Note: Descriptions are shown in the official language in which they were submitted.
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Core Formulation Comprising Pioglitazone Hydrochloride and a Biguanide
This application claims priority from U.S. provisional application
Serial No. 60/201,057, filed May 1, 2000, which is incorporated herein by
reference.
BACKGROUND OF THE INVENTION
Field of the Invention
This invention relates to a core formulation, and, more particularly, to
a core formulation comprising a first layer comprising pioglitazone, which
covers at
least a portion of a core comprising a biguanide, metformin (i.e.,
glucophage), with a
modulating release polymer comprising a silicate.
Description of the Related Art
Metformin and pioglitazone, or their salts such as the hydrochlorides,
maleates, tartrates, etc., are two active ingredients of anti-diabetic drugs
that are
used to treat diabetic patients, e.g. human beings. These two active agents
are
administered orally to patients in need thereof in protocols calling for the
single
administration of either ingredient. Heretofore, there has not been revealed
or hinted
at combining both ingredients and certainly not a physically combined core
formulation comprising both ingredients. The use of such a core formulation is
advantageous to patients and prescribers because both medicaments are
synergistic
to each other in the body when used in the management of blood glucose
control,
i.e., diabetes. Furthermore, the use of a modulating agent, like silica gel,
in the
preparation, controls the rate of drug release over a clinically meaningful
period to
enable better control of the effect of the medicinal agents in such
preparation.
SUMMARY OF THE INVENTION
This invention relates to a core formulation, and, more particularly, to
a core formulation comprising a first layer comprising pioglitazone
hydrochloride,
which covers at least a portion of a core comprising a biguanide, e.g.
metformin, one
or both of which are intimately dispersed in a silicate based modulating
agent.
DETAILED DESCRIPTION OF THE INVENTION
A typical biguanide is metformin. It typically is used clinically as a
pharmaceutically acceptable salt, preferably the hydrochloride salt. A
commercial
form of metformin hydrochloride is available as glucophage. Its chemical name
is
N,N-dimethylimidodicarbonimidic diamide hydrochloride. Metformin
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hydrochloride is a hydrochloride salt of metformin base, and as used herein,
"metformin" means the base compound as well as its pharmaceutically acceptable
salts. Metformin is used clinically to manage non-insulin dependent diabetes
mellitus or "N)DDM", particularly in patients who are not effectively treated
with a
sulfonylurea. While it is not chemically related to the sulfonylureas, it is
routinely
utilized in combination with a sulfonylurea, and has been shown to be
synergistic in
some cases. Other biguanides such as phenformin, buformin etc. can also be
used.
Additionally, in the treatment of a diabetic patient the metformin, for
example, and
the pioglitazone hydrochloride are present in effective amounts to provide
such
treatment.
Metformin is an active ingredient for a commercially available drug
employed to treat diabetes mellitus in a host or mammal, e.g. a human being,
another animal. The typical daily effective dose fox the oral treatment of a
mammal,
i.e., a human, ranges from about 500 mg to about 2550 mg. Typically, the dose
is a
single dose of about 500 mg to about 850 mg.
Pioglitazone hydrochloride, (ACTOS~), is an active ingredient for a
commercially available drug employed to treat diabetes mellitus in a host,
e.g. a
human being. The typical daily effective dose for the oral administration to a
mammal, e.g. a human being, ranges from aboutl5 mg to about 45 mg, given as a
, single dose.
Silicates are pharmaceutical excipients generally regarded as safe and
used therefore to prepare a variety of pharmaceutical systems well documented
in
the patent literature. In this regard, reference is made to Remi~zgton's
Pharmaceutical Sciefaces, 18t~' Edition, Imorgamic Pharmaceutical CherraistYy,
Silicon, pp 340-341, 1990.
