DESC:FIELD OF INVENTION
The present invention relates to fixed dose pharmaceutical composition comprising
Type 2 diabetes therapeutic agents and process of preparation thereof more particularly
to oral formulation comprising fixed dose combination of Sitagliptin, Voglibose and
metformin or pharmaceutically acceptable salts thereof.
BACKGROUND OF INVENTION
Type 2 diabetes(T2D) is a widespread disease, affecting more than 380 million people
worldwide. T2D generally results due to genetic predisposition and associated
environmental factors. The associated environmental factors are usually over nutrition,
defects in insulin action, pancreatic islet ß-cell dysfunction and reduced calories or
energy expenditure.
Lifestyle interventions of medical nutrition therapy and appropriately prescribed
physical activity are the cornerstone of diabetes therapy, but most patients will also
require pharmacologic therapy. There are several existing classes of therapeutic agents
available today for the treatment of T2D. However, treatment with a single
antihyperglycemic agent targetslimited components of the complex pathophysiologyof
T2D and often fails to provide adequate glycemic control, which increases the riskof
diabetic complications. Thus most patients will eventually require combination therapy
with 2 or more antihyperglycemic agents that targets more than one of the primary
defects, which are excessive hepatic glucose production, diminished peripheral
glucose uptake by insulin sensitive tissues and inadequate insulin secretion. Therefore,
there is an ongoing need for new therapies that target core aspects of pathophysiology
and could potentially address persistent unmet medical needs.
Thus there arises a need for combination therapy with agents having complementary
mechanisms of action formulated in a single-dose form called fixed-dose combinations
(FDCs). FDC formulations have unique advantages such as complementary
mechanism of action, synergistic effects, better tolerability, elongated product lifecycle management, and cost savings. Use of FDCs is a rationalapproach for achieving
optimal therapeutic benefits while minimizing pill-burden. Greater convenience with
decreased pill-burden leads to improved adherence, resulting in superior clinical
outcomes and greater cost-effectiveness.
A key step in the design of a combination tablet is selection of effective and welltolerated treatments. Moreover, it is essential that the components have complementary
mechanisms of action and compatible pharmacokinetic profiles.
The present invention provides a FDC combination of T2D therapeutic agents
Sitagliptin, Voglibose and optionally biguanides.
Sitagliptin is a DPPIV inhibitor (Dipeptidyl peptidase-4) which works by glucoselowering mechanism, proven efficacy, by inhibiting the degradation of glucagon-like
peptide-1 and -2 (GLP-1 and -2), and activating glucose-dependant insulinotropic
peptide (GIP) and its function on pancreatic ß cells to produce more insulin, low
propensity for hypoglycemia, and weight neutrality. Among other DPP-IV inhibitors
Sitagliptin appearsto be highly selective and produces approximately two-fold increase
in postprandial active glucagon-like peptide 1 concentrations.
Voglibose is a competitive a glucosisade inhibitors (a-GIs) which reversibly inhibit the
membrane bound intestines a glycosidase hydrolize enzymes which hydrolize
oligosaccharides and disaccharides to glucose and other monosaccharides in the brush
border of the small intestine. Voglibose may also facilitate mobilisotary a endogenous
glycogen -like peptide 1 (GLP-1), which has an inhibitory action on glycogen, thus
lowering fasting glucose levels too. Voglibose treatment has resulted in an increased
release of GLP-1, which is an insulinotrupic hormone and it has also increased release
of GLP-1, which is known to enhance insulin secretion and insulin sensitivity [Goke
B, et al. voglibose is an efficient glucosidase inhibitor and mobilises the endogenous
GLP-1 reserve. Digestion. 1995;56(6):493–501].
Voglibose thus well tolerated and effective as compared with other alpha glucosidase
inhibitors such as acarbose, voglibose and miglitol.
Metformin a biguanide has become the most preferred first-line oral blood glucoselowering agent to manage T2D. Metformin is the first-line pharmacologic treatment
for T2D and the most commonly prescribed drug for this condition worldwide, either
alone or in combination with insulin or other glucose-lowering therapies. The
antihyperglycemic properties of metformin are mainly attributed to suppress hepatic
glucose production, especially hepatic gluconeogenesis, and increased peripheral tissue
insulin sensitivity. Although the precise mechanism of hypoglycemic action of
metformin remains unclear, it probably interrupts mitochondrial oxidative processesin
the liver and corrects abnormalities of intracellular calcium metabolism in insulinsensitive tissues (liver, skeletal muscle, and adipocytes) and cardiovascular tissue.
Metformin is associated with gastrointestinal (GI) adverse effects, particularly
diarrhoea and nausea. These adverse effects may limit the tolerated dose of metformin
and cause patients to discontinue the therapy. Extended-release formulations of
metformin have advantages over immediate- release in terms of affording a more
uniform maintenance of blood plasma active drug concentrations and providing better
patient compliance by reducing the frequency of administrationrequired. Numerous
studies have been conducted to address the formulation and drug release systems of
combination of antidiabetic drugs and attempts have been made to improve the
formulation stability.
The FDC of the present invention provides synergistic effects by:
i. by inhibiting the degradation of glucagon-like peptide-1 and -2 (GLP-1 and -2),
and activating glucose-dependant insulinotropic peptide (GIP) and its function
on pancreatic ß cells to produce more insulin
ii. by inhibiting glucose hydrolyzing enzyme-glucosidase and thereby decreasing
carbohydrate absorption and decreases Post-Prandial Hyperglycaemia (PPHG).
iii. by suppressing the hepatic glucose production and increasing peripheral tissue
insulin sensitivity
The present invention provides a fixed dose combination of DPP-IV inhibitors, alpha
glucosidase inhibitors (aGI) and biguanide which improves improve the glycemic
control in adults with Type -2 diabetes, who experience postprandial hyperglycemia.
Combining multiple drugs in a single-pill formulation can benefit patients through the
potential synergistic or additive increases in efficacy, improved tolerability using lower
doses and convenience in terms of administration and increased patient compliance, as
well as reducing direct medical costs.
SUMMARY OF THE INVENTION:
The present invention provides a pharmaceutical composition comprising the
combined administration of DPP-IV inhibitors, alpha glucosidase inhibitors (aGI) and
biguanide and method for treating and/or preventing metabolic diseases, especially
type 2 diabetes mellitus and/or conditions related thereto (e.g. diabetic complications).
In another aspect the present invention provides an oral dosage form comprising triple
combination of Sitagliptin phosphate monohydrate, Voglibose and Metformin
hydrochloride in a single dosage form wherein the fixed dose combination of
Sitagliptin, Voglibose and metformin are present in a new and innovative dosage form.
