U.S. patent application number 10/623481 was filed with the patent office on 2005-01-20 for dual drug dosage forms with improved separation of drugs.
This patent application is currently assigned to DepoMed, Inc., a corporation of the state of California. Invention is credited to Lim, Jong, Louie-Helm, Jenny, Shell, John N..
Application Number | 20050013863 10/623481 |
Document ID | / |
Family ID | 34063395 |
Filed Date | 2005-01-20 |
United States Patent
Application |
20050013863 |
Kind Code |
A1 |
Lim, Jong ; et al. |
January 20, 2005 |
Dual drug dosage forms with improved separation of drugs
Abstract
Drug tablets that include a prolonged-release core and an
immediate-release layer or shell are prepared with a thin barrier
layer of drug-free polymer between the prolonged-release and
immediate-release portions of the tablet. The barrier layer is
penetrable by gastrointestinal fluid, thereby providing full access
of the gastrointestinal fluid to the prolonged-release core, but
remains intact during the application of the immediate-release
layer, substantially reducing or eliminating any penetration of the
immediate-release drug into the prolonged-release portion.
Inventors: |
Lim, Jong; (San Jose,
CA) ; Shell, John N.; (Roseville, CA) ;
Louie-Helm, Jenny; (Union City, CA) |
Correspondence
Address: |
TOWNSEND AND TOWNSEND AND CREW, LLP
TWO EMBARCADERO CENTER
EIGHTH FLOOR
SAN FRANCISCO
CA
94111-3834
US
|
Assignee: |
DepoMed, Inc., a corporation of the
state of California
Menlo Park
CA
94025-1436
|
Family ID: |
34063395 |
Appl. No.: |
10/623481 |
Filed: |
July 18, 2003 |
Current U.S.
Class: |
424/472 |
Current CPC
Class: |
A61K 31/4415 20130101;
A61K 9/209 20130101; A61P 7/10 20180101; A61K 9/2018 20130101; A61K
45/06 20130101; A61K 9/2054 20130101; A61K 9/0065 20130101; A61K
31/00 20130101; A61K 31/40 20130101; A61P 43/00 20180101; A61K
9/2853 20130101; A61K 9/2077 20130101; A61K 31/155 20130101; A61K
9/2031 20130101; A61K 9/2027 20130101; A61K 2300/00 20130101; A61K
31/00 20130101; A61K 31/4015 20130101; A61P 9/12 20180101 |
Class at
Publication: |
424/472 |
International
Class: |
A61K 009/22; A61K
009/24 |
Claims
What is claimed is:
1. A method for the manufacture of a pharmaceutical tablet which
upon oral ingestion delivers a first drug by immediate release and
a second drug by prolonged release defined as a release rate into
gastrointestinal fluid that is slow enough to leave at least about
40% of said second drug unreleased one hour after ingestion, said
method comprising: (a) dispersing said second drug in a solid
matrix to form a unitary body which upon immersion in
gastrointestinal fluid releases said second drug by prolonged
release; (b) depositing on a surface of said unitary body a
polymeric film that is devoid of either said first drug or said
second drug; (c) depositing over said polymeric film a fluid medium
comprising said first drug and a liquid carrier that does not
remove said polymeric film upon contact therewith; and (d)
evaporating said liquid carrier from said fluid medium thus
deposited to leave a solid layer containing said first drug over
said unitary body.
2. The method of claim 1 in which said solid matrix is a member
selected from the group consisting of celluloses, substituted
celluloses, microcrystalline cellulose, polysaccharides,
substituted polysaccharides, polyl(alkylene oxide)s, poly(vinyl
alcohol), starch, starch-based polymers, crosslinked poly(acrylic
acid)s, and substituted crosslinked poly(acrylic acid)s.
3. The method of claim 1 in which said solid matrix is a member
selected from the group consisting of poly(ethylene oxide),
hydroxypropyl methyl cellulose, and combinations of poly(ethylene
oxide) and hydroxypropyl methyl cellulose.
4. The method of claim 1 in which said polymeric film is a member
selected from the group consisting of poly(ethylene oxide),
hydroxypropyl methyl cellulose, polyvinyl alcohol, combinations of
poly(ethylene oxide) and hydroxypropyl methyl cellulose, and
combinations of polyvinyl alcohol and poly(ethylene oxide).
5. The method of claim 1 in which said fluid medium comprises a
liquid solution of said first drug in a solvent.
6. The method of claim 1 in which said fluid medium comprises a
liquid solution of said first drug and a polymer in a solvent.
7. The method of claim 1 in which said fluid medium comprises a
suspension of said first drug in solid particle form in a liquid
suspending agent.
8. The method of claim 1 in which said fluid medium comprises a
suspension of said first drug in solid particle form and a
dispersing agent, also in solid particle form, in a liquid
suspending agent, said dispersing agent being a substance that
separates into discrete particles upon contact with
gastrointestinal fluid.
