Note: Descriptions are shown in the official language in which they were submitted.
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Core Formulation Comprising Troglitazone and a Biguanide
This application claims priority from U.S. provisional application
Serial No. 60/201,233, 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 troglitazone, which
covers at
least a portion of a core comprising a biguanide, such as for example
metformin
(i.e., glucophage), with a modulating release polymer comprising a silicate.
Description of the Related Art
Metformin and troglitazone, and 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 advantage of such a core
formulation
is advantageous to patients and prescribers because both medicaments are
symGrgistic 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 troglitazone or a
derivative
thereof, e.g. troglitazone hydrochloride, which covers at least a portion of a
core
comprising a biguanide, 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
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2
form of metformin hydrochloride is available as glucophage. Its chemical name
is
N,N-dimethylimidodicarbonimidic diamide hydrochloride. Metformin
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 ("NIDDM"), 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 and the
troglitazone, e.g. its 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 for 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.
Troglitazone hydrochloride, (Rezulin~), 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 about 200 mg to about 400 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 Remington's Pharmaceutical Sciences,
I8'~t
Edition, Inorganic Pharmaceutical Chemistry, 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 (Yi~hitcomb; et al.,
United
States Patent No. 6, 011, 049J. However, a combined form of the drugs, i.e. a
single
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3
integral unit thereof has not heretofore been reported. The present invention
provides such a single integral unit in the form of a core formulation.
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, trisilicic 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,
I~ieselhurh, 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 troglitazone 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 eluarter of the core to about
three
fourths of the tablet core. The first layer should comprise troglitazone
hydrochloride, with or without any silicate, because its dose requirement is
lower
compared to metformin. Additionally, troglitazone hydrochloride is slightly
non-
polar, its solubility rate is slower, and its absorption 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 troglitazone, e.g. its
hydrochloride, in an amount of about 0.01 % to about 20% of the total weight
of the
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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.
Where combinations of the two active ingredients are present in the
first layer and/or the core, the amounts of troglitazone, e.g. its
hydrochloride, ranges
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 can admixed 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 jUI~ Patent No. GB 2
088
365 A], 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-fructofurano syl)imino]-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-glucopyranosyl]-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- f [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-~ j4-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)-
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1,5-[(6,7-dideoxy-1-O-methyl-7-13-D-glucoheptopyranosyl) imino]-D-glucitol;
1.5-
Dideoxy-4-O (. alpha.,D-glucopyrano syl)-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-13-D-glucopyranosyl)-.alpha.-D -glucopyranosyl]-1,5-
imino-D-glucitol; 1.S-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-methy1-4-
13-D-glucopyranosyl)methylimino]-D-glucitol; 1.5-Dideoxy-4-O(.alpha.,D-
glucopyranosyl)-N-[4-deoxy-1-(1-O-methyl-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-f3-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-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-4-O(.alpha.,D-glucopyranosyl)-N- f [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-glucital; 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;1.5-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-
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glucopyranosyl)-N-{[4-deoxy-1-(4-O-D-glucopyranosyl)-4-.alpha.-D -
glucopyranosyl]methyl}-1,5-imino-D-glucitol; 1.5-Dideoxy-6-O(.alpha.,D-
glucopyranosyl)-N- f [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-4-13-D-
glucopyranosyl)imino]-D-glucitol; 1.5-Dideoxy-6-O(.alpha.,D-glucopyranosyl)-N-
[6-deoxy-1-(1-O-methyl-6-O-l3-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-methy1-
4-13-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-glucopyrano syl)-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.
The sulfonylureas are a class of compounds that have been widely
employed to treat diabetes. Such compounds are well known, for example, as
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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
and/or the core.
As indicated above, the modulating silicate polymer, e.g., silica gel,
may be associated with the metformin core alone or with the first layer alone
or with
both the metforxnin and troglitazone 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 each
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 care 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 troglitazone hydrochloride alone as demonstrated by co-
administration of the two agents ~Whitcomb; 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
the individual need. It is further to be understood that the dosages set forth
herein
are examples only and that they do not, to any extent limit the scope of the
practice
of the present invention.
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The core formulation of the present invention may be administered
orally, for example, with inert diluent or with an edible carrier. For 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 present in an amount having a
predetermined rate of degradation or metabolism in the host being 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 troglitazone hydrochloride such as biodegradable polymers,
like
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,
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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
and/or 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, J. 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 with a 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
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
treated, the silicate shell swells to become a gel-like structure in solution
in the body
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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.
As previously discussed, the polymer shell encapsulating the particles
5 of troglitazone, e.g. its hydrochloride, of the first layer and/or the
particles of
metformin of the core, is obtained by any conventional microencapsulation
process
whereby microspheres of metfonnin and/or troglitazone, e.g. its 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,
10 Conte et al, J. 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
troglitazone has a shell coating, e.g. silical gel, 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 polymer shell
material, is one which provides a delay time prior to release of the active
ingredients, i.e. troglitazone and metformin, to the patient being treated for
diabetes
mellitus.
The amount of the polymer, e.g. fumed silica gel, employed will
depend upon the medicament release profile desired, the particular polymer
employed, the particular medicament or medicaments encapsulated or coated and
the
thickness of the coat of polymer contained on the particular medicament. Such
amount can be readily determined by those of ordinary skill in the art with
due
consideration of the factors set forth above.
In a second alternative embodiment, the polymer, e.g. silica gel, is
first combined or mixed with at least one of the medicaments, e.g. the
troglitazone
hydrochloride first layer, whereafter the resultant core having the first
layer thereon
is prepared in any conventional manner, e.g. compression into a tablet.
The amount of the polymer combined or mixed with at least one of
the medicaments, e.g. metformin, troglitazone, depends on the medicament
release
profile desired. This is readily determined by one of ordinary skill in the
art.
CA 02453782 2004-O1-08
WO 03/005993 PCT/USO1/21616
11
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.
Accordingly, based upon the above discussion, the polymer, e.g.
silica gel, is "associated' with the resultant core medicament. By
"associated" or
"association" is meant that the natural polysaccharide polymer, either fully
or
partially coats or encompass the particles of at least one medicament, e.g.
the first
layer of troglitazone, or is combined or mixed with the particles of at least
one
medicament, e.g. metformin, prior to forming the resulting core medicament, in
the
formation of a modulate release core formulation.
It is again to be understood that for either metformin or troglitazone,
any pharmaceutically acceptable form encompasses the free acids, free bases,
salts
and various hydrate forms, including 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
actions of stimulation of anaerobic glycolysis, is covered by this invention
as these,
like metformin, increase the sensitivity to insulin in peripheral tissues.
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.