DETAILED DESCRIPTION OF THE INVENTION
Those skilled in the art will be aware that the present disclosure is subject to variations
and modifications other than those specifically described. It is to be understood thatthe
present disclosure includes all such variations and modifications. The disclosure also
includes all such compositions, components of the composition, referred to or indicated
in this specification, individually or collectively and all combinations of any or more
of such components or composition.
Definitions
For convenience, before further description of the present disclosure, certain terms
employed in the specification, and examples are collected here. These definitions
should be read in the light of the remainder of the disclosure and understood as by a
person of skill in the art. The terms used herein have their meanings recognized and
known to those of skill in the art, however, for convenience and completeness,
particular terms and their meanings are set forth below.
The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at
least one) of the grammatical object of the article.
The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning
that additional elements may be included. It is not intended to be construedas “consists
of only”.
Throughout this specification, unless the context requires otherwise the word
“comprise”, and variations such as “comprises” and “comprising”, will be understood
to imply the inclusion of a stated element or step or group of element or steps but not
the exclusion of any other element or step or group of element or steps.
The term “including” is used to mean “including but not limited to”. “Including” and
“including but not limited to” are used interchangeably.
Unless defined otherwise, all technical and scientific terms used herein have the same
meaning as commonly understood by one of ordinary skill in the art to which this
disclosure belongs. Although any methods and materials similar or equivalent to those
described herein can be used in the practice or testing of the disclosure, the preferred
methods, and materials are now described. All publications mentioned herein are
incorporated herein by reference.
The present disclosure is not to be limited in scope by the specific embodiments
described herein, which are intended for the purposes of exemplification only.
Functionally equivalent products and processes are clearly within the scope of the
disclosure, as described herein.
The term “pharmaceutical composition” refers to delivery system in which active
agents are delivered to the patients. This could be in the form of tablet, capsule,
injection, liquid etc.
The term "T2D therapeutic agents" herein refers to any pharmaceutically acceptable
form of the T2D therapeutic agents including base or its pharmaceutically acceptable
complexes, salts, pro-drug, derivative polymorphs, hydrates, solvates, enantiomers or
racemates, metabolite as dictated by the context of its use.
The term "extended release" herein refers to any composition or dosage form that
comprises a therapeutic agent and which is formulated to provide a longer duration of
pharmacological response after administration of the dosage form than is ordinarily
experienced after administration of a corresponding immediate release composition.
Extended release compositions include, inter alia, those compositions described
elsewhere as "controlled release", "delayed release", "sustained release", "prolonged
release", "programmed release", "time release" and/or "rate controlled"compositions
or dosage forms.
The term “immediate release” herein refers to any composition or dosage form that
comprises a therapeutic agent and which is formulation to provide immediate
pharmacological response after administration of the dosage form.
The term "fixed dose combination" drug refers to a formulation of two or more
medications or active ingredients combined in a single unit dosage form, and availablein
certain fixed doses.
The term "pharmaceutically acceptable" is meant a carrier comprised of a material that
is not biologically or otherwise undesirable.
The term "release-controlling agent," as used herein, refers to an agent that helps to
control the release of the active ingredient.
The term “multi-layered coated tablet”, as used herein, relates to a tablet having more
than two layers. More particularly, it relates to a tablet having two layers.
The present invention provides a pharmaceutical composition for the treatment of T2D
associated disorder, wherein the composition comprises a synergistic fixed dose
combination of T2D agents, wherein the T2D agents acts synergistically by:
i. inhibiting the degradation of glucagon-like peptide-1 and -2 (GLP-1 and -2),
and activating glucose-dependant insulinotropic peptide (GIP) and its function
on pancreatic ß cells to produce more insulin
ii. inhibiting glucose hydrolyzing enzyme-glucosidase and thereby decreasing
carbohydrate absorption and decreases Post-Prandial Hyperglycaemia (PPHG).
iii. suppressing the hepatic glucose production and increasing peripheral tissue
insulin sensitivity.
The T2D therapeutic agents are selected from amylin analogs, DPP IV inhibitor, SGLT
inhibitors, Biguanides, Sulfonylurea, thiazolidinedione, Meglitinides, glucagon-like
peptide-1 receptor agonists, Alpha glucosidase inhibitor or a combination thereof.
Preferably the pharmaceutical composition of the present invention comprises a
combination of two or more T2D therapeutic agents selected from the combination of
DPP IV inhibitor, SGLT inhibitors, Biguanides, Sulfonylurea, thiazolidinedione,
Meglitinides, glucagon-like peptide-1 receptor agonists, Alpha glucosidase inhibitor or
a combination thereof.
In a most preferred embodiment the pharmaceutical composition of the present
invention comprises a combination of two or more T2D therapeutic agents selected
from DPPIV Inhibitor, Alpha glucosidase inhibitor and Biguanides.
In an embodiment the alpha-glucosidase inhibitors are selected from but not limitedto
acarbose, miglitol, Voglibose or pharmaceutically acceptable salts thereof.
In a preferred embodiment alpha-glucosidase inhibitor is Voglibose or
pharmaceutically acceptable salts thereof. Voglibose or a pharmaceutically acceptable
salt thereof may be present in dosage form of may have a dosage form ofapproximately
0.05 to 1mg more preferably 0.2 mg. In a preferred embodiment Voglibose is present
in base form.
In an another embodiment DPPIV Inhibitors are selected from but not limited to
sitagliptin, saxagliptin, linagliptin, Vildagliptin, Gemigliptin, Anagliptin,
Teneligliptin, Trelagliptin, omarigliptin, Evogliptin, Gosogliptin and alogliptin or
pharmaceutically acceptable salts thereof.
In a preferred embodiment DPPIV inhibitors is Sitagliptin or pharmaceutically
acceptable salts thereof which may be present on dosage form of 10-100 mg more
preferably 50 to 100 mg. In a preferred embodiment sitagliptin may be present in its
salts and hydrate form i.e. phosphate monohydrate.
In an another embodiment Biguanides are selected from but not limited to Metformin,
Phenformin or Buformin or pharmaceutically acceptable salts thereof.
In a preferred embodiment Biguanides is Metformin or pharmaceutically acceptable
salts thereof which may be present in dosage form of 200-1200 mg more preferably
500 to 1000 mg. In a preferred embodiment the Metformin is present in its salt form
i.e. hydrochloride salt.
In an embodiment the present invention provides a pharmaceutical composition
comprising effective amount of Sitagliptin phosphate monohydrate, Voglibose and
Metformin hydrochloride.
