SOLID ORAL PHARMACEUTICAL COMPOSITIONS COMPRISING FIXED
DOSE COMBINATION OF METFORMIN AND SITAGLIPTIN OR SALTS
THEREOF
Field of the Invention
The present invention provides solid oral pharmaceutical compositions
comprising combination of metformin and sitagliptin or salts thereof. In particular,
the present invention relates to a pharmaceutical composition comprising
metformin and sitagliptin or salts thereof which is devoid of glidant and/or surface
active agents. The invention also includes process of preparing such
compositions and method of use of such compositions for treating type I I
diabetes.
Background of the Invention
Type 2 diabetes is the most common form of diabetes and it is one of the most
prevalent chronic diseases. Treatment of type 2 diabetes initially starts with diet
and exercise, followed by oral antidiabetic monotherapy. During long-term
treatment these regimens do not sufficiently control hyperglycemia in many
patients, leading to a requirement for combination therapy within several years
following diagnosis. However, co-prescription of two or more oral antidiabetic
drugs may result in treatment regimens that are complex and difficult for many
patients to follow. Combining two or more oral antidiabetic agents into a single
tablet provides a potential means of delivering combination therapy without
adding to the complexity of patients' daily regimens. Such formulations have
been well accepted in other disease indications also, such as hypertension
(Hyzaar®, a combination of losartan potassium and hydrochlorothiazide) and
cholesterol lowering (Vytorin®, a combination of simvastatin and ezetimibe).
Similarly, examples of marketed combination tablets containing two oral
antidiabetic agents include Glucovance (metformin and glyburide), and
Metaglip® (metformin and glipizide).
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.
Sitagliptin is an orally active inhibitor of the dipeptidyl peptidase-4 (DPP-4)
enzyme. Chemically, sitagliptin is 7-[(3R)-3-amino-1 -oxo-4- (2,4,5-trifluorophenyl)
butyl] - 5,6,7,8 tetrahydro -3- (trifluoromethyl) - 1 ,2,4 - triazolo [4,3-a] pyrazine
phosphate ( 1 : 1 ) monohydrate with the following structure:
Sitagliptin phosphate is indicated as an adjunct to diet and exercise to improve
glycemic control in adults with type 2 diabetes mellitus. It is a DPP-4 inhibitor,
which slows down the inactivation of incretin hormones. The incretins are part of
an endogenous system involved in the physiologic regulation of glucose
homeostasis. When blood glucose concentrations are normal or elevated,
Glucagon like peptide-1 (GLP-1 ) and Gastric Inhibitory Peptide (GIP) increase
insulin synthesis and release from pancreatic beta cells by intracellular signaling
pathways involving cyclic AMP. Sitagliptin is marketed in the United States in the
form of tablets under brand name Januvia ®.
Metformin is the member of the biguanide class of an oral antihyperglycemics
and available in various salt forms, e.g. hydrochloride. Metformin is used in the
management of type 2 diabetes mellitus. It is an antihyperglycemic agent which
improves glucose tolerance in patients with type 2 diabetes, lowering both basal
and postprandial plasma glucose. Chemically, metformin hydrochloride is 1-
carbamimidamido-N,N-dimethylmethanimidamide hydrochloride with the
following structure:
Pharmacologic mechanism of action of metformin is different from other classes
of oral antihyperglycemic agents. Metformin decreases hepatic glucose
production, decreases intestinal absorption of glucose, and improves insulin
sensitivity by increasing peripheral glucose uptake and utilization. Unlike
sulfonylureas, metformin does not produce hypoglycemia in either patients
with type 2 diabetes or normal subjects, except in special circumstances) and
does not cause hyperinsulinemia. Metformin is marketed in the United States in
the form of extended release tablets under brand names Fortamet®,
Glucophage® and Glumetza®.
A combination therapy of sitagliptin with metformin HCI (a well established active
ingredient of diabetes management) provides even more effective treatment of
type I I diabetes. Although metformin is effective at lowering blood glucose levels,
its use is associated with gastrointestinal (Gl) adverse effects, particularly
diarrhea 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 immediaterelease
in terms of affording a more uniform maintenance of blood plasma active
drug concentrations and providing better patient compliance by reducing the
frequency of administration required.