9. The method of claim 1 in which said fluid medium is an aqueous
suspension of said first drug, and said first drug is comprised of
particles having a weight-averaged diameter equal to or less than
25 microns.
10. The method of claim 1 in which said fluid medium is an aqueous
suspension of said first drug, and said first drug is comprised of
particles having a weight-averaged diameter equal to or less than
10 microns.
11. The method of claim 1 in which the weight ratio of said
polymeric film to said unitary body is from about 0.005:1 to about
0.2:1.
12. The method of claim 1 in which the weight ratio of said
polymeric film to said unitary body is from about 0.01:1 to about
0.1:1.
13. The method of claim 1 in which the weight ratio of said
polymeric film to said unitary body is from about 0.01:1 to about
0.08:1.
14. The method of claim 1 in which (b) comprises surrounding said
unitary body entirely with said polymeric film, and said solid
layer of (d) is a shell completely encasing said unitary body and
polymeric film.
15. The method of claim 1 in which (b) and (c) comprise depositing
said polymeric film and said first drug over only a portion of the
entire surface of said unitary body, leaving the remainder of said
unitary body exposed.
16. The method of claim 1 in which said liquid carrier of step (c)
is water.
17. The method of claim 1 in which said liquid carrier of step (c)
is an organic solvent.
18. The method of claim 17 in which said organic solvent is a
member selected from the group consisting of ethanol, hexanes,
chloroform, carbon tetrachloride, and dimethyl sulfoxide.
19. A dosage form for delivering a first drug that is immediately
releasable upon ingestion and a second drug that is releasable by
prolonged release defined as a release rate that is slow enough to
leave at least about 40% of said second drug unreleased one hour
after ingestion, said dosage form comprising: a prolonged-release
section comprising said second drug dispersed in a solid matrix
that releases said second drug by prolonged release upon immersion
of said dosage form in gastrointestinal fluid; a polymeric film
adhering to a surface of said prolonged-release section, said
polymeric film being penetrable by gastrointestinal fluid and
devoid of both said first drug and said second drug; and an
immediate-release section comprising a solid layer adhering to said
polymeric film, said solid layer comprising said first drug
dispersed in a matrix that promotes immediate release of said first
drug upon immersion of said dosage form in gastrointestinal
fluid.
20. The dosage form of claim 19 in which said solid matrix is a
member selected from the group consisting of celluloses,
substituted celluloses, microcrystalline cellulose,
polysaccharides, substituted polysaccharides, polyl(alkylene
oxide)s, poly(vinyl alcohol), starch, starch-based polymers,
crosslinked poly(acrylic acid)s, and substituted crosslinked
poly(acrylic acid)s.
21. The dosage form of claim 19 in which said solid matrix is a
member selected from the group consisting of poly(ethylene oxide),
hydroxypropyl methyl cellulose, and combinations of poly(ethylene
oxide) and hydroxypropyl methyl cellulose.
22. The dosage form of claim 19 in which said polymeric film is a
member selected from the group consisting of poly(ethylene oxide),
hydroxypropyl methyl cellulose, polyvinyl alcohol, combinations of
poly(ethylene oxide) and hydroxypropyl methyl cellulose, and
combinations of polyvinyl alcohol and poly(ethylene oxide).
23. The dosage form of claim 19 in which said solid matrix of said
unitary body is defined as a first solid matrix and said fluid
medium comprises said first drug in particle form and a second
solid matrix, also in particle form, said second solid matrix being
a substance that separates into discrete particles upon immersion
in gastrointestinal fluid.
24. The dosage form of claim 19 in which the weight ratio of said
polymeric film to said unitary body is from about 0.005:1 to about
0.2:1.
25. The dosage form of claim 19 in which the weight ratio of said
polymeric film to said unitary body is from about 0.01:1 to about
0.1:1.
26. The dosage form of claim 19 in which the weight ratio of said
polymeric film to said unitary body is from about 0.01:1 to about
0.08:1.
27. The dosage form of claim 19 in which said polymeric film and
said immediate-release section constitute a shell that fully
encases said prolonged-release section.
28. The dosage form of claim 19 in which said polymeric film and
said immediate-release section cover a portion of the surface of
said prolonged-release section, leaving the remainder of said
prolonged-release section exposed.
29. The dosage form of claim 19 in which one of said first and
second drugs is a diuretic and the other is a member selected from
the group consisting of angiotensin converting enzyme inhibitors
and angiotensin II antagonists.
30. The dosage form of claim 29 in which said diuretic is a loop
diuretic.
31. The dosage form of claim 30 in which said loop diuretic is a
member selected from the group consisting of furosemide, torsemide,
ethacrynic acid, and bumetanide.
32. The dosage form of claim 29 in which said diuretic is a
thiazide diuretic.
33. The dosage form of claim 34 in which said thiazide diuretic is
a member selected from the group consisting of chlorothiazide,
bendoflumethazide, hydroflumethazide, trichlorthiazide,
chlorthalidone, indapamide, metolazone, quinethazone and
hydrochlorthiazide.