The pharmaceutical formulations of the invention are preferably in the form of oral
dosage form present in form of solid or liquid dosage form. In a preferred embodiment
the oral dosage form is solid dosage form such as tablet, caplets, pills, pellets, capsules,
including soft gelatin capsules, hard gelatin capsule or HPMC capsule or powder.
In an another embodiment the present invention provides oral solid pharmaceutical
formulation comprising fixed dose combinations of Sitagliptin phosphate
monohydrate, Voglibose and Metformin Hydrochloride.
In a preferred embodiment the present invention is an oral tablet dosage form
comprising:
i. 50 to 100 mg Sitagliptin phosphate monohydrate and;
ii. 0.2 mg Voglibose and;
iii. 500 to 1000 mg Metformin Hydrochloride
and pharmaceutically acceptable carriers or excipients may be utilized in formulating
the tablets, and are those utilized in the art of pharmaceutical preparations.
In another embodiment the pharmaceutical combination is present in the form of
immediate release, modified release, dual release, extended release or in sustained
release form. In another embodiment the pharmaceutical combination is present in the
form of multi-layer tablet composition or tablet-in-tablet composition.
In an another embodiment the pharmaceutical composition comprising a triple fixed
dose combination of Sitagliptin phosphate monohydrate, Voglibose and Metformin
hydrochloride wherein the composition exhibits both immediate and extended drug
release profile, wherein Sitagliptin phosphate monohydrate, Voglibose exhibits
immediate drug release profile and Metformin exhibits extended drug release profile.
According to one embodiment of the present invention wherein atleast one layer
provides an extended release of drug and atleast one layer provides immediate release
of drug.
In an embodiment the present invention provides oral fixed dose pharmaceutical
composition comprising:
a. About 20 to 60 wt.% of Sitagliptin or pharmaceutically acceptable salts thereof
and;
b. About 0.005 to 0.5 wt.% of Voglibose or pharmaceutically acceptable salts
thereof and;
c. About 60 to 90 wt.% of Metformin or pharmaceutically acceptable salts thereof
In an another embodiment the present invention provides a bi-layer tablet formulation
comprising dual release layers wherein upper layer is immediate release and lower
layer is extended release.
In an another embodiment the present invention provides a bi-layer composition
comprising an immediate having Sitagliptin phosphate monohydrate and Voglibose
with one or more pharmaceutical acceptable excipients.
In an another embodiment the immediate release layer comprising Sitagliptin
phosphate monohydrate present in an amount ranging from 20 to 60 wt.% based on
total weight of immediate release layer more preferably 20 to 50 wt.%
In an another embodiment Sitagliptin phosphate monohydrate is present in dosage from
50- 200 mg more preferably 50-100 mg.
In an another embodiment the immediate release layer comprising Voglibose presentin
an amount ranging from 0.05-1% based on total weight of immediate release.
In an another embodiment Voglibose is present in dosage form of 0.05-1 mg more
preferably 0.2 mg.
In an another embodiment the present invention provides bilayer tablet composition
comprising:
I. an immediate release layer comprising:
a. About 20 to 60 wt.% of Sitagliptin or pharmaceutically acceptable salts thereof
and;
b. About 0.005 to 0.5 wt.% of Voglibose or pharmaceutically acceptable salts
thereof and;
II. an extended release layer comprising:
a. About 60 to 90 wt.% of Metformin or pharmaceutically acceptable salts
thereof
In an another embodiment the immediate release layer further comprises one or more
excipients selected from group consisting of diluent, glidant, binder, disintegrant,
surfactant, lubricant, coloring agent.
Examples of fillers/diluents that can be used in the present invention are acacia, alginic
acid, cellulose, dextrin, dextrates, sucrose, tylose, pregelatinized starch, calcium
sulfate, amylose, glycine, bentonite, maltose, sorbitol, ethylcellulose, gelatin,calcium
phosphate, dibasic calcium phosphate, tribasic calcium sulfate, lactose, sucrose,
glucose, mannitol, sorbitol, microcrystalline cellulose, pectin, polyacrylates, cellulose
acetate, hydroxypropylmethyl cellulose, calcium carbonate, calcium carboxy
methylcellulose, Colloidal silicon dioxide, Talc, Magnesium stearate and others
including combinations thereof.
In an another embodiment diluent is microcrystalline cellulose present in an amount
ranging from 10-50 wt.% more preferably 15 to 45 wt.% based on total weight of
immediate layer.
Examples of disintegrant that can be used in the present invention are sodium
carboxymethyl starch, sodium carboxymethyl cellulose, potassium carboxymethyl
cellulose, sodium starch glycolate, alginates, pregelatinized starch, croscarmellose
sodium, hydroy propyl cellulose (HPC), cross-linked PVP like collidone or
combinationsthereof.
In most preferred embodiment disintegrant used is croscarmellose sodium present inan
amount ranging from 0.5-5 wt.% more preferably 1-3 wt.% based on total weight of
immediate layer.
Examples of Binders that can be used in the present invention are hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, polyethylene glycol,
and the like; water-insoluble polymers, for example, ethyl cellulose, polyvinyl
chloride, aminoalkyl and the like; and enteric polymers, for example,
hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer L, cellulose
acetate phthalate, hydroxypropylmethyl cellulose acetate succinate, carboxyvinyl
polymer or combination thereof.
In an another embodiment preferred binder is Polyvinyl Pyrrolidone present in an
amount ranging from 1-5 wt.% more preferably 2-4 wt.% based on total weight of
immediate release layer.
Examples of Glidant that can be used in the present invention are colloidal silicon
dioxide, magnesium trisilicate, talcum, powdered cellulose, starch, tribasic calcium
phosphate, calcium stearate, glycerylbehenate, glycerylmonostearate, magnesium
laurylsulfate, magnesium stearate, polyethyleneglycol, potassium benzonate, Sodium
stearate, sodium stearyl fumarate, stearic acid or combination thereof.
In most preferred embodiment glidant are colloidal silicon dioxide present in an amount
ranging from 0.05 to 1 wt.% based on total weight of immediate release layer.
Examples of lubricant that can be used in the present invention are stearic acid,
magnesium stearate, calcium or zinc stearate, sodium stearyl fumarate and metal
stearates.
In most preferred embodiment lubricant is Magnesium Stearate present in an amount
ranging from 0.2 to 2 wt.% more preferably 0.5 to 1 wt.%.
Examples of surfactant that can be used in the present invention are polysorbate 80
(Tween 80), polysorbate 60, poloxamers polysorbate, 40, polysorbate 20,
cremophors, tyloxapols, poloxamers, benzalkonium chloride, benzethonium chloride,
cetyl alcohol, carbomer, cholesterol, cocamidopropyl betaine, glyceryl monostearate,
lanolin alcohols, sodium lauryl sulfate, nonoxynol 9, octoxynol 40, polyoxyl 35 castor
oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 steate, sorbitan monolaurate,
sorbitan monooleate, or a combination thereof.