Numerous studies have been conducted to address the formulation and drug
release systems of combination of antidiabetic drugs and attempts have been
made to achieve the combination formulation having desired dissolution profile.
U.S. Patent No. US 6,340,475 discloses a controlled-release oral drug dosage
formulation designed for gastric retention and controlled delivery of metformin
into the gastric cavity.
Extended-release formulations of metformin are disclosed in several other U.S.
Patent No. 6,635,280; 6,866,866; 6,475,521 and 6,660,300.
European patent application No. EP 1537880 A 1 discloses a sustained release
formulation of DPP-IV inhibitors and a hydrophilic polymer.
U.S. Application publication No. US 200701 72525 and US 20080064701
discloses pharmaceutical composition comprising a DPP-4 inhibitor and a slowrelease
form of metformin.
PCT publication No. WO 20091 11200 discloses a formulation comprising an
inner core comprising metformin hydrochloride. The inner core is coated with a
sustained-release polymer and further comprises a coating comprising an
immediate release composition of sitagliptin.
PCT publication number WO 2009099734 discloses pharmaceutical
composition comprising a tablet core comprised of metformin and an extended
release excipient (HPMC). The tablet core is then coated with immediate release
polymer comprising sitagliptin.
U.S. Application publication No. 200901 05265 discloses a fixed-dose
combination of metformin and sitagliptin. The application discloses use of
surfactants in the composition in order to achieve desired dissolution profile.
U.S. Application publication No. 201 003301 77 discloses a fixed-dose
combination of metformin and sitagliptin. The application discloses use of glidant
as excipient.
Various types of formulations have been suggested in the art for fixed dose
combination of metformin and sitagliptin composition. The art in the broad sense
teaches to incorporate glidant and/or surface active agents in the formulation in
order to achieve the consistent tablet weight, dose uniformity and desired
dissolution profile.
There is still exists an enduring need for an alternate, improved and stable fixed
dose combination formulation of metformin and sitagliptin.
Summary of the Invention
In one general aspect, there is provided a solid oral pharmaceutical composition
comprising sitagliptin or a salt thereof, metformin or a salt thereof and one or
more pharmaceutically acceptable excipients, wherein the composition is devoid
of glidant and /or surface active agents.
In another general aspect, there is provided a solid oral pharmaceutical
composition comprising about 3 to 20% by weight of sitagliptin or a salt thereof;
about 25 to 94% by weight of metformin or a salt thereof; about 0.1 to 10% by
weight of a lubricant, and about 0 to 35% by weight of a binding agent.
In another general aspect, there is provided a solid oral pharmaceutical
composition comprising at least one component of sitagliptin or a salt thereof, at
least one component of metformin or a salt thereof and one or more
pharmaceutically acceptable excipients, wherein the composition is devoid of
glidant and /or surface active agents.
In another general aspect, there is provided a solid oral pharmaceutical
composition comprising sitagliptin or a salt thereof, metformin or a salt thereof
and one or more pharmaceutically acceptable excipients, wherein the
pharmaceutically acceptable excipients comprises one or more diluents,
disintegrants, binder, anti-oxidants; and the composition is devoid of glidant and
/or surface active agent.
In another general aspect, the solid oral pharmaceutical composition is in the
form of a multilayer tablet, a bilayer tablet or a trilayer tablet.
In another general aspect, there is provided a solid oral pharmaceutical
composition comprising sitagliptin or a salt thereof, metformin or a salt thereof
and one or more pharmaceutically acceptable excipients, wherein the
composition retains at least 90% w/w of the total potency of metformin and
sitagliptin or salts thereof after storage at 30°C and 60% relative humidity for at
least 3 months and characterized in that the composition is devoid of glidant.
In another general aspect, there is provides a solid oral pharmaceutical
composition of metformin or salts thereof and sitagliptin or salts thereof prepared
by dry granulation, wet granulation, slugging or direct compression.
In another general aspect, there is provided a solid oral pharmaceutical
composition comprising at least one immediate release component comprising
sitagliptin or a salt thereof, at least one extended release component comprising
metformin or a salt thereof, and one or more pharmaceutically acceptable
excipients; wherein the composition is devoid of glidant and /or surface active
agents.
