U.S. patent application number 09/784288 was filed with the patent office on 2001-10-25 for core formulation.
Invention is credited to Adjei, Akwete L., Cutie, Anthony J., Zhu, Yaping.
Application Number | 20010034374 09/784288 |
Document ID | / |
Family ID | 26680526 |
Filed Date | 2001-10-25 |
United States Patent
Application |
20010034374 |
Kind Code |
A1 |
Adjei, Akwete L. ; et
al. |
October 25, 2001 |
Core formulation
Abstract
This invention relates to a controlled release combination drug
product comprising troglitazone, e.g. its hydrochloride, and a
biguamide, e.g. metformin. In particular, the product comprises a
core of metformin, at least a portion thereof has a layer or coat
thereon of troglitazone.
Inventors: |
Adjei, Akwete L.;
(Bridgewater, NJ) ; Zhu, Yaping; (Highland Park,
NJ) ; Cutie, Anthony J.; (Bridgewater, NJ) |
Correspondence
Address: |
Jerome Rosenstock, Esq
c/o FROMMER LAWRENCE & HAUG LLP
745 Fifth Avenue
New York
NY
10151
US
|
Family ID: |
26680526 |
Appl. No.: |
09/784288 |
Filed: |
February 15, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60201233 |
May 1, 2000 |
|
|
|
Current U.S.
Class: |
514/635 ;
424/471 |
Current CPC
Class: |
A61K 31/155 20130101;
A61K 9/209 20130101; A61K 31/427 20130101; A61K 31/427 20130101;
Y10S 514/866 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 31/155 20130101 |
Class at
Publication: |
514/635 ;
424/471 |
International
Class: |
A61K 009/24; A61K
031/155 |
Claims
We claim:
1. A core formulation comprising, (a) a first layer comprising
troglitazone or a pharmaceutically acceptable salt thereof as an
active ingredient, (b) a core, at least a portion of which is
enclosed by said first layer, comprising a biguanide as an active
ingredient; and (c) a polymer selected from the group consisting of
a silicate; diatomacous earth; Fuller's earth, Kieselhurh, Celite;
talc; attapulgite; micas; montmorilonite, kaolin, aluminum oxide,
bentonite, pumice; silanes and siloxanes and a mixture of any of
the foregoing polymers, and a mixture thereof, associated with at
least one of said active ingredients.
2. The formulation as defined in claim 1 wherein said first layer
comprises troglitazone hydrochloride present in an amount ranging
from about 1 mg to about 15 mg and said core comprises metformin
present in an amount ranging from about 100 mg to about 500 mg.
3. The formulation as defined in claim 1, wherein said polymer is
associated by forming a shell having a predetermined rate of active
ingredient release covering at least a portion of said first layer
to provide a predetermined delay in the time period of release of
at least said troglitazone active ingredient.
4. The formulation as defined in claim 1, wherein said troglitazone
and/or said biguanide are present as biodegradable microspheres
with said polymer associated therewith by having a shell coating
and where said shell coating has a predetermined rate of active
ingredient release.
5. A method of administering troglitazone and metformin to a
mammal, which comprises treating the mammal with the formulation
defined in claim 2.
6. A method for producing a controlled release formulation, which
comprises: (a) producing a hollow outer shell comprising a gel-like
material of a polymer selected from the group consisting of silica
gel, fumed silica gel, silicic acid, disilicic acid, trisilic 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; montmorilonite, kaolin, aluminum
oxide (Hydrargilite), bentonite, Bentonite Magma.TM., pumice; a
silane, a siloxane and a mixture of any of the foregoing polymers
having a predetermined rate of medicament release to provide a
predetermined delay in the time period of release of the contents
destined to be enclosed by said shell; (b) inserting a core
comprising metformin and having an outer layer comprising
troglitazone partially enclosing said core, into said hollow outer
shell; and (c) sealing said core within said hollow outer
shell.
7. A method of producing a modulated release formulation of
troglitazone hydrochloride medicament and metformin medicament,
which comprises: (a) forming a core of the metformin medicament;
and (b) depositing a layer of the troglitazone hydrochloride
medicament on at least a portion of a surface of said core; and (c)
associating a polymer selected from the group consisting of silica
gel, fumed silica gel, silicic acid, disilicic acid, trisilic 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; montmorilonite, kaolin, aluminum
oxide, bentonite, pumice; silanes and siloxanes and a mixture of
any of the foregoing with at least one of the medicaments to form
the modulated release formulation.