Heretofore, the silicates have not been shown to modulate the release
of the hypoglycemic drugs metformin and pioglitazone hydrochloride when
administered together to try to improve the control and effectiveness of
either drug,
although co-administration of the two has been proposed ~Whitcomb; et al.,
United
States Patent No. 6,011,049. However, a combined form of the drugs, i.e. a
single
integral unit thereof has not heretofore been reported. The present invention
provides such a single integral unit in the form of a core formulation.
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A typical silicate for this purpose is Purified Siliceous Earth
(National Formulary XVI), also known in some forms as silica gel or fumed
silica.
It is typically used in oral pharmaceutical preparations as a bulking agent.
As used
herein, "silicate" means silicic acid, disilicic acid, tricisilic acid,
metasilicic acid,
and orthosilicic acid in their free or salt forms; silicon dioxide in either
of its
amporphous, crystalline, or precipitated forms; diatomacous earth; Fuller's
earth,
Kieselhurh, Celite; talc; attapulgite; micas; clays such as montmorilonite
(MontmoriloniteTM), kaolin, aluminum oxide (Hydrargilite), bentone
(BentoniteTM),
bentonite (Bentonite MagmaTM) and pumice; silanes and siloxanes. These are
used
typically as adsorbents, carriers, dispersants, fillers, thickeners.
As indicated above, the relative concentrations of each drug is such
that a first layer comprising pioglitazone hydrochloride is prepared. The
first layer
covers at least a portion of a core comprising metformin with a portion or all
of the
amount of the silicate. Depending upon the rate of administration of the core
preparation, the metabolism of the patient destined to be treated, and the
desired
concentrations of each ingredient for each drug, the first layer may cover
only a
portion of the core or encompass the entire core. For example, one quarter of
the
core to about three fourths of the tablet core. The first layer should
comprise
pioglitazone hydrochloride with or without any silicate, because its dose
requirement
is lower compared to metformin. Additionally, pioglitazone hydrochloride is
slightly non-polar, its solubility rate is slower, and its absozption rate
thus is
dependent on its dissolution rate in the contents of the gastrointestinal
tract
compared with metformin.
It is to be understood, depending upon the desired rate of
administration to the patient, either the first layer or the core may
additionally
contain a mixture of the two active ingredients or both the first layer and
the core
may contain the two active ingredients with different and varying
concentrations of
one or both active ingredients.
The first layer of the core comprises pioglitazone hydrochloride in an
amount of about 0.01 % to about 20% of the total weight of the core
formulation,
whereas, the metformin in the core is present in an amount of about 10% to
about
97.5% of the total weight of the core formulation.
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Where combinations of the two active ingrdients are present in the
first layer and/or the core, the amounts of pioglitazone hydrochloride range
from
about 1 mg to about 45 mg whereas the metformin ranges from about 100 mg to
about 2550 mg.
Finally, it is to be understood that a third pharmacologically active
material, e.g. a drug, such as for example a sulfonylurea,an a-glucosidase
inhibitor ,
a meglitinide, and an ACE inhibitor may be employed in an admixture with the
active ingredients in the first layer and/or the core.