34. The dosage form of claim 29 in which said diuretic is a
potassium-sparing diuretic.
35. The dosage form of claim 34 in which said potassium-sparing
diuretic is a member selected from the group consisting of
amiloride hydrochloride and triamterene.
36. The dosage form of claim 19 in which said first drug is a
member selected from the group consisting of lisinopril and
losartan, and said second drug is a diuretic.
37. The dosage form of claim 19 in which said first drug is a
glitazone, and said second drug is metformin hydrochloride.
38. The dosage form of claim 19 in which said first drug is
pyridoxine hydrochloride, and said second drug is a member selected
from the group consisting of atorvastatin, simvastatin,
pravastatin, lovastatin, cerivastatin, rosuvastatin, and
fluvastatin.
39. The dosage form of claim 19 in which said first drug is
pyridoxine hydrochloride, and said second drug is a member selected
from the group consisting of atorvastatin and simvastatin.
40. The dosage form of claim 19 in which said second drug is a
member selected from the group consisting of metformin
hydrochloride, vancomycin hydrochloride, captopril, erythromycin
lactobionate, ranitidine hydrochloride, sertraline hydrochloride,
ticlopidine hydrochloride, amoxicillin, cefuroxime axetil,
cefaclor, clindamycin, doxifluridine, tramadol, fluoxitine
hydrochloride, ciprofloxacin hydrochloride, gancyclovir, bupropion,
lisinopril, cefaclor, saguinavir, ritonavir, nelfinavir,
clarithromycin, azithromycin, ceftazidine, cyclosporin, digoxin,
paclitaxel, iron salts, topiramate, and ketoconazole.
41. The dosage form of claim 19 in which said second drug is a
member selected from the group consisting of lisinopril, enalapril,
captopril, fosinopril, quinapril, ramipril, and benazepril.
42. The dosage form of claim 19 in which said second drug is a
member selected from the group consisting of losartan, valsartan,
candesartan, irbesartan, telmisartan, and eprosartan.
43. The dosage form of claim 19 in which said first drug is a
sulfonylurea selected from the group consisting of glimepiride,
glyburide, and glipizide, and said second drug is metformin
hydrochloride.
44. The dosage form of claim 19 in which said first drug is
glimepiride and said second drug is metformin hydrochloride.
45. The dosage form of claim 19 in which said first drug is
glyburide and said second drug is metformin hydrochloride.
46. The dosage form of claim 19 in which said first drug is
glipizide and said second drug is metformin hydrochloride.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention is in the field of pharmacology, and relates
to drug dosage forms that are designed to deliver drugs
concurrently in both immediate-release and prolonged-release
delivery profiles.
[0003] 2. Description of the Prior Art
[0004] Certain pharmacological therapies either require or benefit
from the sequential administration of two or more drugs. While this
can be accomplished if the administration is done according to a
strict time schedule, many patients have difficulty complying with
such a schedule without the assistance of a medical professional.
Some therapies involve only an immediate but rapidly declining
high-level dosage and a prolonged dosage at a low or moderate
level, the two dosages being either of the same drug or of a
different drug. Even two-dosage therapies such as these however can
be troublesome to maintain if a separate administration is needed
for each dosage. Certain pharmaceutical formulations have therefore
been developed that combine both functions into a single dosage
form. This simplifies the therapy and reduces or eliminates the
chances of improper administration.
[0005] Many unitary dosage forms have been proposed that combine an
immediate release drug with a prolonged release drug by placing the
drugs in different layers of a tablet or by placing one drug in a
quickly-dissolving or quickly-dispersing shell that surrounds the
slowly dissolving or swellable core that contains the other drug.
The immediate-release layer or shell is typically formed by coating
the pre-formed prolonged-release portion with a solution or a
suspension of the immediate-release drug and a polymer and then
allowing the liquid carrier in which the drug and polymer are
dissolved or suspended to evaporate, leaving a solid dry outer
layer. In some cases, however, the liquid carrier tends to cause
swelling of the outer surface of the prolonged-release portion. As
the prolonged-release matrix swells, some of the drug intended for
immediate release enters the prolonged-release matrix. When the
immediate-release drug is applied as a suspension of particles, the
particles tend to become trapped in the prolonged-release matrix.
High-potency drugs that are intended for immediate release are
therefore retained rather than released. The problem can be
particularly acute when the drug is insoluble or of low solubility,
since unintended retention of the drug in the prolonged-release
portion can significantly reduce the amount of the drug that is
available for absorption into the patient's bloodstream.