8. A method of treating diabetes mellitus in a patient in need
thereof, which comprises administering to the patient the
formulation of claim 1 wherein said active ingredients are each
present in an effective amount.
9. A drug controlled-release pharmaceutical composition comprising
an effective amount of troglitazone hydrochloride combined with an
effective amount of metformin associated with an effective
controlled-release amount of a polymer selected from the group
consisting of silica gel, fumed silica gel, silicic acid, disilicic
acid, trisilic 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;
montmorilonite, kaolin, aluminum oxide, bentonite, pumice; silanes
and siloxanes and a mixture of any of the foregoing polymers.
10. A method of treating diabetes mellitus in a patient in need
thereof, which comprises, administering to the patient the
composition of claim 9.
11. A drug controlled-release pharmaceutical composition comprising
an effective amount of troglitazone hydrochloride combined with an
effective amount of phenformin associated with an effective
controlled-release amount of a polymer selected from the group
consisting of silica gel, fumed silica gel, silicic acid, disilicic
acid, trisilic 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;
montmorilonite, kaolin, aluminum oxide, bentonite, pumice; silane;
a siloxane and a mixture of any of the foregoing polymers.
12. A controlled-release pharmaceutical composition comprising an
effective amount of troglitazone hydrochloride combined with an
effective amount of buformin associated with an effective
controlled-release amount of a polymer selected from the group
consisting of silica gel, fumed silica gel, silicic acid, disilicic
acid, trisilic 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;
montmorilonite, kaolin, aluminum oxide, bentonite, pumice; a
silane; a siloxane and a mixture of any of the foregoing
polymersor.
13. A method of treating diabetes mellitus in a patient in need
thereof, which comprises, administering to the patient the
composition of claim 11.
14. A method of treating diabetes mellitus in a patient in need
thereof, which comprises, administering to the patient the
composition of claim 12.
15. A method of treating diabetes mellitus in a patient in need
thereof, which comprises, administering to the patient the
composition of claim 1 wherein the biguanide is phenformin.
16. A method of treating diabetes mellitus in a patient in need
thereof, which comprises, administering to the patient the
composition of claim 1 wherein the biguanide is buformin.
17. A method of treating diabetes mellitus in a patient in need
thereof, which comprises, administering to the patient the
composition of claim 1 wherein the biguanide is metformin.
Description
[0001] This application claims priority from U.S. provisional
application Ser. No. 60/201,233, filed May 1, 2000, which is
incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] 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.
[0004] 2. 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 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
[0005] 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
[0006] 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
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.
[0007] 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.
[0008] Troglitazone hydrochloride, (Rezulin.RTM.), 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.
[0009] 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, 18.sup.th
Edition, Inorganic Pharmaceutical Chemistry, Silicon, pp 340-341,
1990.
[0010] 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.,
U.S. Pat. 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.
[0011] 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, Kieselhurh, Celite; talc;
attapulgite; micas; clays such as montmorilonite
(Montmorilonite.TM.), kaolin, aluminum oxide (Hydrargilite),
bentone (Bentonite.TM.), bentonite (Bentonite Magma.TM.) and
pumice; silanes and siloxanes. These are used typically as
adsorbents, carriers, dispersants, fillers, thickeners.
[0012] 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 quarter 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.
[0013] 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.
[0014] 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 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.
[0015] 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.
[0016] Finally, it is to be understood that a third
pharmacologically active material, e.g. a drug, such as for example
a sulfonylurea, an .alpha.-glucosidase inhibitor, a meglitinide,
and an ACE inhibitor can admixed with the active ingredients in the
first layer and/or the core.