In an another embodiment the preferred surfactant is sodium lauryl sulfate present in
an amount ranging from 1-10 wt.% more preferably 2-5 wt.% based on total weightof
immediate release layer.
In an another embodiment the immediate release layer further comprises coloring agent
present in an amount ranging from 0.05 to 0.1 wt.% based on total weight of immediate
release layer.
In an another embodiment the bilayer tablet composition comprising immediate release
layer having:
a. Sitagliptin phosphate monohydrate present in an amount ranging from 20 to 60
wt.% based on immediate release layer and;
b. Voglibose present in an amount ranging from 0.005 to 0.5 wt.% based on
immediate release layer and;
c. one or more pharmaceutically acceptable excipients
In an another embodiment the bilayer tablet composition comprising immediate
release layer having:
a. Sitagliptin phosphate monohydrate present in an amount ranging from 20
to 60 wt.% based on total weight immediate release layer and;
b. Voglibose present in an amount ranging from 0.005 to 0.5 wt.% of based
on total weight of immediate release layer and;
c. One or more diluents present in an amount ranging from 20 to 50 wt.%
based on total weight of immediate release layer and;
d. One or more disintegrant present in an amount ranging from 0.5 to 5 wt.%
based on total weight of immediate release layer
e. One or more binder present in an amount ranging from 0.5 to 5 wt.% based
on total weight of immediate release layer
f. One or more lubricant present in an amount ranging from 0.5 to 5 wt.%
based on total weight of immediate release layer
g. One or more Glidant present in an amount ranging from 0.05 to 2 wt.%
based on total weight of immediate release layer.
In an another embodiment the bilayer tablet composition comprising extended release
layer having:
a. Metformin hydrochloride present in an amount ranging from 60 to 80% based on total
weight of extended release layer and;
b. One or more diluent present in an amount ranging from 0.05 to 5% based on total
weight of extended release layer and;
c. One or more release controlling polymer present in an amount ranging from 2 to 20%
based on total weight of extended release layer and;
d. One or more binder present in an amount ranging from 0.05 to 5% based on total
weight of extended release layer and
e. One or more Glidant present in an amount ranging from 0.05 to 5% based on total
weight of extended release layer and
f. One or more lubricant present in an amount ranging from 0.05 to 5% based on total
weight of extended release layer
The present invention provides a bi-layer tablet comprising immediate release layer
having:
i. Sitagliptin phosphate monohydrate present in an amount ranging from 20 to 60
wt.% based on immediate release layer and;
ii. Voglibose present in an amount ranging from 0.05-1% based on total weight
of immediate release and;
iii. microcrystalline cellulose as diluent present in an amount ranging from 15 to
45 wt.% based on total weight of immediate layer and;
14
iv. croscarmellose sodium as disintegrant present in an amountranging from
1-3wt.% based on total weight of immediate layer and;
v. Polyvinyl Pyrrolidone as disintegrant present in an amount ranging
from 2-4wt.% based on total weight of immediate release layer and;
vi. colloidal silicon dioxide as Glidant present in an amount ranging from
0.05 to1 wt.% based on total weight of immediate release layer and;
vii. Magnesium Stearate as lubricant present in an amount ranging from 0.5
to 1wt.%. based on total weight of immediate release layer and;
viii. Sodium Lauryl sulfate as surfactant present in an amount ranging from
2-5wt.% based on total weight of immediate release layer.
In an another embodiment the present invention provides a bi-layer composition
comprising an extended release comprising effective amount of Metformin
hydrochloride and one or more excipients.
In an another embodiment the extended release comprising metformin present in
anamount ranging from 60-90 wt.% more preferably 65-85 wt.% based on total
weight of extended release layer.
In an another embodiment the extended release layer comprising one or more
pharmaceutically acceptable excipient selected from release controlling
polymers, diluents, binders, disintegrants, surfactants, colouring agents,
glidants, lubricants, solvents.
In an embodiment the extended release layer comprises release controlling
polymerare selected from but not limited to hydroxypropylmethyl cellulose e.g.,
Hypromellose 2208, Hypromellose K4M and Hypromellose K100 LVCR,
methyl cellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxyethyl
cellulose, hydroxyethylmethyl cellulose, carboxy methylcellulose, cellulose
acetate phthalate, hydroxypropylmethyl cellulose phthalate,
hydroxypropylmethyl cellulose acetate succinate, cellulose acetate butyrate,
15
cellulose acetate, and cellulose acetate trimellitate; acrylic copolymers such as
methacrylic acid copolymers, e.g., Eudragit® RS, Eudragit® RL, and
Eudragit® NE 30 D; polyvinyl alcohol; polyvinyl acetate; polyalkylene
glycolsuch as polyethylene glycol; triglycerides; waxes, e.g., Compritol ,
Lubritab , and Gelucire®; lipids; fatty acids or their salts/derivatives; a mixture
of polyvinyl acetate and polyvinyl pyrrolidone, e.g., Kollidon® SR; and
mixtures thereof.
In an another embodiment the preferred the extended release layer comprises
release controlling polymer is hydroxypropylmethyl cellulose more preferably
commercially available Hypromellpose 2208 (HPMC K 100 M Prem) present
in an amount ranging from 5-20 wt.% based on total weight of extended release
layer.
In an another embodiment the extended release layer comprises combination of
one or more rate controlling polymer which is carbomer present in an amount
ranging from 2 to 10 wt.% based on total weight of extended release layer.
Examples of binding agents present in the extended release layer include but are
notlimited to hydroxypropylcellulose (HPC), hydroxypropylmethyl cellulose
(HPMC), hydroxyethyl cellulose, starch 1500, polyvinylpyrrolidone
(povidone), and co- povidone or a combination thereof.
In an another embodiment preferred binder is polyvinylpyrrolidone present in
an amount ranging from 1-5 wt.% based on total weight of extended release
layer.
Examples of diluents present in the extended release layer include but are not
limited to mannitol, sorbitol, anhydrous dibasic calcium phosphate, lactose
monohydrate, dibasic calcium phosphate dihydrate, microcrystalline cellulose,
powdered cellulose, pre-gelatinized starch or a combination thereof.
In an another embodiment preferred diluent is Microcrystalline Cellulose
present in an amount ranging 0.5-2 wt.% based on total weight of extended
16
release layer.
Examples of glidants present in the extended release layer include colloidal
silicon dioxide, calcium phosphate tribasic, magnesium silicate, and talc or a
combination thereof.