SUMMARY OF THE INVENTION
[0006] It has now been discovered that a drug dosage form that
includes a prolonged-release core and an immediate-release layer or
shell can be manufactured in a manner that reduces or prevents any
migration of drug from the immediate-release portion into the
prolonged-release portion, by interposing a thin protective layer
of drug-free polymer between the prolonged-release and
immediate-release portions. The protective layer is penetrable by,
or dissolved in, water or gastrointestinal fluid, thereby providing
full access of the gastrointestinal fluid to the prolonged-release
core. The protective layer remains intact however during the
application of the immediate-release layer, substantially reducing
or eliminating any penetration by the immediate-release drug. The
protective layer thereby allows immediate release of the entire
dose of drug in the outer layer. The inclusion of the protective
layer also serves to prevent interaction of the prolonged-release
and immediate-release drugs, which is of value in cases where
interaction between the two drugs may be detrimental to the
activity of either or both of the drugs.
[0007] This discovery extends to dosage forms in which the
immediate-release layer is applied either as a solution of the drug
in an aqueous or organic solvent or as a suspension of solid
particles of the drug in an aqueous or organic liquid carrier. In
most cases, the liquid carrier also contains dissolved, dispersed
or suspended polymer to assist in the formation of an immediate
release coating. The discovery is of particular interest as applied
to immediate-release layers applied as suspensions of solid
particles, but also those that are applied as solutions. A
disclosure of certain dosage forms in which the immediate-release
layer is prepared from particulate suspensions is found in commonly
owned, co-pending U.S. patent application Ser. No. 10/066,146,
filed Feb. 1, 2002, entitled "Manufacture of Oral Dosage Forms
Delivering Both Immediate-Release and Sustained-Release Drugs," Lim
et al., inventors, the contents of which are incorporated herein by
reference.
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
[0008] The dosage forms of this invention are designed for oral
ingestion, and the prolonged-release portion of the dosage form is
one that delivers its drug to the digestive system continuously
over a period of time of at least an hour and preferably several
hours. The drug is retained in a matrix or supporting body of
pharmaceutically inert solid, and the prolonged delivery rate can
be achieved by using a matrix that allows the gastrointestinal
fluid to permeate the matrix and leach out the drug (i.e., allow
the drug to diffuse out from the matrix as the drug slowly
dissolves in the permeating fluid), or a matrix that slowly
dissolves or erodes to expose the drug to the gastrointestinal
fluid, or one that dissolves or erodes while allowing the
gastrointestinal fluid to permeate. The delivery rate is preferably
slow enough that at least about 40% of the drug remains unreleased
one hour after ingestion, more preferably at least about 60% and
most preferably at least about 80%. In most cases, the drug will be
substantially all released within about ten hours and preferably
within about eight hours, and in many cases, the matrix supporting
the drug will remain substantially intact until all of the drug is
released. "Substantially intact" in this sense means that the
matrix retains at least most of its size and shape rather than
dissolving or disintegrating into fragments. In this specification,
the term "prolonged-release" is equivalent to the terms
"controlled-release" and "sustained-release" as used in the prior
art.
[0009] In certain preferred embodiments of the invention, the
supporting matrix in the prolonged-release portion of the tablet is
a material that swells upon contact with gastrointestinal fluid to
a size that is large enough to promote retention in the stomach
while the subject is in the digestive state, which is also referred
to as the postprandial or "fed" mode. The "fed" mode is one of two
modes of activity of the stomach that differ by their distinctive
patterns of gastroduodenal motor activity. The "fed" mode is
induced by food ingestion and begins with a rapid and profound
change in the motor pattern of the upper gastrointestinal (GI)
tract. The change consists of a reduction in the amplitude of the
contractions that the stomach undergoes and a reduction in the
pyloric opening to a partially closed state. The result is a
sieving process that allows liquids and small particles to pass
through the partially open pylorus while indigestible particles
that are larger than the pylorus are retropelled and retained in
the stomach. This process causes the stomach to retain particles
that are greater than about 1 cm in size for about 4 to 6 hours.
The prolonged-release matrix in these embodiments of the invention
is therefore selected as one that swells to a size large enough to
be retropelled and thereby retained in the stomach, causing the
prolonged release of the drug to occur in the stomach rather than
in the intestines.
[0010] Disclosures of oral dosage forms that swell to sizes that
will prolong the residence time in the stomach are found in U.S.
Pat. No. 5,007,790 ("Sustained-Release Oral Drug Dosage Form,"
Shell, inventor; Apr. 16, 1991); U.S. Pat. No. 5,582,837
("Alkyl-Substituted Cellulose-Based Sustained-Release Oral Drug
Dosage Forms," Shell, inventor; Dec. 10, 1996); U.S. Pat. No.
5,972,389 ("Gastric-Retentive Oral Drug Dosage Forms for the
Controlled Release of Sparingly Soluble Drugs and Insoluble
Matter," Shell et al., inventors; Oct. 26, 1999); International
(PCT) Patent Application WO 98/55107 ("Gastric-Retentive Oral Drug
Dosage Forms for Controlled Release of Highly Soluble Drugs," Shell
et al., inventors; publication date Dec. 10, 1998); U.S. patent
application Publication No. US 2001/0018707 A1 ("Extending the
Duration of Drug Release Within the Stomach During the Fed Mode,"
Shell et al., inventors, publication date Aug. 30, 2001); and
International (PCT) Patent Application WO 96/26718 ("Controlled
Release Tablet," Kim, inventor: publication date Sep. 6, 1996).