The alpha.-glucosidase inhibitors [Jean-Bernard Ducep et al., US
Patent No. 5,504,078], bisglucosylmoranoline derivatives [UK Patent No. GB 2
088
365 AJ, and glucosylmoranoline derivatives [European Patent No. 87112480.6]
include the following medicaments: 1.5-Dideoxy-4-O(.alpha.,D-glucopyranosyl)-
1,5-[6,7-dideoxy-7-D-glucoheptopyranosyl)imino]-D-glucitol; 1.5-Dideoxy-4-
O(.alpha.,D-glucopyranosyl)-1,5-[(1-deoxy-D-fructofuranosyl)iminoJ-D-glucitol;
1.5-Dideoxy-4-O(.alpha.,D-glucopyranosyl)-1,5-[(4-deoxy-4-D-
glucopyranosyl)imino]-D-glucitol; 1.5-Dideoxy-4-O(.alpha.,D-glucopyranosyl)-N-
[6-deoxy-1-(6-O-D-glucopyranosyl)-.alpha.-D-glucopyranosylJ-1, 5-imino-D-
glucitol; 1.5-Dideoxy-4-O(.alpha.,D-glucopyranosyl)-N-[6,7-dideoxy-1-(6-O-D-
glucopyranosyl)-7-.alpha.-D -glucoheptopyranosyl]-1,5-imino-D-glucitol; 1.5-
Dideoxy-4-O(.alpha.,D-glucopyranosyl)-1,5-[(4-deoxy-4-D-
glucopyranosyl)methylimino]-D-glucitol; 1.5-Dideoxy-4-O(.alpha.,D-
glucopyranosyl)-N-[4-deoxy-1-(4-O-D-glucopyranosyl)-.alpha.-D-glucopyranosyl]-
1,5-imino-D-glucitol; 1.5-Dideoxy-4-O(.alpha.,D-glucopyranosyl)-1,5-{ [2(1-D-
arabinofuranose)ethyl]imino}-D-glucitol; 1.5-Dideoxy-4-O(.alpha.,D-
glucopyranosyl)-N-[4-deoxy-1-(6-O-D-glucopyranosyl)-.alpha.-D-glucopyranosyl]-
1,5-imino-D-glucitol; 1.5-Dideoxy-4-O(.alpha.,D-glucopyranosyl)-N-{ [4-deoxy-1-
(4-O-D-glucopyranosyl)-4-.alpha.-D -glucopyranosyl]methyl}-1,5-imino-D-
glucitol;
1.5-Dideoxy-4-O(.alpha.,D-glucopyranosyl)-N-{ [4-deoxy-1-(6-O-D-
glucopyranosyl)-4-.alpha.-D -glucopyranosyl]methyl}-1,5-imino-D-glucitol; 1.5-
Dideoxy-4-O(.alpha.,D-glucopyranosyl)-1,5-[(6-deoxy-1-O-methyl-6-13-D-
glucopyranosyl)-imino-D -glucitol; 1.5-Dideoxy-4-O(.alpha.,D-glucopyranosyl)-
1,5-[(6,7-dideoxy-1-O-methyl-7-13-D-glucoheptopyranosyl) imino]-D-glucitol;
1.5-
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Dideoxy-4-O(.alpha.,D-glucopyranosyl)-1,5-[(1-deoxy-2-O-methyl-13-D-
fructofuranosyl)imino]-D-glucitol, 1.5-Dideoxy-4-O(.alpha.,D-glucopyranosyl)-
1,5-
[(4-deoxy-1-O-methyl-4-13-D-glucopyranosyl)imino]-D-glucitol; 1.5-Dideoxy-4-
O(.alpha.,D-glucopyranosyl)-N-[6-deoxy-1-(1-O-methyl-6-O-l3-D-glucopyranosyl)-
5 .alpha.-D -glucopyranosyl]-1,5-imino-D-glucitol; 1.5-Dideoxy-4-O(.alpha.,D-
glucopyranosyl)-N-[6,7-dideoxy-1-(1-O-methyl-6-O-13-D-glucopyranosyl)-7-
.alpha.-
D-glucoheptopyranosyl]-1,5-imino-D-glucitol; 1.5-Dideoxy-4-O(.alpha.,D-
glucopyranosyl)-1,5-[(4-deoxy-1-O-methyl-4-13-D-glucopyranosyl)methylimino]-D-
glucitol; 1.5-Dideoxy-4-O(.alpha.,D-glucopyranosyl)-N-[4-deoxy-1-(1-O-methy1-4-
O-8-D-glucopyranosyl)-.alpha.-D -glucopyranosyl]-1,5-imino-D-glucitol; 1.5-