In a preferred embodiment the preferred glidant is colloidal silicon dioxide
present inamount ranging from 0.05-0.5 wt.% based on total weight of extended
release layer.
In a preferred embodiment the preferred lubricant is Magnesium stearate present
inan amount ranging from 0.05-1 wt.% based on total weight of extended release
layer.
In an another embodiment the present invention provides a bilayer tablet
composition comprising an extended release layer having:
i. Metformin hydrochloride present in an amount ranging from 65-85
wt.% based on total weight of extended release layer and;
ii. hydroxypropylmethyl cellulose more preferably commercially available
Hypromellpose as release controlling polymer present in an amount
ranging from 5-20 wt.% based on total weight of extended release layer
and;
iii. polyvinylpyrrolidone as binder present in an amount ranging from 1-5
wt.% based on total weight of extended release layer and;
iv. Microcrystalline Cellulose as diluent present in an amount ranging 0.5-
2 wt.%based on total weight of extended release layer and;
v. colloidal silicon dioxide as glidant present in amount ranging from 0.05-
0.5 wt.% based on total weight of extended release layer and;
vi. Magnesium stearate as lubricant present in an amount ranging from
0.05-1 wt.% based on total weight of extended release layer.
In an another embodiment the present invention provides a process of
preparation of bi-layer tablet for oral administration comprising of an immediate
17
release layer containing 50/100 mg sitagliptin, 0.8 mg Voglibose wherein
sitagliptin and Vogliboseare combined with various acceptable pharmaceutical
excipients using a wet granulation method. The granules were lubricated with
Glidant, lubricant, disintegrant and Diluent to obtain a lubricated granules of
immediate layer.
For extended release layer, Metformin hydrochloride was dry mixed with rate
controlling polymer and diluent. The dry mixed blend was then mixed with
binder solution using a wet granulation method. The wet granules were dried
and further lubricated with rate controlling polymer, glidant and lubricant to
obtain extendedlayer granules.
In an another embodiment immediate layer granules and extended layer granules
were compressed to form bi-layer tablet.
The following examples represent various embodiments according to the
present invention. The examples are given solely for the purpose of illustration
and are not tobe construed as liming the present invention in any way, as many
other variations thereof are possible within the scope of the invention.
EXAMPLES
Example-1
Formula for film coated bilayered tablet comprising Sitagliptin 100 mg, Voglibose 0.2
mg and Metformin (ER) 1000 mg
Ingredients % Role of ingredients
Part-1- Sitagliptin Phosphate Monohydrate & Voglibose (Upper Layer)
Sitagliptin Phosphate Monohydrate 52.56 Active
Voglibose 0.08 Active
Microcrystalline cellulose 15.16 Diluent
Croscarmellose sodium 1.72 Disintegrant
Sodium Lauryl Sulphate 2 Surfactant
18
Col. Sunset Yellow Lake 0.08 Colouring Agent
Binder Preparation
Polyvinyl Pyrrolidone (PVPK-30) 2.56 Binder
Purified water q.s. Solvent
Lubrication
Col. Sunset Yellow Lake 0.08 Colouring Agent
Colloidal silicon dioxide 0.8 Glidant
Magnesium stearate 0.56 Lubricant
Croscarmellose sodium 2.4 Disintegrant
MCC PH-102 22 Diluent
Part -2-Metformin Hydrochloride (Lower Layer)
Metformin Hydrochloride 80.65 Active
Hypromellose 2208 (HPMC K 100 M
Prem ) Ruitai
6.05 Sustained Release
Polymer
Microcrystalline Cellulose 0.80 Diluent
Binder Preparation
Polyvinyl Pyrrolidone (PVPK-30) 2.50 Binder
Purified water q.s. Solvent
Lubrication
Hypromellose 2208 (HPMC K 100 M
Prem )Ruitai
9.30 Sustained Release
Polymer
Colloidal silicon dioxide 0.20 Glidant
Magnesium Stearate 0.40 Lubricant
Coating
Akoat-512 q.s. Film Former
Col. Sunset Yellow Lake q.s. Colouring Agent
Purified Water q.s. Solvent
19
A bi-layer tablet was formulated for oral administration, comprising of an immediate
release layer containing Sitagliptin Phosphate Monohydrate 100 mg, Voglibose 0.2 mg
and an extended release layer containing Metformin (ER) 1000 mg.
The immediate release layer of present invention is prepared as follows:
Voglibose and Sitagliptin Phosphate Monohydrate were mixed with Microcrystalline
cellulose, Croscarmellose sodium, Sodium Lauryl Sulphate and Iron Oxide of (Ferric
Oxide) Red were mixed in rapid mixer granulator. The obtained dry mixture was
mixed with binder to form granules using wet granulation method. The wet granules
were dried and lubricated with Magnesium stearate to obtain dry granules of immediate
release layer comprising Sitagliptin and /.
The extended release layer of present invention is prepared as follows:
Metformin, Hypromellose and Microcrystalline Cellulose were mixed to obtain dry
mix. To this mixture binder solution was added to obtain granules using wet
granulation method. The wet granules were dried and lubricated with Hypromellose,
colloidal silicon dioxide and magnesium stearate to obtain extended release granules.
The immediate release and extended release granules were compressed in rotary
compression tablet machine to prepare bi-layer tablet.