Each of the documents cited in this paragraph is incorporated
herein in its entirety.
[0011] In general, gastric-retentive (swellable) matrices contain
binders that are water-swellable polymers, and suitable polymers
are those that are non-toxic, that swell in a dimensionally
unrestricted manner upon imbibition of water, and that release the
drug gradually over time. Examples of polymers meeting this
description are:
[0012] cellulose polymers and substituted cellulose polymers,
including alkyl-substituted, hydroxyalkyl-substituted, and
carboxyalkyl-substituted celluloses, specific examples being,
although not limited to, hydroxymethyl cellulose, hydroxyethyl
cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
and carboxymethylcellulose, and microcrystalline cellulose
[0013] polysaccharides and substituted polysaccharides (with
substituents such as those listed above)
[0014] poly(alkylene oxide)s
[0015] chitosan
[0016] poly(vinyl alcohol)
[0017] xanthan gum
[0018] maleic anhydride copolymers
[0019] poly(vinyl pyrrolidone)
[0020] starch and starch-based polymers
[0021] maltodextrins
[0022] poly (2-ethyl-2-oxazoline)
[0023] poly(ethyleneimine)
[0024] polyurethane hydrogels
[0025] crosslinked poly(acrylic acid)s and substituted crosslinked
poly(acrylic acid)s (with substituents such as those listed
above)
[0026] Further examples are copolymers of the polymers listed
above, including block copolymers and graft polymers. Specific
examples of copolymers are PLURONIC.RTM. and TECTONIC.RTM., which
are polyethylene oxide-polypropylene oxide block copolymers
available from BASF Corporation, Chemicals Div., Wyandotte, Mich.,
USA. Further examples are hydrolyzed starch polyacrylonitrile graft
copolymers, commonly known as "Super Slurper" and available from
Illinois Corn Growers Association, Bloomington, Ill., USA.
Particularly preferred polymers are poly(ethylene oxide),
hydroxypropyl methyl cellulose, and combinations of poly(ethylene
oxide) and hydroxypropyl methyl cellulose.
[0027] The immediate-release portion of the dosage form is either a
coating applied or deposited over the entire surface of a unitary
prolonged-release core, or a single layer of a tablet constructed
in two or more layers, one of the other layers being the
prolonged-released portion. Immediate release of the drug from the
immediate-release layer is achieved in any of a variety of ways.
One example is by placing the drug in a layer or coating that is
sufficiently thin to allow fast penetration by gastrointestinal
fluid which then leaches the drug at a rapid rate. Another example
is by incorporating the drug in a mixture that includes a
supporting binder or other inert material that dissolves readily in
gastrointestinal fluid, releasing the drug as the material
dissolves. A third is the use of a supporting binder or other inert
material that rapidly disintegrates into fine particles upon
contact with gastrointestinal fluid, with both the binder particles
and the drug quickly dispersing into the fluid. Examples of
materials that rapidly disintegrate and disperse are lactose and
microcrystalline cellulose. Hydroxypropyl methyl cellulose is a
component that can serve both as a suspending agent and as a
binder.
[0028] The dosage forms of this invention include those in which
the same drug is used in both the immediate-release and the
prolonged-release portions as well as those in which one drug is
formulated for immediate release and another drug, different from
the first, is formulated for prolonged release. In cases involving
the same drug, the invention serves to assure that the full
immediate-release dosage of the drug is achieved rather than loss
of the immediate-release effect. In cases involving one drug for
immediate release and a different drug for prolonged release, the
invention prevents the two drugs from commingling to the detriment
of one or the other and assures that the full immediate-release
dosage is achieved rather than a portion being lost to the
prolonged-release region of the dosage form.
[0029] This invention extends to both high-solubility and
low-solubility drugs, as well as drugs that are combined with an
additive that serves to solubilize the drug or suspend it in a
liquid carrier. Any of these drugs can be used as the
immediate-release drug. Immediate-release drugs that are either
sparingly soluble or insoluble in water, regardless of the
solubility of the prolonged-release drug, are of particular
interest in certain embodiments of this invention. The
immediate-release drug in these dosage forms is of sufficiently low
solubility that it remains a solid particle during the preparation
of the dosage form. In certain embodiments of the invention, the
dispersing medium is water or an aqueous solution that may contain
other components. The term "at most sparingly soluble" as used
herein denotes a drug having a solubility in water at 25.degree. C.
that is generally less than 2% by weight, preferably less than 0.5%
by weight. When the drug is in particulate form, the preferred
particle size is equal to or less than about 25 microns in
diameter, more preferably equal to or less than about 10 microns in
diameter, still more preferably within the range of from about 0.3
micron to about 10 microns in diameter, and most preferably with
the range of from about 1 micron to about 5 microns in diameter,
all on a weight-average basis.