In another general aspect, the extended release component of the solid oral
pharmaceutical composition constitute either a matrix of metformin or salts
thereof, one or more pharmaceutical excipients and one or more rate controlling
agents, or a compressed layer of metformin or salts thereof and one or more
pharmaceutical excipients coated with one or more rate controlling agents, or
both.
In another general aspect, there is provided a solid oral pharmaceutical
composition comprising:
(a) at least one first component comprising sitagliptin, metformin or salts thereof
and one or more pharmaceutical excipients exhibiting immediate release;
(b) at least one second component comprising metformin or salt thereof and one
or more pharmaceutical excipients exhibiting extended release, and
(c) at least one third component comprising metformin or salts thereof and one or
more pharmaceutical excipients exhibiting immediate release, wherein the first
and second components are at last partially coated with third component, and
characterized in that the composition is devoid of glidant and /or surface active
agents.
In another general aspect, there is provided a process for preparing a solid oral
pharmaceutical composition comprising sitagliptin or a salt thereof and metformin
or a salt thereof, the process comprises the steps of:
(a) providing at least one component comprising metformin or a salt thereof,
optionally with sitagliptin or a salt thereof;
(b) providing at least one component comprising sitagliptin or a salt thereof,
optionally with metformin or a salt thereof; and
(c) combining the components of step (a) and (b),
wherein the composition is devoid of glidant and /or surface active agents.
In another general aspect, there is provided a method of treating Type 2 diabetes
in a patient which method comprises administering the solid oral pharmaceutical
composition as substantially described herein.
Detailed Description Of The Invention
The inventors of the present invention have surprisingly found that it is possible
to achieve metformin and sitagliptin combination composition having desired
dissolution profile without using glidant and/or surface active agents, the resulting
formulation may also posses enhanced formulation robustness and stability.
In particular, the inventors have found that when the composition of metformin
and sitagliptin is devised by judicially using pharmaceutical excipients other than
glidants and/or surface active agents, the resulting formulation may exhibit
bioequivalency to equivalent doses of their single entity formulations and or
achieve consistent tablet weight and dose uniformity.
The present invention relates to solid oral pharmaceutical composition
comprising sitagliptin or a salt thereof, metformin or a salt thereof and one or
more pharmaceutically acceptable excipients, wherein the composition is devoid
of glidant and /or surface active agents.
The term "compartment" used herein throughout the specification is used to
intend a part of the dosage form comprising one or both of metformin and
sitagliptin, and optional other active ingredients, optionally together with
pharmaceutical excipients. The part of the dosage form can be in the form of a
layer (formed by coating or compression), granules, pellets, tablets, or minitablets.
Preferably, the compartments comprise a homogenous mixture of
components. In each compartment, at least one type of active ingredient is
contained.
In one embodiment, at least in one, optionally in two compartments both
metformin and sitagliptin are present. The compartments can comprise
immediate or extended release compositions. According to the invention, the
composition is devoid of glidant and /or surface active agents.
Preferably, the compartments are provided in the form of a layer. The
pharmaceutical dosage form comprising the compartments will then represent a
bilayer tablet, a trilayer tablet or a multilayer tablet, preferably bilayer tablet.
The term "tablet" used throughout the specification refers to and intended to
encompass compressed pharmaceutical dosage formulations of all shapes and
sizes, whether coated or uncoated.
The term "layer" used throughout the specification refers to denote a spatial part
of the pharmaceutical composition or dosage form other than that formed by
applying a coating.
The term "coating" used throughout the specification refers to a layer which at
least partly covers an object and is applied by various coating processes known
in the art.
The terms "metformin" and "sitagliptin" used throughout the specifications refers
to any pharmaceutically acceptable salts of metformin and sitagliptin. The
preferred salt of metformin is metformin hydrochloride. The preferred salt of
sitagliptin is sitagliptin phosphate, more preferably its monohydrate.
The term "immediate release" used throughout the specification refers that within
2 hours, preferably within 1.5 hour, more preferably within 1 hour and most
preferably within 30 minutes, at least 80%, preferably at least 85%, more
preferably at least 90% of the drug being present in the compartment is dissolved
or released.