Example-2
Formula for film coated bilayered tablet comprising Sitagliptin 100 mg, Voglibose 0.2
mg and Metformin (ER) 500 mg
Ingredients % Role of ingredients
Part-1- Sitagliptin Phosphate Monohydrate & Voglibose (Upper Layer)
Sitagliptin Phosphate
Monohydrate
52.56 Active
Voglibose 0.08 Active
Microcrystalline cellulose 15.16 Diluent
Croscarmellose sodium 1.72 Disintegrant
Sodium Lauryl Sulphate 2 Surfactant
20
Col. Sunset Yellow Lake 0.08 Colouring Agent
Binder Preparation
Polyvinyl Pyrrolidone (PVPK30)
2.56 Binder
Purified water q.s. Solvent
Lubrication
Col. Sunset Yellow Lake 0.08 Colouring Agent
Colloidal silicon dioxide 0.8 Glidant
Magnesium stearate 0.56 Lubricant
Croscarmellose sodium 2.4 Disintegrant
MCC PH-102 22 Diluent
Part -2-Metformin Hydrochloride (Lower Layer)
Metformin Hydrochloride 70.92 Active
Hypromellose 2208 (HPMC K
100 M Prem ) Ruitai
7.10 Sustained Release
Polymer
Microcrystalline Cellulose 1.66 Diluent
Binder Preparation
Polyvinyl Pyrrolidone (PVPK30)
2.55 Binder
Purified water q.s. Solvent
Lubrication
Hypromellose 2208 (HPMC K
100 M Prem )Ruitai
17.02 Sustained Release
Polymer
Colloidal silicon dioxide 0.25 Glidant
Magnesium Stearate 0.50 Lubricant
Coating
Akoat-512 q.s. Film Former
Col. Sunset Yellow Lake q.s. Colouring Agent
21
Purified Water q.s. Solvent
Example-3:
Formula for film coated bilayered tablet comprising Sitagliptin 50 mg, Voglibose 0.2
mg and Metformin (ER) 1000 mg
Ingredients % Role of ingredients
Part-1- Sitagliptin Phosphate Monohydrate & Voglibose (Upper Layer)
Sitagliptin Phosphate
Monohydrate
26.30 Active
Voglibose 0.08 Active
Microcrystalline cellulose 41.45 Diluent
Croscarmellose sodium 1.72 Disintegrant
Sodium Lauryl Sulphate 2 Surfactant
Col. Sunset Yellow Lake 0.08 Colouring Agent
Binder Preparation
Polyvinyl Pyrrolidone (PVPK30)
2.56 Binder
Purified water q.s. Solvent
Lubrication
Col. Sunset Yellow Lake 0.08 Colouring Agent
Colloidal silicon dioxide 0.08 Glidant
Magnesium stearate 0.56 Lubricant
Croscarmellose sodium 2.5 Disintegrant
MCC PH-102 22 Diluent
Part -2-Metformin Hydrochloride (Lower Layer)
Metformin Hydrochloride 80.65 Active
Hypromellose 2208 (HPMC K
100 M Prem ) Ruitai
6.05 Sustained Release
Polymer
22
Microcrystalline Cellulose 0.80 Diluent
Binder Preparation
Polyvinyl Pyrrolidone (PVPK30)
2.60 Binder
Purified water q.s. Solvent
Lubrication
Hypromellose 2208 (HPMC K
100 M Prem )Ruitai
9.27 Sustained Release
Polymer
Colloidal silicon dioxide 0.20 Glidant
Magnesium Stearate 0.44 Lubricant
Coating
Akoat-512 q.s. Film Former
Col. Sunset Yellow Lake q.s. Colouring Agent
Purified Water q.s. Solvent
Example-4
Formula for film coated bilayered tablet comprising Sitagliptin 50 mg, Voglibose 0.2
mg and Metformin (ER) 500 mg
Ingredients % Role of ingredients
Part-1- Sitagliptin Phosphate Monohydrate & Voglibose (Upper Layer)
Sitagliptin Phosphate Monohydrate 52.56 Active
Voglibose 0.08 Active
Microcrystalline cellulose 15.16 Diluent
Croscarmellose sodium 1.72 Disintegrant
Sodium Lauryl Sulphate 2 Surfactant
Col. Sunset Yellow Lake 0.08 Colouring Agent
Binder Preparation
Polyvinyl Pyrrolidone (PVPK-30) 2.56 Binder
23
Purified water q.s. Solvent
Lubrication
Col. Sunset Yellow Lake 0.08 Colouring Agent
Colloidal silicon dioxide 0.8 Glidant
Magnesium stearate 0.56 Lubricant
Croscarmellose sodium 2.4 Disintegrant
MCC PH-102 22 Diluent
Part -2-Metformin Hydrochloride (Lower Layer)
Metformin Hydrochloride 80.65 Active
Hypromellose 2208 (HPMC K 100 M
Prem ) Ruitai
6.05 Sustained Release
Polymer
Microcrystalline Cellulose 0.80 Diluent
Binder Preparation
Polyvinyl Pyrrolidone (PVPK-30) 2.50 Binder
Purified water q.s. Solvent
Lubrication
Hypromellose 2208 (HPMC K 100 M
Prem )Ruitai
9.30 Sustained Release
Polymer
Colloidal silicon dioxide 0.20 Glidant
Magnesium Stearate 0.40 Lubricant
Coating
Akoat-512 q.s. Film Former
Col. Sunset Yellow Lake q.s. Colouring Agent
Purified Water q.s. Solvent
24
Example-5
Sitagliptin 50 mg, Voglibose 0.2 mg and Metformin (ER) 500 mg
Ingredients % Role of ingredients
Part-1- Sitagliptin Phosphate Monohydrate & Voglibose (Upper Layer)
Sitagliptin Phosphate
Monohydrate
22.14 Active
Microcrystalline cellulose 45 Diluent
Lactose monohydrate 22.32 Diluent
crospovidone 3.85 Disintegrant
Col. Ferric oxide red 0.178 colorant
Binder Preparation
Hydroxy propyl cellulose 0.178 Binder
Voglibose 0.07 Active
Isopropyl alcohol Q.S. Solvent
Purified water Q.S. Solvent
PRE-LUBRICATION MATERIALS
Crospovidone 2.67 disintegrant
Colloidal silicon dioxide 0.5 Glidant
Lubrication
Magnesium stearate 1.25 Lubricant
Part -2-Metformin Hydrochloride (ER) Layer
Metformin Hydrochloride 74.62 Active
Dibasic calcium phosphate 1.19 Diluent
HPMC (K200 M) 13.43 Release controller
Carbo. Homopol. Type- B
(Acrypol 974 P)
6.26 Release controller
BINDER MATERIALS:
Polyvinylpyrrolidone 0.89 Binder
25
Purified water q.s. solvent
PRE-LUBRICATION MATERIALS
Carbo. Homopol. Type- B
(Acrypol 974 P)
Release controller 2.98
Talcum Glidant 0.14
Magnesium stearate lubricant 0.44
Coating
Instacoat Universal q.s. Coating agent
Isopropyl alcohol q.s. solvent
Methylene chloride q.s. Solvent
EXAMPLE-6
Sitagliptin 100 mg, Voglibose 0.2 mg and Metformin (ER) 1000 mg
Ingredients % Role of ingredients
Part-1- Sitagliptin Phosphate Monohydrate & Voglibose (Upper Layer)
Sitagliptin Phosphate
Monohydrate
44.28 Active
Microcrystalline cellulose 30 Diluent
Lactose monohydrate 15.35 Diluent
crospovidone 3.85 Disintegrant
Col. Ferric oxide red 0.178 colorant
Binder Preparation
Hydroxy propyl cellulose 1.78 Binder
Voglibose 0.07 Active
Isopropyl alcohol Q.S. Solvent
Purified water Q.S. Solvent
PRE-LUBRICATION MATERIALS
26
Crospovidone 2.67 disintegrant
Colloidal silicon dioxide 0.5 Glidant
Lubrication
Magnesium stearate 1.25 Lubricant
Part -2-Metformin Hydrochloride (ER) Layer
PREMIX MATERIALS