[0030] This invention is also applicable to dosage forms in which
the dispersing medium for the immediate-release drug is an organic
liquid, such as for example, ethanol, hexanes, chloroform, carbon
tetrachloride, or dimethyl sulfoxide. An advantage of the use of a
relatively volatile organic liquid is a rapid rate of evaporation
to leave a dry coating. Organic liquids are also useful for drugs
that are unstable in aqueous solutions.
[0031] The intermediate layer of drug-free polymer that serves as a
barrier to migration of the immediate-release drug into the
prolonged-release matrix during application of the
immediate-release layer can be applied over the prolonged-release
segment as a solution or a suspension of the polymer, in the same
manner by which the immediate-release drug is applied over the
barrier layer. The polymer is one that is penetrable by
gastrointestinal fluid and can be either soluble in
gastrointestinal fluid or insoluble but erodible upon contact with
gastrointestinal fluid, or simply insoluble. The polymer can also
be one that swells upon imbibition of water in the same manner as
the prolonged-release matrix. Polymers that are soluble or erodible
in gastrointestinal fluid will be those of which a sufficient
amount remains during the formation of the immediate-release layer
to serve as a barrier until the immediate-release layer is fully
applied and dried. The ability of the polymer to do this may vary
with the thickness of the layer, the molecular weight of the
polymer and, for swellable polymers, the swelling characteristics
of the polymer. A small degree of swellability may be favorable to
accommodate any swelling of the prolonged-release matrix that may
occur during the application of the polymer over the matrix without
creating fissures in the polymer layer.
[0032] The same polymers listed above for use as the matrix in the
prolonged-release portion of the dosage form can be used in the
barrier layer. In many cases, it will be beneficial to use the same
polymer as both the prolonged-release matrix and the barrier layer,
for purposes of compatibility between the core and the barrier.
When the matrix is a mixture of polymers, the barrier polymer can
be one or more of the polymers of the mixture. When the same
polymer is used in both regions, a form of the polymer having a
lower molecular weight is preferably used in the barrier layer
since a polymer of lower molecular weight will more readily release
the immediate-release drug to the gastric environment. Preferred
polymers for use in forming the film are poly(ethylene oxide)
hydroxypropyl methyl cellulose, poly(vinyl alcohol), combinations
of poly(ethylene oxide) and hydroxypropyl methyl cellulose, and
combinations of poly(vinyl alcohol) and poly(ethylene oxide).
[0033] As noted above, the amount of the polymer in the
intermediate layer may affect the barrier characteristics of the
layer but it may also affect the performance of the dosage form
upon ingestion, i.e., the intermediate layer may further lower the
rate of release of drug from the prolonged-release portion once the
prolonged-release portion is exposed. In general, however, the
amount can vary widely. In most cases, best results will be
achieved when the weight ratio of the polymer in the intermediate
layer to the prolonged-release core is from about 0.005:1 to about
0.2:1, preferably from about 0.01:1 to about 0.1:1, and most
preferably from about 0.01:1 to about 0.08:1.
[0034] The immediate-release drug can thus be deposited as a
suspension or a solution over a unitary core of the
prolonged-release drug coated with the intermediate layer.
Deposition can be achieved by coating techniques commonly used in
the pharmaceutical formulation art, such as spraying, pan coating,
and the like. Alternatively, the immediate-release drug can be
combined with particles of a binding matrix and compressed over a
preformed layer of the prolonged-release drug to form a layered
tablet. In either case, the immediate-release coating or layer
separates relatively quickly from the remainder of the tablet after
ingestion, leaving the remainder intact.
[0035] The choice of drugs for use in either the prolonged-release
or immediate-release portions of the dosage form is not critical to
the invention, and many different types of drugs can be used. The
selection will depend on the condition to be treated, the therapy
being sought and the needs of the particular patient. Drugs of high
solubility in water as well as drugs of low solubility can occupy
either the prolonged-release or immediate-release portions.
Examples of high-solubility drugs are metformin hydrochloride,
vancomycin hydrochloride, captopril, lisinopril, erythromycin
lactobionate, ranitidine hydrochloride, sertraline hydrochloride,
ticlopidine hydrochloride, baclofen, amoxicillin, cefuroxime
axetil, cefaclor, clindamycin, levodopa, doxifluridine, tramadol,
fluoxetine hydrochloride, bupropion, potassium chloride, and esters
of ampicillin. Examples low solubility drugs are saguinavir,
ritonavir, nelfinavir, thiamphenicol, ciprofloxacin hydrochloride,
calcium carbonate, clarithromycin, azithromycin, ceftazidime,
acyclovir, ganciclovir, cyclosporin, digoxin, paclitaxel, iron
salts, topiramate, ketoconazole, and sulfonylureas such as
glimepiride, glyburide, and glipizide. Other drugs suitable for use
will be apparent to those skilled in the art.