The term "extended release" used throughout the specification refers that at least
95% of the drug being present in the component is not dissolved or released, not
before 2 hours, preferably not before 3 hours, and more preferably not before 4
hours.
A suitable test for determining the dissolution is the test using Apparatus 2
according to the US Pharmacopoeia 32-NF 27, described in General chapter 7 11
(Dissolution). Conditions chosen for the test were Apparatus 2 with 100 rpm in
phosphate buffer medium pH 6.8.
In another embodiment, the solid oral pharmaceutical composition is in the form
of a multilayer tablet, a bilayer tablet or a trilayer tablet.
In an embodiment, the first and second compartments employed in the
composition of the invention may include polymers and pharmaceutically
acceptable excipients to enable formation of a bilayer coated tablet.
In another embodiment, the extended release compartment in the composition of
the present invention may contain additional anti-diabetic agents other than
metformin.
The inventors of the present invention have further determined that if the
composition of the present invention is formulated without using glidant,
particularly in the core of the composition, the composition may achieve
consistent tablet weight and dose uniformity.
In another embodiment, the extended release compartment of the composition is
substantially free of surface active agents.
In another embodiment, the solid oral pharmaceutical composition of the
invention is substantially free of surface active agents.
In another embodiment, the extended release compartment according to present
invention does not contain disintegrants and wherein the immediate release
compartment contains one or more disintegrants but no rate controlling agent.
In another embodiment, the first and third compartment according to the present
invention does not comprise any rate controlling agent, in particular not the rate
controlling agent that used in the first compartment.
Suitable rate controlling agents may be selected from the group consisting of
hydrophilic agents (e.g. water-soluble polymers), lipophilic agents (waterinsoluble
polymers) and inert matrix agents, wherein the hydrophilic agents are
selected from the group of pharmaceutical excipients which generate a gel in
contact with water, including cellulose derivatives such as hydroxypropyl methyl
cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose and
the like; noncellulose polysaccharides such as galactomannanes, guar gum,
carob gum, gum arabicum, alginates, pectins, and the like; polyvinylpyrrolidone;
polyvinylacetate polymers and copolymers; acrylic acid polymers and
copolymers, polyethylene oxide and mixtures thereof; the lipophilic agents are
selected from the group consisting of waxes such as white wax, bees wax,
carnauba wax and the like; fatty acids and alcohols such as stearic acid, palmitic
acid, lauric acid and the like, and cetyl alcohol, cetostearyl alcohol, stearyl
alcohol and the like; fatty acids esters such as monostearates of propylene glycol
and fatty acid esters of sucrose, sucrose distearate and the like; and glycerides
such as mono-, di- or triglycerides, e.g. palmitin, stearin, behenic, laurin, myristin,
hydrogenated vegetable, castor, cottonseed oils, glyceril behenate and the like;
ethyl cellulose; acrylic acid polymers and copolymers (available commercially
under Eudragit® brand); and mixtures thereof; and the inert agents are selected
from the group consisting of thermoplastic polymers, which are insoluble and
indigestible in the gastrointestinal fluids, such as polyvinyl chloride, polyethylene,
vinyl acetate/vinyl chloride copolymers, polymethylmethacrylates, polyamides,
silicones, ethyl cellulose, polystyrene, and mixtures thereof. The amount of rate
controlling agent in the composition ranges from about 10 to about 50% w/w,
preferably from about 15% to about 45% by weight of the composition.
The oral solid dosage form composition of the present invention further
comprises various pharmaceutical excipients suitable for oral administration.
Such excipients are selected from the group consisting of binding agents, fillers,
filler-binders, disintegrants, lubricants, sweeteners, flavourings and colouring
agents, preferably the excipients are selected from the group consisting of
binding agents, filler-binders, and lubricants.