Metformin Hydrochloride 74.62 Active
Dibasic calcium phosphate 1.19 Diluent
HPMC (K200 M) 13.43 Release controller
Carbo. Homopol. Type- B
(Acrypol 974 P)
6.26 Release controller
BINDER MATERIALS:
Polyvinylpyrrolidone 0.89 Binder
Purified water q.s. solvent
PRE-LUBRICATION MATERIALS
Carbo. Homopol. Type- B
(Acrypol 974 P)
Release controller 2.98
Talcum Glidant 0.14
Magnesium stearate lubricant 0.44
Coating
Instacoat Universal q.s. Coating agent
Isopropyl alcohol q.s. solvent
Methylene chloride q.s. Solvent
Example 7
Sitagliptin 50 mg, Voglibose 0.2 mg and Metformin (ER) 1000 mg
Ingredients % Role of ingredients
Part-1- Sitagliptin Phosphate Monohydrate & Voglibose (Upper Layer)
27
Sitagliptin Phosphate
Monohydrate
22.14 Active
Microcrystalline cellulose 45 Diluent
Lactose monohydrate 22.32 Diluent
crospovidone 3.85 Disintegrant
Col. Ferric oxide red 0.178 colorant
Binder Preparation
Hydroxy propyl cellulose 0.178 Binder
Voglibose 0.07 Active
Isopropyl alcohol Q.S. Solvent
Purified water Q.S. Solvent
PRE-LUBRICATION MATERIALS
Crospovidone 2.67 disintegrant
Colloidal silicon dioxide 0.5 Glidant
Lubrication
Magnesium stearate 1.25 Lubricant
Part -2-Metformin Hydrochloride (ER) Layer
Metformin Hydrochloride 74.62 Active
Dibasic calcium phosphate 1.19 Diluent
HPMC (K200 M) 13.43 Release controller
Carbo. Homopol. Type- B
(Acrypol 974 P)
6.26 Release controller
BINDER MATERIALS:
Polyvinylpyrrolidone 0.89 Binder
Purified water q.s. solvent
PRE-LUBRICATION MATERIALS
Carbo. Homopol. Type- B
(Acrypol 974 P)
2.98 Release controller
28
Talcum 0.14 glidant
Magnesium stearate 0.44 lubricant
Coating
Instacoat Universal q.s. Coating agent
Isopropyl alcohol q.s. solvent
Methylene chloride q.s. Solvent
Example-8
Ingredients % Role of ingredients
Part-1- Sitagliptin Phosphate Monohydrate & Voglibose (Upper Layer)
Sitagliptin Phosphate
Monohydrate
44.28 Active
Microcrystalline cellulose 30 Diluent
Lactose monohydrate 15.35 Diluent
crospovidone 3.85 Disintegrant
Col. Ferric oxide red 0.178 colorant
Binder Preparation
Hydroxy propyl cellulose 1.78 Binder
Voglibose 0.07 Active
Isopropyl alcohol Q.S. Solvent
Purified water Q.S. Solvent
PRE-LUBRICATION MATERIALS
Crospovidone 2.67 disintegrant
Colloidal silicon dioxide 0.5 Glidant
Lubrication
Magnesium stearate 1.25 Lubricant
Part -2-Metformin Hydrochloride (ER) Layer
PREMIX MATERIALS
29
Metformin Hydrochloride 74.62 Active
Dibasic calcium phosphate 1.19 Diluent
HPMC (K200 M) 13.43 Release controller
Carbo. Homopol. Type- B
(Acrypol 974 P)
6.26 Release controller
BINDER MATERIALS:
Polyvinylpyrrolidone 0.89 Binder
Purified water q.s. solvent
PRE-LUBRICATION MATERIALS
Carbo. Homopol. Type- B
(Acrypol 974 P)
Release controller 2.98
Talcum Glidant 0.14
Magnesium stearate lubricant 0.44
Coating
Instacoat Universal q.s. Coating agent
Isopropyl alcohol q.s. solvent
Methylene chloride q.s. Solvent
Stability study
Sitagliptin 50 mg, Voglibose 0.2 mg and Metformin hydrochloride 500 mg (ER) tablets
was subjected to stability study under 30°C ± 2°C/ 75% ± 5% RH
Test Acceptance
criteria Initial 3 month 6 month 9 month 12 month
Description One layer
light red to
red
coloured
and the
other layer
white to off
One layer
light red
to red
coloured
and the
other
layer
One layer
light red
to red
coloured
and the
other
layer
One layer
light red
to red
coloured
and the
other
layer
One layer
light red
to red
coloured
and the
other
layer
One layer
light red to
red
coloured
and the
other layer
white to off
30
white
coloured,
oval
shaped,
biconvex,
plain on
both sides,
bilayered
film coated
tablet
white to
off white
coloured,
oval
shaped,
biconvex,
plain on
both
sides,
bilayered
film
coated
tablet
white to
off white
coloured,
oval
shaped,
biconvex,
plain on
both
sides,
bilayered
film
coated
tablet
white to
off white
coloured,
oval
shaped,
biconvex,
plain on
both
sides,
bilayered
film
coated
tablet
white to
off white
coloured,
oval
shaped,
biconvex,
plain on
both
sides,
bilayered
film
coated
tablet
white
coloured,
oval
shaped,
biconvex,
plain on
both sides,
bilayered
film coated
tablet
Average weight 975 mg ±
5%
976.46
mg
983.50
mg
985.74
mg
977.77
mg
980.34 mg
Dissolution
Sitagliptin
phosphate
monohydrate
eq to Sitagliptin
50 mg
Not less
than 70%
in 60
minutes
Avg:
99.07 %
Min:
98.04 %
Max:
99.88 %
Avg:
98.06 %
Min:
94.32 %
Max:
101.22 %
Avg:
95.02 %
Min:
90.13 %
Max:
97. %
Avg:
95.88 %
Min:
94.19 %
Max:
97.60 %
Avg:
95.82 %
Min:
92.96 %
Max:
97.08 %
Metformin Hydrochloride…………………………500 mg (As extended release)
For 30 minutes Between
20% to
30%
NA NA NA NA Avg:
27.78%
Min:
26.47%
Max:
29.01%
For 1st hour Not more
than 50%
Avg:
41.66 %
Min: 39.77 %
Max:
43.12 %
Avg:
41.69 %
Min:
40.36 %
Max:
43.06 %
Avg:
43.73 %
Min:
42.66 %
Max:
44.73 %
Avg:
43.07 %
Min:
40.70 %
Max:
44.53 %
NA
For 1.5 hour Between
45% to
55%
Avg:
51.87 %
Min:
50.67 %
Max:
52.99 %
31
For 3rd hour Between
50% to
80%
Avg:
71.67 %
Min: 70.62 %
Max:
72.77%
Avg:
70.32 %
Min:
69.73 %
Max:
70.84%
Avg:
73.56 %
Min:
72.47 %
Max:
74.90%
Avg:
74.43 %
Min:
73.09 %
Max:
75.95%
NA
For 10th hour Not less
than 80%
Avg:
98.35 %
Min: 96.11 %
Max:
99.93%
Avg:
97.14 %
Min:
95.07 %
Max:
98.50%
Avg:
99.93 %
Min:
99.15 %
Max:
100.63%
Avg:
98.59 %
Min:
97.66 %
Max:
99.58%
Avg:
98.14 %
Min:
97.04%
Max:
99.06 %
Assay: Each film coated bilayered tablet contains:
Sitagliptin
phosphate
monohydrate
eq to Sitagliptin
50 mg
Not less
than
45.00 mg
and not
more
than
55.00 mg
(not less
than
110.00 %
of label
claim)
50.79 mg
101.58%
50.33 mg
100.66%
50.06 mg
100.12%
49.82 mg
99.64%
49.83 mg
99.66%
Metformin
hydrochloride
500 mg (As
extended
release)
Not less
than
450.00
mg and
not more
than
550.00
mg
(not less
than
90.00 %
and not
more
than
110.00%
of label
claim)
496.93 mg
99.39%
497.70
mg
99.54%
500.76
mg
100.15%
498.55
mg
99.71%
499.21
mg
99.84%
32
Voglibose…….