[0036] One of the many areas of interest for this invention are
combinations of a diuretic and either an angiotensin converting
enzyme inhibitor or an angiotensin II antagonist. Preferably, the
angiotensin converting enzyme inhibitor or angiotensin II
antagonist will occupy the immediate-release portion and the
diuretic the prolonged-release portion, although for certain
patients a more appropriate dosage form may be one in which the
diuretic occupies the immediate-release portion and the angiotensin
converting enzyme inhibitor or angiotensin II antagonist occupies
the prolonged-release portion. Lisinopril is an example of an
angiotensin converting enzyme inhibitor, and examples of other
similar drugs are enalapril, captopril, fosinopril, quinapril,
ramipril, and benazepril. Losartan is an example of an angiotensin
II antagonist, and examples of other drugs of this class that might
be used are valsartan, candesartan, irbesartan, telmisartan, and
eprosartan. Loop diuretics, i.e., those acting on the
sodium-potassium symporter in the ascending loop of Henle in the
kidneys to decrease the rate of readsorption of water and sodium,
are also of particular interest. Examples are furosemide,
torsemide, ethacrynic acid, and bumetanide. Thiazides and
thiazide-like diuretics are believed to act primarily on the
sodium-potassium symporter in the distal convoluted tubule.
Examples of this type of diuretic are chlorothiazide and its
sodium, salt, bendoflumethazide, hydroflumethazide,
trichlorthiazide, chlorthalidone, indapamide, metolazone,
quinethazone and hydrochlorothiazide. Potassium-sparing diuretics
act in the late distal tubule and collecting duct. Exampes are
amiloride hydrochloride and triamterene.
[0037] Another class of combinations of particular interest is
metformin hydrochloride as the prolonged-release drug, and a
glitazone as the immediate-release drug. Examples of glitazones are
rosiglitazone (maleate), pioglitazone, and troglitazone. Yet
another class of combinations is pyridoxine hydrochloride as the
immediate-release drug, and a statin as the prolonged-release drug.
Examples of statins are atorvastatin, simvastatin, pravastatin,
lovastatin, cerivastatin, rosuvastatin, and fluvastatin. Of these,
atorvastatin and simvastatin are preferred.
[0038] The amounts of drugs in the immediate-release and
prolonged-release portions can vary widely, depending on the
potencies of the drugs and the desired dosage rates. Amounts of
either drug in a single dosage form can range from about 1 mg to
about 1,000 mg. In most cases the appropriate amounts will range
from about 5 mg to about 500 mg. This paragraph sets forth a number
of examples, others of which will be readily apparent to those
skilled in the formulation and prescription of these drugs. In
dosage forms that include furosemide, for example, or other drugs
of similar potency as prolonged-release diuretics, a preferred
dosage range of the diuretic is 10-120 mg. Lisinopril when present
is preferably in an amount of about 5 mg to about 40 mg. Losartan
when present is preferably in an amount of about 10 mg to about 100
mg. Loop diuretics when present are preferably in an amount of
about 5 mg to about 200 mg. When metformin hydrochloride is used as
the prolonged-release drug with a glitazone in the
immediate-release layer, a 500-mg metformin hydrochloride dose, for
example, can be accompanied by a 4-8-mg dose of a glitazone such as
rosiglitazone maleate. In some cases, the amount of drug in the
immediate-release portion will exceed the amount in the
prolonged-release portion. Dosage forms for example that contain
pyridoxine hydrochloride as the immediate-release drug and a statin
such as atorvastatin or simvastatin as the prolonged-release drug
may contain 100-200 mg of pyridoxine hydrochloride and either 20-40
mg of atorvastatin or 40-80 mg of simvastatin.
[0039] Preferred dosage forms in accordance with this invention are
tablets, and the size, shape, and dimensions of the tablets are not
critical to the invention. In embodiments where a swellable matrix
is used, the tablet upon swelling is preferably large enough to
reach the dimensions that will cause it to be retained in the
stomach during the fed mode. The tablet may be circular or
elongated. An elongated tablet may be 18 to 22 mm in length, 6.5 to
10 mm in width, and 6.2 to 7.5 mm in height. A specific example is
one that is 20 mm in length, 6.7 mm in width, and 6.4 mm in height.
Again, these are merely examples; the shapes and sizes can be
varied considerably.
[0040] Tablets in accordance with this invention can be prepared by
conventional mixing, comminution, and tableting techniques that are
well known in the pharmaceutical industry. The prolonged-release
portion can for example be fabricated by direct compression in
punches and dies fitted to a rotary tablet press, or by ejection or
compression molding, granulation followed by compression, or the
formation of a paste that is then extruded into a mold or into an
extrudate which is then cut into short lengths. The intermediate
(barrier) layer can be applied as a coating over the
prolonged-release portion by spraying, dipping, or pan-coating, and
the immediate-release portion can be applied as a coating over the
intermediate layer by the same techniques, or as an additional
layer by tableting or compression in the same manner as the
prolonged-release portion.
[0041] The following examples, both actual and prophetic, are
offered for purposes of illustration and are not intended to limit
the scope of the invention.