[0017] The alpha.-glucosidase inhibitors [Jean-Bernard Ducep et
al., U.S. Pat. No. 5,504,078], bisglucosylmoranoline derivatives
[UK 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-fructofuranosy-
l)imino]-D-glucitol;
1.5-Dideoxy-4-O(.alpha.,D-glucopyranosyl)-1,5-[(4-deo-
xy-4-D-glucopyranosyl)imino]-D-glucitol;
1.5-Dideoxy-4-O(.alpha.,D-glucopy-
ranosyl)-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-dideox-
y-1-(6-O-D-glucopyranosyl)-7-.alpha.-D-glucoheptopyranosyl]-1,5-imino-D-gl-
ucitol;
1.5-Dideoxy-4-O(.alpha.,D-glucopyranosyl)-1,5-[(4-deoxy-4-D-glucop-
yranosyl)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-arabinof-
uranose)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-glucopyran-
osyl)-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-.bet-
a.-D-glucopyranosyl)-imino-D -glucitol;
1.5-Dideoxy-4-O(.alpha.,D-glucopyr-
anosyl)-1,5-[(6,7-dideoxy-1-O-methyl-7-13-D-glucoheptopyranosyl)
imino]-D-glucitol;
1.5-Dideoxy-4-O(.alpha.,D-glucopyranosyl)-1,5-[(1-deox-
y-2-O-methyl-.beta.-D-fructofuranosyl)imino]-D-glucitol,
1.5-Dideoxy-4-O(.alpha.,D-glucopyranosyl)-1,5-[(4-deoxy-1-O-methyl-4-.bet-
a.-D-glucopyranosyl)imino]-D-glucitol;
1.5-Dideoxy-4-O(.alpha.,D-glucopyra-
nosyl)-N-[6-deoxy-1-(1-O-methyl-6-O-.beta.-D-glucopyranosyl)-.alpha.-D-glu-
copyranosyl]-1,5-imino-D-glucitol;
1.5-Dideoxy-4-O(.alpha.,D-glucopyranosy-
l)-N-[6,7-dideoxy-1-(1-O-methyl-6-O-.beta.-D-glucopyranosyl)-7-.alpha.-D-g-
lucoheptopyranosyl]-1,5-imino-D-glucitol;
1.5-Dideoxy-4-O(.alpha.,D-glucop-
yranosyl)-1,5-[(4-deoxy-1-O-methyl-4-.beta.-D-glucopyranosyl)methylimino]--
D-glucitol;
1.5-Dideoxy-4-O(.alpha.,D-glucopyranosyl)-N-[4-deoxy-1-(1-O-me-
thyl-4-O-8-D-glucopyranosyl)-.alpha.-D-glucopyranosyl]-1,5-imino-D-glucito-
l;
1.5-Dideoxy-4-O(.alpha.,D-glucopyranosyl)-1,5-{[2-(1-O-methyl-1-.beta.--
D-arabinofuranosyl)ethyl]imino}-D-glucitol;
1.5-Dideoxy-4-O(.alpha.,D-gluc-
opyranosyl)-N-[4-deoxy-1-(1-O-methyl-6-O-.beta.-D-glucopyranosyl)-alpha.-D-
-glucopyranosyl]-1,5-imino-D-glucitol;
1.5-Dideoxy-4-O(.alpha.,D-glucopyra-
nosyl)-N-{[4-deoxy-1-(1-O-methyl-4-O-.beta.-D-glucopyranosyl)-4-.alpha.-D--
glucopyranosyl]methyl }-1,5-imino-D-glucitol;
1.5-Dideoxy-4-O(.alpha.,D-gl-
ucopyranosyl)-N-{[4-deoxy-1-(1-O-methyl-6-O-.beta.-D-glucopyranosyl)-4-.al-
pha.-D-glucopyranosyl]methyl}-1,5-imino-D-glucitol;
1.5-Dideoxy-6-O(.alpha.,D-glucopyranosyl)-1,5-[6,7-dideoxy-7-D-glucohepto-
pyranosyl)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-glucopyrano-
syl)-.alpha.-D-glucopyranosyl]-1,5-imino-D-glucitol;
1.5-Dideoxy-6-O(.alpha.,D-glucopyranosyl)-N-[6,7-dideoxy-1-(6-O-D-glucopy-
ranosyl)-7-.alpha.-D-glucoheptopyranosyl]-1,5-imino-D-glucitol;
1.5-Dideoxy-6-O(.alpha.,D-glucopyranosyl)-1,5-[(4-deoxy-4-D-glucopyranosy-
l)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-gluci-
tol;
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-d-
eoxy-1-(6-O-D-glucopyranosyl)-.alpha.-D
glucopyranosyl]-1,5-imino-D-glucit- ol;
1.5-Dideoxy-6-O(.alpha.,D-glucopyranosyl)-N-{[4-deoxy-1-(4-O-D-glucopy-
ranosyl)-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-glucopyran-
osyl)-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-.bet-
a.-D-glucopyranosyl)-imino-D-glucitol;
1.5-Dideoxy-6-O(.alpha.,D-glucopyra-
nosyl)-1,5-[(6,7-dideoxy-1-O-methyl-7-.beta.-D-glucoheptopyranosyl)
imino]-D-glucitol;
1.5-Dideoxy-6-O(.alpha.,D-glucopyranosyl)-1,5-[(1-deox-
y-2-O-methyl-.beta.-D-fructofuranosyl)imino]-D-glucitol;
1.5-Dideoxy-6-O(.alpha.,D-glucopyranosyl)-1,5-[(4-deoxy-1-O-methyl-4-.bet-
a.-D-glucopyranosyl)imino]-D-glucitol;
1.5-Dideoxy-6-O(.alpha.,D-glucopyra-
nosyl)-N-[6-deoxy-1-(1-O-methyl-6-O-.beta.-D-glucopyranosyl)-.alpha.-D-glu-
copyranosyl]-1,5-imino-D-glucitol;
1.5-Dideoxy-6-O(.alpha.,D-glucopyranosy-
l)-N-[6,7-dideoxy-1-(1-O-methyl-6-O-.beta.-D-glucopyranosyl)-7-.alpha.-D-g-
lucoheptopyranosyl]-1,5-imino-D-glucitol;
1.5-Dideoxy-6-O(.alpha.,D-glucop-
