sup.nd. Ed., edited by A.
Wade and P. J. Weller, 1994, pages 223, 229 and 392, and many other
pharmaceutical references, describe the common use of water soluble
polymers such as HPMC, HPC-L, and PVP as binders, either as wet
binders or dry binders, in immediate and sustained release tablet
formulations. For non-sustained release applications, not more than
5% is used of these binders. Higher amounts are not recommended due
to impedance of the dissolution rate for many drugs. Amounts higher
than 5% of especially HPMC are commonly used only for sustained
release dosage forms, and are generally of high molecular weight
grades. In the present invention, however, the binder includes use
at levels of greater than 5%.
[0010] U.S. Pat. No. 5,225,197 discloses a chewable tablet
formulation. The present invention is not a chewable tablet.
[0011] JP 84-185584 discloses the utilization of HPC, PVP and other
binders together with difficulty soluble drugs by use of heat. The
claimed invention does not use heat.
SUMMARY OF THE INVENTION
[0012] Disclosed is a non-sustained release pharmaceutical tablet
composition which comprises: a rapidly precipitating drug in an
amount from about 5 to about 60%, microcrystalline cellulose and at
least one member selected from the group consisting of a binder in
an amount of from about 2 to about 25% and a superdisintegrant in
an amount from about 6 to about 40% where the rapidly precipitating
drug, microcrystalline cellulose, binder and superdisintegrant are
mixed and compressed into a tablet without heating, solvent or
grinding.
[0013] Also disclosed is a non-sustained release pharmaceutical
tablet composition which is: TABLE-US-00001 Item Amount (from about
to about) % delavirdine mesylate 10-40 hydroxypropyl
methylcellulose 5-20 croscarmellose sodium 6-35 microcrystalline
cellulose 10-50 lactose 0-15 colloidal silicon dioxide 0-5
magnesium stearate 0-5
where the delavirdine mesylate, microcrystalline cellulose,
hydroxypropyl methylcellulose and croscarmellose sodium are mixed
and compressed into a tablet without heating, solvent or
grinding.
DETAILED DESCRIPTION OF THE INVENTION
[0014] The tablets of the present invention require a rapidly
precipitating drug (5-60%), microcrystalline cellulose (10-50%), a
binder (2-25%) and superdisintegrant (6-40%). While not required,
it is often highly desirable to use one or more of the following
pharmaceutical ingredients--microcrystalline cellulose (0-50%),
lactose (0-80), a flow agent (0-5) and a lubricant (0-5%).
[0015] A rapidly precipitating drug is a pharmaceutical compound,
or its salt form, which when introduced in water, or simulated
physiological fluids at body temperature, begins to dissolve fairly
rapidly and then begins to rapidly precipitate out of solution
within 60 min to a less soluble form which provides a concentration
that is less than therapeutic. This precipitation results in slow
and incomplete dissolution. In most cases, the amount precipitating
can be up to 90% or greater which leave about 10% or less available
for therapeutic activity. It is preferred that the rapidly
precipitating drug is a fairly soluble or highly soluble salt form
of a poorly soluble free base or free acid drug or an anhydrous
form of a poorly soluble free base or free acid drug. The rapidly
precipitating drugs are prone to supersaturation as is known to
those skilled in the art. It is preferred that the rapidly
precipitating drug be selected from the group consisting of
delavirdine mesylate, phenytoin, furosemide, pseudoephedrine,
clindamycin hydrochloride, clonidine hydrochloride, diphenhydramine
hydrochloride, fluphenazine hydrochloride, griseofulvin,
hydromorphone hydrochloride, naloxone hydrochloride,
oxytetracycline hydrochloride, phenylephrine hydrochloride,
pheniramine maleate, tetracycline hydrochloride, verapamil
hydrochloride, propoxyphene hydrochloride, propoxyphene napsylate,
hydrocodine bitartrate, acyclovir sodium, albuterol sulfate,
ampicillin sodium, benztropine mesylate, benzphetamine
hydrochloride, bupivacaine hydrochloride, bupropin hydrochloride,
chlorphenamine maleate, chlorpromazine hydrochloride. It is most
preferred that the rapidly precipitating drug is delavirdine
mesylate. The rapidly precipitating drug should be present in an
amount of about 5 to about 60%, preferably in an amount of about 10
to about 40%.