Dideoxy-4-O(.alpha.,D-glucopyranosyl)-1,5-{ [2-(1-O-methyl-1-13-D-
arabinofuranosyl)ethyl]imino}-D-glucitol; 1.5-Dideoxy-4-O(.alpha.,D-
glucopyranosyl)-N-[4-deoxy-1-(1-O-methyl-6-O-13-D-glucopyranosyl)-.alpha.-D-
glucopyranosyl]-1,5-imino-D-glucitol; 1.5-Dideoxy-4-O(.alpha.,D-
gl.ucopyranosyl)-
N-{ [4-deoxy-1-(1-O-methyl-4-O-13-D-glucopyranosyl)-4-.alpha.-D-
glucopyranosyl]methyl}-1,5-imino-D-glucitol; 1.5-Dideoxy-4-O(.alpha.,D-
glucopyranosyl)-N-{ [4-deoxy-1-(1-O-methyl-6-O-13-D-glucopyranosyl)-4-.alpha.-
D-
glucopyranosyl]methyl}-1,5-imino-D-glucitol; 1.5-Dideoxy-6-O(.alpha.,D-
glucopyranosyl)-1,5-[6,7-dideoxy-7-D-glucoheptopyranosyl)imino]-D-glucitol;
1.5-
Dideoxy-6-O(.alpha.,D-glucopyranosyl)-1,5-[(1-deoxy-D-fructofuranosyl)imino]-D-
glucitol; 1.5-Dideoxy-6-O(.alpha.,D-glucopyranosyl)-1,5-[(4-deoxy-4-D-
glucopyranosyl)imino]-D-glucitol; 1.5-Dideoxy-6-O(.alpha.,D-glucopyranosyl)-N-
[6-deoxy-1-(6-O-D-glucopyranosyl)-.alpha.-D-glucopyranosyl]-1,5-imino-D-
glucitol; 1.5-Dideoxy-6-O(.alpha.,D-glucopyranosyl)-N-[6,7-dideoxy-1-(6-O-D-
glucopyranosyl)-7-.alpha.-D -glucoheptopyranosyl]-1,5-imino-D-glucitol;l.5-
Dideoxy-6-O (. alpha.,D-glucopyranosyl)-1,5- [(4-deoxy-4-D-
glucopyranosyl)methylimino]-D-glucitol; 1.5-Dideoxy-6-O(.alpha.,D-
glucopyranosyl)-N-[4-deoxy-1-(4-O-D-glucopyranosyl)-.alpha.-D-glucopyranosyl]-
1,5-imino-D-glucitol; 1.5-Dideoxy-6-O(.alpha.,D-glucopyranosyl)-1,5-{ [2(1-D-
arabinofuranose)ethyl]imino}-D-glucitol; 1.5-Dideoxy-6-O(.alpha.,D-
glucopyranosyl)-N-[4-deoxy-1-(6-O-D-glucopyranosyl)-.alpha.-D-glucopyranosyl]-
1,5-imino-D-glucitol; 1.5-Dideoxy-6-O(.alpha.,D-glucopyranosyl)-N-{ [4-deoxy-1-
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(4-O-D-glucopyranosyl)-4-.alpha.-D -glucopyranosyl]methyl}-1,5-imino-D-
glucitol;
1.5-Dideoxy-6-O(.alpha.,D-glucopyranosyl)-N-{ [4-deoxy-1-(6-O-D-
glucopyranosyl)-4-.alpha.-D -glucopyranosyl]methyl}-1,5-imino-D-glucitol; 1.5-
Dideoxy-6-O(.alpha.,D-glucopyranosyl)-1,5-[(6-deoxy-1-O-methyl-6-13-D-
glucopyranosyl) -imino-D-glucitol; 1.5-Dideoxy-6-O(.alpha.,D-glucopyranosyl)-
1,5-
[(6,7-dideoxy-1-O-methyl-7-13-D-glucoheptopyranosyl) imino]-D-glucitol; 1.5-
Dideoxy-6-O(.alpha.,D-glucopyranosyl)-1,5-[(1-deoxy-2-O-methyl-13-D-
fructofuranosyl)imino]-D-glucitol; 1.5-Dideoxy-6-O(.alpha.,D-glucopyranosyl)-
1,5-
[(4-deoxy-1-O-methyl-4-l3-D-glucopyranosyl)imino]-D-glucitol; 1.5-Dideoxy-6-
O(.alpha.,D-glucopyranosyl)-N-[6-deoxy-1-(1-O-methyl-6-O-13-D-glucopyranosyl)-
.alpha.-D -glucopyranosyl]-1,5-imino-D-glucitol; 1.5-Dideoxy-6-O(.alpha.,D-
glucopyranosyl)-N-[6,7-dideoxy-1-(1-O-methyl-6-O-13-D-glucopyranosyl) -7-
.alpha.-D-glucoheptopyranosyl]-1,5-imino-D-glucitol; 1.5-Dideoxy-6-O(.alpha.,D-