0.2mg
Not less
than
0.1800
mg and
not more
than
0.2200
mg
(not less
than
90.00%
and not
more
than
110.00%
of label
claimed)
0.2036 mg
101.80%
0.2018
mg
100.90%
0.2032
mg
101.60%
0.1988
mg
99.40%
0.1982
mg
99.10%
Related substance by HPLC:
Sitagliptin Phosphate monohydrate IP Eq Sitagliptin 50 mg
Single
maximum
unknown
impurity
Not more
than
0.2%
Not detected 0.066% 0.072% 0.095% 0.127%
Metformin Hydrochloride IP 500 mg (As extended release)
Dicyandiamide
impurity
Not more
than
0.2%
0.003% 0.005% 0.006% 0.006% 0.008%
Single
maximum
unknown
impurity
Not more
than
0.1%
0.005% 0.014% 0.016% 0.027% 0.036%
Total unknown
impurities:
Sum of all
unknown
impurities of
Sitagliptin+
sum of all
unknown
impurities of
metformin
hydrochloride
Not more
than
2.0%
0.009% 0.162% 0.223% 0.362% 0.381%
33
Microbial contamination: As below
Total aerobic
bacterial count
Not more
than
1000
cfu/g
complies NA NA NA complies
Total combined
yeast and
mould count
Not more
than 100
cfu/g
complies NA NA NA complies
Test for specified microorganisms: As below
Escherichia
Coli
Should
be
absent/g
complies NA NA NA Complies ,CLAIMS:1. An oral fixed dose pharmaceutical composition comprising effective amount of Sitagliptin, Voglibose and Metformin or pharmaceutically acceptable salts thereof.
2. The oral fixed dose pharmaceutical composition as claimed in claim 1 comprising:
a. about 20 to 60 wt.% of Sitagliptin or pharmaceutically acceptable salts thereof and;
b. about 0.005 to 0.5 wt.% of Voglibose or pharmaceutically acceptable salts thereof and;
c. About 60 to 90 wt.% of Metformin or pharmaceutically acceptable salts thereof
3. The oral fixed dose composition as claimed in claimed in claim 1 is tablet composition.
4. The tablet composition as claimed in claim 3 is a bilayer tablet composition comprising dual release layers wherein upper layer is immediate release and lower layer is extended release
5. The bilayer tablet composition as claimed in claim 4 comprises:
I. an immediate release layer comprising:
a. About 20 to 60 wt.% of Sitagliptin or pharmaceutically acceptable
salts thereof and;
b. About 0.005 to 0.5 wt.% of Voglibose or pharmaceutically
acceptable salts thereof and;
II. an extended release layer comprising:
a. About 60 to 90 wt.% of Metformin or pharmaceutically acceptable
salts thereof
6. The bilayer tablet as claimed in claim 5 comprising immediate release layer
having Sitagliptin phosphate monohydrate present in an amount ranging
from 20 to 60 wt.% based on immediate release layer and;
b. Voglibose present in an amount ranging from 0.005 to 0.5 wt.%
based on immediate release layer and;
c. one or more pharmaceutically acceptable excipients
7. The bilayer tablet as claimed in claim 6 wherein immediate release
comprises:
a. Sitagliptin phosphate monohydrate present in an amount ranging
from 20 to 60 wt.% based on total weight immediate release layer
and;
b. Voglibose present in an amount ranging from 0.005 to 0.5 wt.% of
based on total weight of immediate release layer and;
c. One or more diluents present in an amount ranging from 20 to 50
wt.% based on total weight of immediate release layer and;
d. One or more disintegrant present in an amount ranging from 0.5 to
5 wt.% based on total weight of immediate release layer
e. One or more binder present in an amount ranging from 0.5 to 5 wt.%
based on total weight of immediate release layer
f. One or more lubricant present in an amount ranging from 0.5 to 5
wt.% based on total weight of immediate release layer
g. One or more Glidant present in an amount ranging from 0.05 to 2
wt.% based on total weight of immediate release layer.
8. The bilayer tablet as claimed in claim 5 wherein extended release layer
comprises:
a. Metformin hydrochloride present in an amount ranging from 60 to
80% based on total weight of extended release layer and;
b. One or more pharmaceutically acceptable excipient
The bilayer tablet as claimed in claim 8 wherein extended release layer comprises:
a. Metformin hydrochloride present in an amount ranging from 60 to 80% based on total weight of extended release layer and;
b. One or more diluent present in an amount ranging from 0.05 to 5% based on total weight of extended release layer and;
c. One or more release controlling polymer present in an amount
ranging from 2 to 20% based on total weight of extended release
layer and;
d. One or more binder present in an amount ranging from 0.05 to 5% based on total weight of extended release layer and
e. One or more Glidant present in an amount ranging from 0.05 to 5% based on total weight of extended release layer and
f. One or more lubricant present in an amount ranging from 0.05 to 5% based on total weight of extended release layer.

Dated this 01st November 2023
Siddhartha Dulakakhoria
DGM-Patent
Akums Drugs & Pharmaceuticals limited
(Authorized representative for Applicant)