[0016] Delavirdine,
1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethyl-amino)-2-p-
yridinyl]piperazine is known, see U.S. Pat. No. 5,563,142 (Example
105). Delavirdine mesylate is also known in two different crystal
forms "S" and "T", see, International Publication WO 95/28398 based
on PCT application PCT/US95/02166.
[0017] The tablet formulation of the present invention is a
non-sustained release pharmaceutical tablet composition which
comprises a rapidly precipitating drug in an amount from about 5 to
about 60%, microcrystalline cellulose (10-50%) and at least one
member selected from the group consisting of a binder in an amount
of from about 2 to about 25% and a superdisintegrant in an amount
from about 6 to about 40% where the rapidly precipitating drug,
microcrystalline cellulose, binder and superdisintegrant are mixed
and compressed into a tablet without heating, solvent or grinding.
It is preferred that the binder, microcrystalline cellulose and
superdisintegrant all be present.
[0018] The tablet formulation of the present invention can use a
binder. The binder is preferably selected from the group consisting
of hydroxypropyl methylcellulose, PVP, hydroxypropyl cellulose,
microcrystalline cellulose, hydroxymethylcellulose, carbopol and
sodium carboxymethylcellulose; it is more preferred that the binder
be selected from the group consisting of hydroxypropyl
methylcellulose and more preferably 2910 U.S.P. No. 3 cps. Also
preferred is PVP. It is preferred that the binder be present in an
amount of hydroxypropyl methylcellulose of from about 5 to about
20%, PVP from about 2 to about 15%, hydroxypropyl cellulose or
hydroxyethylcellulose from about 5 to about 20%, carbopol,
methylcellulose, and sodium carboxymethylcellulose from about 3 to
about 20%. It is apparent to those skilled in the art that the
binders of the present invention are polymeric binders as opposed
to non-polymeric binders.
[0019] The superdisintegrant is selected from the group consisting
of croscarmellose sodium, sodium starch glycolate, L-hydroxypropyl
cellulose; it is more preferred that the superdisintegrant be
croscarmellose. The superdisintegrant should be present in an
amount of from about 6% to about 40%. It is preferred that the
superdisintegrant is present in an amount of from about 6 to about
35%; it is more preferred that the superdisintegrant be present in
an amount of about 10 to about 30%. This is one of the agents
responsible for delaying the precipitation of the rapidly
precipitating drug.
[0020] The microcrystalline cellulose is not absolutely necessary
to prepare the tablet formulation of the present invention.
However, it is highly desirable to have it present in most cases.
The tablet formulation can use a microcrystalline cellulose
diluent.
[0021] When present, it is preferred that it can be selected from
the group consisting of microcrystalline cellulose coarse powder,
microcrystalline cellulose medium powder and microcrystalline
cellulose 200; it is more preferred that the microcrystalline
cellulose be microcrystalline cellulose N.F. coarse powder. The
microcrystalline cellulose should be present in an amount of from
about 5% to about 50%. It is preferred that the microcrystalline
cellulose be present in an amount of from about 10 to about
50%.
[0022] The lactose is not absolutely necessary to prepare the
tablet formulation of the present invention. However, it is highly
desirable to have it present in most cases in an amount up to about
80%. When present, it is preferred that it be selected from the
group consisting of lactose monohydrate spray process standard,
lactose monohydrate, lactose anhydrous, lactose dihydrate, DMV
lactose; it is more preferred that the lactose be N.F. monohydrate
spray process standard lactose. The lactose can be present in an
amount of from about 0% to about 80%. It is preferred that the
lactose be present in an amount of from about 5 to about 20%.
[0023] The flow agent is not absolutely necessary to prepare the
tablet formulation of the present invention. However, it is highly
desirable to have it present in most cases. When present, it is
preferred that it be selected from the group consisting of
colloidal silicon dioxide and talc; it is more preferable that the
flow agent be selected from the group consisting of colloidal
silicon dioxide N.F. When present, the flow agent should be present
in an amount up to about 5%. It is preferred that the flow agent be
present in an amount of from 0.25 to about 2%.
[0024] The lubricant is not absolutely necessary to prepare the
tablet formulation of the present invention. However, it is highly
desirable to have it present in most cases. When present, it is
preferred that the lubricant is selected from the group consisting
of magnesium stearate and stearic acid; it is more preferred that
the lubricant be magnesium stearate. When present, the lubricant
should be present in an amount up to about 5%. It is preferred that
the lubricant be present in an amount of 0.25 to about 2%.