The fillers and/or filler-binder are selected from the group consisting of different
grades of starches, such as maize starch, potato starch, rice starch, wheat
starch, pregelatinized starch, fully pregelatinized starch, cellulose, such as
microcrystalline cellulose or silicified microcrystalline cellulose, mannitol,
erythritol, lactose, such as lactose monohydrate and lactose anhydrous, calcium
salts, such as calcium hydrogen phosphate dihydrate, anhydrous dibasic calcium
phosphate, sorbitol, and xylitol, particularly preferred, the fillers and/or fillerbinders
are selected from the group consisting of pregelatinized starch,
microcrystalline cellulose, lactose monohydrate, and lactose, even further
preferred the filler and/or filler-binder is selected from the group consisting of
microcrystalline cellulose and anhydrous dibasic calcium phosphate.
The lubricants are selected from the group consisting of stearic acid, sodium
stearyl fumarate and magnesium stearate, particularly preferred, the lubricant is
magnesium stearate.
Binding agents are selected from the group consisting of polyvinyl pyrrolidone
(Povidone), copolymers of vinylpyrrolidone with other vinylderivatives
(Copovidone), hydroxypropyl methylcellulose, methylcellulose,
hydroxypropylcellulose, powdered acacia, gelatin, guar gum, carbomer such as
carbopol, polymethacrylates and starch.
In an embodiment, the immediate release (second and/or third) compartment
additionally comprises disintegrants.
The solid oral pharmaceutical composition of the present invention can be
prepared by methods known to the person skilled in the art.
Preferably, the components comprising metformin or salts thereof and sitagliptin
or salts thereof are formed by dry granulation, wet granulation, slugging or direct
compression or by coating process. The compartments then can be processed in
different orders and methods known to the person skilled in the art to form a
dosage form.
In an embodiment, the process of preparing the solid oral pharmaceutical
composition of metformin and sitagliptin or salts thereof comprises steps of:
(a) providing at least one component comprising metformin or a salt thereof,
optionally with sitagliptin or a salt thereof;
(b) providing at least one component comprising sitagliptin or a salt thereof,
optionally with metformin or a salt thereof; and
(c) combining the components of step (a) and (b),
wherein the composition is devoid of glidant and /or surface active agents.
In a further embodiment, granulation liquids can be added, especially in second
compartment, if the composition comprises metformin or pharmaceutically
acceptable salts thereof, as also described elsewhere herein. Granulation liquid
is removed during further processing of the respective compositions, however,
some residual water is required in order to render granulate compressible.
In another embodiment, the solid oral composition is in the form of a bilayer
tablet and comprises a first layer comprising 90% of metformin or salts thereof
exhibiting extended release, a second layer comprising sitagliptin or salts thereof
and 5% metformin or salt thereof exhibiting immediate release and an
immediate-release coating over the two layers comprising 5% of metformin or
salts thereof. In a further preferred embodiment, the first layer is devoid of
glidant. In a further preferred embodiment, the tablet is devoid of surface active
agents.
The present invention is further illustrated by the following examples which are
provided merely to be exemplary of the invention and do not limit the scope of
the invention. Certain modifications and equivalents will be apparent to those
skilled in the art and are intended to be included within the scope of the present
invention.
Example : Sitagliptin Phosphate and Metformin Extended Release Tablet
Table 1
Process: First (Extended Release Granules) component of Metformin HCI was
prepared by mixing Metformin, Microcrystalline cellulose, Maize starch,
Hypromellose 2208, Carbopol with water. The mixture was granulated to form
granules. The granules were then lubricated with Magnesium stearate.
The second component (Immediate Release Granules) component of Metformin
HCI and Sitagliptin Phosphate was prepared by mixing Metformin, Sitagliptin,
PVP, Kollidon VA 64 with water. The mixture was granulated to form granules.
The granules were then lubricated with Magnesium stearate.
The first (Extended Release Granules) and second components (Immediate
Release Granules) were then compressed to form a tablet.
The tablet was then further coated with a mixture of Metformin HCI, Opadry
white, PEG 4000 and water.
Example 2: Sitagliptin Phosphate and Metformin Extended Release Tablet
Table 2
Process: First (Extended Release Granules) component of Metformin HCI was
prepared by mixing Metformin, Microcrystalline cellulose, Maize starch,
Hypromellose 2208, Carbopol with water. The mixture was granulated to form
granules. The granules were then lubricated with talc.
The second component (Immediate Release Granules) component of Metformin
HCI and Sitagliptin Phosphate was prepared by mixing Metformin, Sitagliptin,
PVP, Kollidon VA 64 with water. The mixture was granulated to form granules.