yranosyl)-1,5-[(4-deoxy-1-O-methyl-4-.beta.-D
glucopyranosyl)methylimino]-- D-glucitol;
1.5-Dideoxy-6-O(.alpha.,D-glucopyranosyl)-N-[4-deoxy-1-(1-O-me-
thyl-4-O-.beta.-D-glucopyranosyl)-.alpha.-D-glucopyranosyl]-1,5-imino-D-gl-
ucitol;
1.5-Dideoxy-6-O(.alpha.,D-glucopyranosyl)-1,5-{[2-(1-O-methyl-1-.b-
eta.-D-arabinofuranosyl)ethyl]imino}-D-glucitol;
1.5-Dideoxy-6-O(.alpha.,D-
-glucopyranosyl)-N-[4-deoxy-1-(1-O-methyl-6-O-.beta.-D-glucopyranosyl)-.al-
pha.-D-glucopyranosyl]-1,5-imino-D-glucitol;
1.5-Dideoxy-6-O(.alpha.,D-glu-
copyranosyl)-N-([4-deoxy-1-(1-O-methyl-4-O-.beta.-D-glucopyranosyl)-4-.alp-
ha.-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-.beta.-D-glucopyranosyl)--
4-.alpha.-D-glucopyranosyl]methyl}-1,5-imino-D-glucitol.
[0018] 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, maleic, tartaric,
citric, ascorbic, maleic, hydroxymaleic, dihydroxymaleic, benzoic,
2-acetoxybenzoic, mandelic and like acids; and with organic
sulfonic acids such as methanesulfonic acid and p-toluenesulfonic
acid.
[0019] 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, glibomuride, 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.
[0020] 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 metformin 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.
[0021] 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.
[0022] 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
troglitazone hydrochloride alone as demonstrated by
co-administration of the two agents [Whitcomb; et al., U.S. Pat.
No. 6,011, 049], 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.
[0023] 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.
[0024] 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.RTM., 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.
[0025] 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.
[0026] 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,.
[0027] 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.
[0028] 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, reference is made to U.S. Pat. Nos. 4,166,800, and
4,389,330, which disclose additional shell forming materials and
are incorporated hereinto by reference in their entirety.
[0029] 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. Pat. Nos. 4,166,800 and 4,389,330, Conte et al, J.
Controlled Release, vol. 26, (1993), pages 39-47; and U.S. Pat. No.
4,839,177; all of which are incorporated hereinto by reference in
their entirety.
[0030] 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.
Pat. 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.
[0031] 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.
[0032] 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.
[0033] 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 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.
[0034] As previously discussed, the polymer shell encapsulating the
particles 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
metformin 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. Pat.
Nos. 4,166,800 and 4,389,330, Conte et al, J. Controlled Release,
vol. 26, (1993), pages 39-47; and U.S. Pat. No. 4,839,177; all of
which are incorporated hereinto by reference in their entirety.
[0035] 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. Pat. 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.
[0036] 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.
[0037] 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.
[0038] 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. Typically, for a release 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.
[0039] 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.
[0040] 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.
[0041] 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 our typical biguanides
included in this application are phenformin, buformin etc.
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