glucopyranosyl)-1,5-[(4-deoxy-1-O-methyl-4-f3-D-glucopyranosyl)methylimino]-D-
glucitol; 1.5-Dideoxy-6-O(.alpha.,D-glucopyranosyl)-N-[4-deoxy-1-(1-O-methyl-4-
O-13-D-glucopyranosyl)-.alpha.-D -glucopyranosyl]-1,5-imino-D-glucitol; 1.5-
Dideoxy-6-O(.alpha.,D-glucopyranosyl)-1,5-{ [2-(1-O-methyl-1-B-D-
arabinofuranosyl)ethyl]imino}-D-glucitol; 1.5-Dideoxy-6-O(.alpha.,D-
glucopyranosyl)-N-[4-deoxy-1-(1-O-methyl-6-O-13-D-glucopyranosyl)-.alpha.-D -
glucopyranosyl]-1,5-imino-D-glucitol; 1.5-Dideoxy-6-O(.alpha.,D-
glucopyranosyl)-
N-([4-deoxy-1-(1-O-methyl-4-O-13-D-glucopyranosyl)-4-.alpha.-D-
glucopyranosyl]methyl}-1,5-imino-D-glucitol; 1.5-Dideoxy-6-O(.alpha.,D-
glucopyranosyl)-N-( [4-deoxy-1-( 1-O-methyl-6-O-13-D-glucopyranosyl)-4-.
alpha.-D-
glucopyranosyl]methyl }-1,5-imino-D-glucitol.
The list of medicaments includes acid addition salt forms with such
inorganic acids, such as, for example, hydrochloric, hydrobromic, sulfuric,
phosphoric and like acids; with organic carboxylic acids such as, for example,
acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric,
malefic,
tartaric, citric, ascorbic, malefic, hydroxymaleic, dihydroxymaleic, benzoic,
2-
acetoxybenzoic, mandelic and like acids; and with organic sulfonic acids such
as
methanesulfonic acid and p-toluenesulfonic acid.
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The sulfonylureas are a class of compounds that have been widely
employed to treat diabetes. Such compounds are well known, for example as
described in U.S. Pat. Nos. 3,454,635; 3,669,966; 2,968,158; 3,501,495;
3,708,486;
3,668,215; 3,654,357; and 3,097,242. Especially preferred sulfonylureas to be
employed in the combinations or core formulations of this invention are
glyburide,
gliquidone, glipizide, tolbutamide, tolazamide, glisoxepid, chlorpropamide,
glibornuride, gliclazide, glimepiride, phenbutamide, and tolcyclamide. Other
medicaments, such as, for example, an antibiotic, a vitamin, a drug that works
on the
heart or in the liver, may be admixed with the active ingredients in the first
layer
1.0 and/or the core.
As indicated above, the modylating silicate polymer, e.g. silica gel,
e.g. may be associated with the metformin core alone or with the first layer
alone or
with both the metformin and pioglitazone hydrochloride. The type of
association as
well as the concentration of the modulating agent is dependent upon the
concentrations of the core active ingredient, and the layer active ingredient,
the
degree of coverage of the core by the first layer and the desired rate of
administration of every active ingredient.