[0025] As is known to those skilled art, the tablet can be colored,
flavored and/or film coated as is known to those skilled in the
art.
[0026] The tablet composition of the present invention is prepared
as is known to those skilled in the art as direct compression. It
is preferred to first mix the rapidly precipitating drug with the
microcrystalline cellulose very thoroughly by methods well known to
those skilled in the art, preferably by use of a high shear mixer.
The hydroxypropyl methylcellulose, croscarmellose, lactose, and
screened colloidal silicon dioxide are mixed separately, preferably
in a high shear mixer, and added to the drug-microcrystalline
cellulose mixture and all the ingredients are thoroughly mixed,
preferably in a high shear mixer. The magnesium stearate is
screened and added to the drug mixture and mixed well. The
resulting mixture is compressed by methods well known to those
skilled in the art to produce tablets containing the desired amount
of active pharmaceutical agent. These tablets can then be film
coated and polished as is known to those skilled in the art. These
tablets comply with applicable U.S.P. and/or F.D.A.
requirements/law and are well suited to commercial production and
use. Alternatively, but less preferably, the binder can be solvated
and used in a wet granulation process.
Definitions and Conventions
[0027] The definitions and explanations below are for the terms as
used throughout this entire document including both the
specification and the claims.
Definitions
[0028] Delavirdine refers to
1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-py-
ridinyl]piperazine.
[0029] Delavirdine mesylate refers to
1-[5-methanesulfonamidoindolyl-2-carbon-yl]-4-[3-(1-methylethylamino)-2-p-
yridinyl]piperazine mesylate salt.
[0030] A "rapidly precipitating drug" is a pharmaceutical compound,
or its salt form, which when introduced in water, or simulated
physiological fluids at body temperature, begins to dissolve fairly
rapidly and then begins to rapidly precipitate out of solution
within 60 min to a less soluble form which provides a concentration
that is less than therapeutic.
[0031] All temperatures are in degrees Centigrade.
[0032] Pharmaceutically acceptable refers to those properties
and/or substances which are acceptable to the patient from a
pharmacological/toxicological point of view and to the
manufacturing pharmaceutical chemist from a physical/chemical point
of view regarding composition, formulation, stability, patient
acceptance and bioavailability.
[0033] When two or more solids are used in a mixture, they are
expressed as weight/weight designated wt/wt or wt.wt.
[0034] PVP refers to polyvinylpyrrolidone.
EXAMPLES
[0035] Without further elaboration, it is believed that one skilled
in the art can, using the preceding description, practice the
present invention to its fullest extent. The following detailed
examples describe how to prepare the various compounds and/or
perform the various processes of the invention and are to be
construed as merely illustrative, and not limitations of the
preceding disclosure in any way whatsoever. Those skilled in the
art will promptly recognize appropriate variations from the
procedures both as to reactants and as to reaction conditions and
techniques.
Example 1
Delavirdine Mesylate 200 mg Tablet Formulation
[0036] TABLE-US-00002 Item 200 mg tablet (wt.wt) Amount/tablet %
delavirdine mesylate 200.00 mg 30.2 microcrystalline cellulose N.F.
198.76 mg 30.0 coarse powder lactose NF monohydrate spray 71.29 mg
10.7 process standard hydroxypropyl methylcellulose 75.00 mg 11.3
2910 U.S. P. 3 cps croscarmellose sodium N.F. 110.00 mg 16.6 Type A
colloidal silicon dioxide N.F. 1.50 mg 0.23 magnesium stearate N.F.
powder 5.00 mg 0.76 food grade-V bolted
[0037] The above tablets are manufactured by intensely mixing the
delavirdine mesylate and the microcrystalline cellulose in a high
shear mixer. Then add and mix the hydroxypropyl methylcellulose,
croscarmellose, lactose, and screened colloidal silicon dioxide in
high shear mixer. Finally add screened magnesium stearate and
lubricate in high shear mixer. The resulting mixer is compressed,
film-coated, and polished as is known to those skilled in the art
to give tablets which have about 200 mg of delavirdine
mesylate/tablet and comply with U.S.P. and/or F.D.A.
requirements.
* * * * *