EXAMPLE 1
[0042] This example illustrates the preparation of tablets in
accordance with this invention that contain 500 mg metformin
hydrochloride as the prolonged-release component and 1 mg
glimepiride as the immediate-release component.
[0043] Pre-formed tablets containing 500 mg of metformin
hydrochloride in a matrix of hydroxypropyl methyl cellulose,
poly(ethylene oxide), microcrystalline cellulose, and magnesium
stearate were used as a starting material. A barrier layer solution
was prepared by dissolving OPADRY.RTM. YS-1-19025-A Clear ("OPADRY
Clear," hydroxypropyl methyl cellulose, available from Colorcon,
West Point, Pa., USA) in purified water to a concentration of 8
weight percent. This solution was sprayed onto the metformin
hydrochloride tablets until the tablet weight increased by
approximately 1%.
[0044] A suspension for applying the immediate-release layer was
prepared by dissolving polyethylene sorbitan monooleate in purified
water, dispersing glimepiride (micronized, 2-4 micron average
particle size) in the solution, and adding OPADRY Clear. The
resulting suspension contained 0.24% polyethylene sorbitan
monooleate, 0.20% glimepiride, 7.56% OPADRY Clear, with water as
the balance. The suspension was sprayed onto the barrier layer on
the metformin hydrochloride tablets until the tablet weight
increased by approximately 4%.
EXAMPLE 2
[0045] This example likewise illustrates the preparation of tablets
in accordance with this invention that contain metformin
hydrochloride as the prolonged-release component and glimepiride as
the immediate-release component, but with a higher amount of
glimepiride (2 mg) than Example 1.
[0046] Pre-formed metformin hydrochloride tablets identical to
those used as a starting material in Example 1 were used. Likewise,
an identical Opadry solution was used as the barrier layer
solution. This solution was sprayed onto the tablets to achieve a
weight increase of 1%.
[0047] To prepare the immediate-release layer, a suspension similar
to that of Example 1 was prepared except that it contained 0.40%
glimepiride rather than 0.20%. The suspension was sprayed onto the
barrier layer until the tablet weight increased by approximately
4%.
EXAMPLE 3
[0048] This example illustrates the preparation of tablets in
accordance with this invention that contain 500 mg metformin
hydrochloride as the prolonged-release component and 2 mg
glimepiride as the immediate-release component, but using a
poly(vinyl alcohol)-poly(ethylene oxide) poly(ethylene oxide) both
as the barrier layer and as a component in the immediate-release
layer. The poly(vinyl alcohol)-poly(ethylene oxide) used in the
barrier layer is KOLLICOAT.RTM. IR, a product available from BASF
Corporation, Chemicals Division, Wyandotte, Mich., USA.
[0049] Pre-formed metformin hydrochloride tablets identical to
those used as a starting material in the preceding examples are
used. The barrier layer solution is then prepared by dissolving the
KOLLICOAT IR in purified water to a concentration of 8% by weight.
This solution is then sprayed onto the pre-formed tablets to
achieve a weight increase of 1%.
[0050] The immediate-release drug-containing coating suspension is
prepared by dissolving polyethylene sorbitan monooleate in purified
water, dispersing glimepiride (micronized, 2-4 micron average
particle size) in the solution, adding KOLLICOAT IR, and mixing the
suspension for 45-60 minutes to allow the suspension to aerate. The
resulting suspension contains 0.24% polyethylene sorbitan
monooleate, 0.20% glimepiride, 7.56% KOLLICOAT, with water as the
balance. The suspension is sprayed onto the barrier layer until the
tablet weight increases by approximately 6%.
EXAMPLE 4
[0051] This example illustrates the preparation of tablets in
accordance with this invention that contain 20-40 mg atorvastatin
as the prolonged-release component and 100-200 mg pyridoxine
hydrochloride as the immediate-release component, again using
KOLLICOAT IR both as the barrier layer and as a component in the
immediate-release layer.
[0052] Pre-formed atorvastatin tablets containing 20 or 40 mg in a
matrix of hydroxypropyl methyl cellulose, poly(ethylene oxide),
microcrystalline cellulose, and magnesium stearate are used as a
starting material. The barrier layer solution is then prepared by
dissolving the KOLLICOAT IR in purified water to a concentration of
8% by weight. This solution is sprayed onto the pre-formed tablets
to achieve a weight increase of 0.5-2%.
[0053] The immediate-release drug-containing coating suspension is
prepared by dissolving with mixing the required amount of
pyridoxine hydrochloride in purified water, then adding KOLLICOAT
with further mixing and deacration. The resulting solution is
applied to the barrier layer until the tablet weight increases by
approximately 6%.
[0054] The foregoing is offered primarily for purposes of
illustration. It will be readily apparent to those skilled in the
art that further drugs can be included, and that the shapes,
components, additives, proportions, methods of formulation, and
other parameters described herein can be modified further or
substituted in various ways without departing from the spirit and
scope of the invention.
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