The resultant core having the first layer thereon is prepared by any
conventional means known in the pharmaceutical art, e.g. compression,
tabletting
technology, spraying technology, or encapsulation in a pharmaceutically
acceptable
presentation, such as a gelatin capsule. In particular, typically, the core
formulation
of the present invention is preferably fabricated by compression into a
tablet.
The resultant core formulation of the present invention is useful to
treat diabetes mellitus. Surprisingly the resultant core formulation of the
invention
is as user friendly and clinically effective as compared to the administration
of
metformin alone or pioglitazone hydrochloride alone as demonstrated by co-
administration of the two agents (Whitcoznb; et al., United States Patent No.
6,011,049J, where in general, the incidence of adverse events was not
influenced by
age or menopausal status; and further, patients treated with the combination
therapy
attained better glycemic control than with either monotherapy.
It is to be understood, however, that for any particular subject being
treated, e.g., a mammal, specific dosage regimens should be adjusted according
to
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the individual need. It is further to be understood that the dosages set forth
herein
are exemplary only and that they do not, to any extent limit the scope of the
practice
of the present invention.
The core formulation of the present invention may be administered
orally, for example, with inert diluent or with an edible carrier. Fox the
purpose of
oral therapeutic administration, the core formulation may have other
excipients
incorporated therein. The subject core formulation may also contain the
following
adjuvants: a binder such as microcrystalline cellulose, gum tragacanth or
gelatin; an
excipient such as starch or lactose, a disintegrating agent such as alginic
acid,
Primogel~, corn starch and the like; a lubricant such as magnesium stearate or
Sterotex; a glidant such as colloidal silicon dioxide; and a sweetening agent
such as
sucrose or saccharin may be added or a flavoring agent such as peppermint,
methyl
salicylate or orange flavoring.
The subject core formulation of the invention may contain other
various materials which modify the physical form of the dosage unit (the
subject
core formulation), for example, as coatings. Thus, the subject core
formulation of
the present invention may be coated with sugar, shellac or other enteric
coating
agents. Materials used in preparing these various compositions should be
pharmaceutically pure and non-toxic in the amounts used.
In an alternative embodiment of the present invention. the resultant
core formulation (having a first layer completely or partially covering the
core), is
treated whereby an outer shell is formed, at least a portion of which
comprises the
biodegradable modulating silicate material is presemt in an amount having a
predetermined rate of degradation or metabolism in the host being present
treated.
The silicate material is a high molecular weight compound, which is
physiologically acceptable and excreted from the body of the human being or
other
animal almost intact.
The biodegradable silicate material, comprising the outer shell,
having a predetermined rate of degradation or metabolism or break down, is
selected
from silic acid and its derivatives, examples of which include those listed
previously. Other materials well known in the art, which do not react with
metformin and/or pioglitazone hydrochloride such as biodegradable polymers,
like
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polyorthoesters, polyanhydrides, polyamides based on glutamic acid, polyalkyl
cyanoacrylates, polyesters of lactic and glycolic acid, polyactide polymers,
cellulosic polymers, polyvinyl acetate, polyvinyl alcohol, polyvinylchloride,
natural
and synthetic rubbers, polyacrylates, polystyrene, etc. may be used.
Additionally,
reference is made to U.S. Patents Nos. 4,166,800, and 4,389,330, which
disclose
additional shell forming materials and are incorporated hereinto by reference
in their
entirety.
The shell encapsulating the particles of pioglitazone hydrochloride of
the first layer and/or the particles of metformin of the core is obtained by
any
conventional microencapsulation process whereby microspheres of metformin
andlor pioglitazone hydrochloride are formed, e.g. a solvent removal process,
a
phase separation technique, coacervation etc. In this regard reference is made
to
U.S. Patents Nos. 4,166,800 and 4,389,330, Conte et al, T. Controlled Release,
vol.