The granules were then lubricated with Magnesium stearate.
The first (Extended Release Granules) and second components (Immediate
Release Granules) were then compressed to form a tablet.
The tablet was then further coated with a mixture of Metformin HCI, Opadry
white, PEG 4000 and water.
Example 3: Sitagliptin Phosphate and Metformin Extended Release Tablet
Table 3
Process: First (Extended Release Granules) component of Metformin HCI was
prepared by mixing Metformin, Microcrystalline cellulose, Maize starch,
Hypromellose 2208, Sodium Lauryl Sulfate and Carbopol with water. The mixture
was granulated to form granules. The granules were then lubricated with
Magnesium stearate.
The second component (Immediate Release Granules) component of Metformin
HCI and Sitagliptin Phosphate was prepared by mixing Metformin, Sitagliptin,
PVP, Kollidon VA 64 with water. The mixture was granulated to form granules.
The granules were then lubricated with Magnesium stearate.
The first (Extended Release Granules) and second components (Immediate
Release Granules) were then compressed to form a tablet.
The tablet was then further coated with a mixture of Metformin HCI, Opadry
white, PEG 4000 and water.
Claims:
1. A solid oral pharmaceutical composition comprising sitagliptin or a salt
thereof, metformin or a salt thereof and one or more pharmaceutically
acceptable excipients, wherein the composition is devoid of glidant and/or
surface active agent.
2. The solid oral pharmaceutical composition of claim 1, wherein the
composition comprising about 3 to 20% by weight of sitagliptin or a salt
thereof; about 25 to 94% by weight of metformin or a salt thereof; about
0.1 to 10% by weight of a lubricant; and about 0 to 35% by weight of a
binding agent.
3. The solid oral pharmaceutical composition of claim 1, wherein the
composition comprises at least one immediate release component
comprising sitagliptin or a salt thereof, at least one extended release
component comprising metformin or a salt thereof.
4. The solid oral pharmaceutical composition of claim 3, wherein the
extended release component in the composition constitute a matrix of
metformin or salts thereof, one or more pharmaceutical excipients and one
or more rate controlling agents.
5. The solid oral pharmaceutical composition of claim 3, wherein the
extended release component in the composition constitute a compressed
layer of metformin or salts thereof and one or more pharmaceutical
excipients coated with one or more rate controlling agents, or both.
6. The solid oral pharmaceutical composition of claim 4 or 5, wherein the rate
controlling agent comprises one or more hydrophilic agents, lipophilic
agents and inert matrix agents or mixtures thereof.
7. A process for preparing the solid oral pharmaceutical composition of claim
5, which process comprises the steps of:
(a) providing at least one component comprising metformin or a salt
thereof, optionally with sitagliptin or a salt thereof;
(b) providing at least one component comprising sitagliptin or a salt
thereof, optionally with metformin or a salt thereof, and
(c) combining the components of step (a) and (b).
8. A multilayer tablet comprising:
(a) at least one layer comprising sitagliptin or a salt thereof, optionally
metformin or a salt thereof and one or more pharmaceutical excipients
exhibiting immediate release, and
(b) at least one layer comprising metformin or salt thereof and one or more
pharmaceutical excipients exhibiting extended release,
wherein the composition is devoid of glidant and/or surface active agent.
9. A solid oral pharmaceutical composition comprising:
(a) at least one first component comprising sitagliptin, metformin or salts
thereof and one or more pharmaceutical excipients exhibiting immediate
release;
(b) at least one second component comprising metformin or salt thereof
and one or more pharmaceutical excipients exhibiting extended release,
and
(c) at least one third component comprising metformin or salts thereof and
one or more pharmaceutical excipients exhibiting immediate release,
wherein the first and second components are at last partially coated with
third component; and
characterized in that the composition is devoid of glidant and /or surface
active agents.
10.The solid oral pharmaceutical composition of claim 1 or 9, wherein the
composition is in the form of a bilayer tablet, a trilayer tablet or a multilayer
tablet.
11.Use of the solid oral pharmaceutical composition of claim 1 or 9 for
treating Type 2 diabetes in a patient.