26, (1993), pages 39-47; and U.S. Patent No. 4,839,177; all of which are
incorporated hereinto by reference in their entirety.
In a variation of the above alternative embodiment, the resultant core
formulation is treated whereby only the top surface area of the first layer
comprising
pioglitazone hydrochloride has a shell coating thereon. In this regard,
reference is
made to U.S. Patent No. 5,916,584, incorporated hereinto by reference in its
entirety,
which describes the process for forming such a shell. The resulting core
formulation
having the first layer encapsulated by the shell comprising the shell
material, is one
which provides a delay time prior to release of the active ingredients, i.e.
pioglitazone hydrochloride .and metformin, to the patient being treated for
diabetes
mellitus.
In a second alternative embodiment of the present invention, the
resultant core formulation (having a first layer completely or partially
covering the
core) is treated whereby an outer shell comprising a natural polysaccaride, in
its free
acid a or salt form such as guar gum; gum arabic; gum karaya; gum Benjamin,
plantago ovata gum; agar; carrageenan; cellulose; gelatin; pectin; or
galacturonic
acid is formed which encloses the particles of the first layer and/or the
core.
Silicates are naturally occurring polymers consisting of silicon
chains. These polymers have the propensity to absorb water thus swelling to
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become gel-like structures in solution. The gel dissolves slowly thus
releasing its
drug payloads in a dissolution controlled manner.
The silicate shell, provides excellent stability to the core formulation
while at the same time modulates drug release. Upon ingestion by a patient
being
5 treated, the silicate shell swells to become a gel-like structure in
solution in the body
of the patient, e.g. the stomach. The gel ultimately dissolves slowly, e.g.
typically,
in several minutes to a few hours, usually within a day, releasing its drug
payload,
e.g. metformin and/or pioglitazone hydrochloride in a dissolution controlled
manner.
The shell is formed using any conventional coating technique, as
10 previously discussed, see U.S. Patents Nos. 4,166,800 and 4,839,177.
The rate of release is dependent on the shell's thickness and amount
of the polymeric material contained therein for a particular medicament
formulation.
Typically, for a release of of about 2 to 6 hours, the thickness ranges from
about
0.0001 mm to about 1 mm with a concentration of the polymeric material.
ranging
from about 10 ppm to about 100,000 ppm.
In a variation of the above second alternative embodiment, the
polysaccharide polymeric material, e.g. silicate, may be incorporated into or
combined or mixed with the first layer comprising metformin and/or the core of
pioglitazone in an effective amount to provide the desired stability and
controlled
release of these medicaments. Typically, the silicate is provided in an amount
ranging from about 10 ppm to about 100,000 ppm,in one both or of the
medicaments
to effect a desired release profile e.g. 15 minutes to about 12 hours of one
or both of
the medicaments of the core.
As discussed above, it is to be understood that the resultant core
formulation may be treated with the polymeric material whereby only the top
surface area of the first layer comprising poglitazone hydrochloride has a
coating
hereon. In this regard reference is again made to U.S. Patent No. 5,916,584.
Thus
as described above a delay time is provided prior to release of the release of
the
medicaments.
It is to be understood that for either metformin or pioglitazone, any
pharmaceutically acceptable form thereof can be employed. Such a form
encompasses the free acids, free bases, salts and various hydrate forms,
including
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11
semi-hydrate forms of these medicaments, as well as other pharmaceutical
materials
which are used in the formulation process as acceptable excipient materials
generally known to those skilled in the art.
It is understood that any one of the biguanides, i.e. drugs having the action
of
the stimulation of anaerobic glycolysis, is covered by this invention as
these, like
metformin, increase the sensitivity to insulin in peripheral tissues of the
host, e.g. a
human being or another animal. These compounds also are involved in the
inhibition
of glucose absorption from the intestine, suppression of hepatic
gluconeogenesis,
and inhibition of fatty acid oxidation. Examples of other typical biguanides
included
in this application are phenformin, buformin etc.
