Field of the Invention:
The present invention relates to a new sustained release dosage form of metformin or
its pharmaceutically acceptable salts. The formulation of the present invention shows
a sustained action for long period of time with less fluctuations of metformin
hydrochloride in the plasma.
Background of Invention:
Metformin is an antihyperglycemic agent of the biguanide class used in the treatment
of non-insulin dependent diabetes mellitus.
Metformin hydrochloride has intrinsically poor permeability in the lower portion of
the gastrointestinal tract leading to absorption almost exclusively in the upper part of
the gastrointestinal tract. Its oral bioavailability is in the range of 40 to 60%
decreasing with increasing dosage, which suggests some kind of saturable absorption
process, or permeability/transit time limited absorption. It also has very high water
solubility. (>300 mg/ml at 25°C) This can lead to difficulty in providing a slow
release rate from a formulation and problems in controlling the initial burst of drug
from such a formulation. These two difficulties are further compounded by the high
unit dose, from about 500 mg or more per tablet, usually required for metformin
hydrochloride. Drugs that have absorption limited to the upper gastrointestinal tract
coupled with poor absorption in the distal small intestine, large intestine and colon are
usually regarded as inappropriate candidates for formulation into oral controlled
delivery systems. This limitation on absorption (for example, in the upper
gastrointestinal tract) is referred to as the "absorption window".
Oral controlled release delivery systems function by releasing their payload of drug
over an extended period of time following administration. Thus, controlled release
dosage forms may only spend a relatively short period in the regions of the
gastrointestinal tract where good absorption of certain drugs can occur. The dosage
form will pass on to regions of the intestine where absorption of certain drugs is poor
or non-existent, still releasing its contained drug albeit with a significant percentage
of its payload still to be delivered. Drug when released from the dosage form in the
2

circumstances described will not be absorbed. Thus, administration of a drug subject
to a window of absorption in a conventional controlled release delivery system can
lead to subtherapeutic blood levels and ineffective treatment of the disease state for
which the drug was intended.
Drugs with very high solubility in water (for example, greater than 100 mg/ml) can be
difficult to formulate into a controlled release oral dosage form. Solubility is a driving
force for a drug substance to dissolve in water; the greater the solubility the greater
the rate of dissolution when all other factors are maintained constant.
In a controlled release dosage form, the formulator tries to reduce the rate of
dissolution by, for example, embedding the drug in a polymeric matrix or surrounding
it with a polymeric barrier membrane through which drug must diffuse to be released
for absorption. To reduce the rate of release of drug from the dosage form to an
appropriate level consistent with the blood level profile desired for a drug possessing
very high water solubility, very large amounts of polymer would be required for the
matrix or barrier membrane. If the total daily dose of drug to be delivered is of the
order of only a few milligrams this may be feasible, but many drugs having the
solubility properties described require total daily doses of the order of many hundreds
of milligrams. Whilst it is possible to create oral controlled release dosage forms for
such products by use of large amounts of polymer, an unacceptably large dosage form
may result.
A further problem with highly water soluble drugs formulated into a controlled
release dosage form is that a significant and variable "burst" of drug can occur from
these systems. The burst of highly water-soluble drug is the initial rapid release of
drug that occurs from oral controlled release dosage forms when first contacting fluid,
such as gastric fluids, prior to release controlling mechanisms of the dosage form
establishing themselves and a stable release rate being provided. Hydration of any
polymer matrix used to formulate the dosage form is a pre-requirement of establishing
a stable release rate. However, if the polymer used is slow to hydrate, then an
undesirable variable burst can occur.
In the prior art, many techniques have been used to provide controlled and extended-
release pharmaceutical dosage forms in order to maintain therapeutic levels of
3

medicaments and to minimize the effects of missed doses of drugs caused by a lack of
patient compliance. There are number of different modified release dosage forms
available commercially. However, some of these are expensive to manufacture and
can be difficult to swallow, particularly in elderly patients. The commercially
available formulation of metformin is Glucophage XR®, Fortamet® and Glumetza®.
All these commercially available have a Tmax less than 8 hrs and Cmax of more than
1000ng/ml.
Some of the techniques to make modified release dosage form of drugs as described
in prior art are as follows:
W099/47128 discloses a method of prolonging the release of a highly water- soluble
drug. A biphasic controlled release delivery system for metformin hydrochloride,
which has prolonged gastric residence and that swells following hydration are
described.
U.S. Pat. No. 6,099,859 describes a controlled release antihyperglycemic tablet,
which has a semipermeable coating on a core with a passageway formed in the
membrane to allow for osmotic diffusion of the drug from the core.
WO 02/28181 describes a monolithic sustained release formulation of metformin
hydrochloride. The method of making the formulation involves hot melt granulation
followed by wet granulation with binders of extrusion.
WO 2004/012699 A2 discloses modified release dosage form comprising of a highly
soluble active ingredient, which utilizes dual retard technique comprising micro
matrix particles containing active ingredient (s) one or more hydrophobic release
controlling agents and coating of one or more hydrophobic release controling agents.
US2003/0170302 discloses extended release pharmaceutical tablet of metformin
comprising a core containing metformin and a coating permeable to metformin. US
6475521 describe a biphasic controlled release delivery system for high solubility
pharmaceuticals using biphasic controlled release delivery system for treating
diabetes.
4

US application US2004/0086566 describes a waxy matrix dosage forms comprising a
pharmaceutically effective amount of metformin and a waxy matrix material.
Thus the present invention provides a novel controlled release formulation of
metformin or its pharmaceutically acceptable salts thereof, which provide freedom
from burst effect, associated with formulation of controlled release of highly water-
soluble. Further, the invention provides a novel controlled release formulation of
metformin hydrochloride, which has low fluctuation of metformin hydrochloride in
plasma, lower Cmax and longer Tmax compared with commercially available
formulation. This assures that the metformin is released over sustained period of time
over extended period, which effectively increases the efficacy.
Objects of the invention
The object of the present invention is to provide a sustained release oral
pharmaceutical dosage form comprising (1) a core comprising as an active ingredient
metformin or its pharmaceutically acceptable salts, hydrophilic substance and / or
hydrophobic substance (2) coating with permeable polymer, wherein the dosage form
provides a mean time to maximum plasma concentration (T max) of metformin of
more than about 7.5 hours after administration.
Another object of the present invention is to provide a sustained release oral
pharmaceutical dosage form of metformin or its pharmaceutically acceptable salts,
said dosage form providing an in vivo plasma profile for lOOOmg metformin
hydrochloride sustained release dosage form selected from:
(a) Mean Tmax of about 7.5 hours or more
(b) Mean Cmax less than about 1000ng/ml
(c) Mean AUC24 of more than about 7000 ng.hr/ml
Yet another object of the present invention is the method of preparing sustained
release oral pharmaceutical dosage form comprising metformin hydrochloride and its
pharmaceutically acceptable salts.
5

BRIEF DESCRIPTION OF ACCOMPANYINGFIGURES
Figure 1 Dissolution Profile
Figure 2 Time vs Concentration (uxjm/ml) graph
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed towards a sustained release oral pharmaceutical
dosage form comprising (1) a core comprising as an active ingredient metformin or
its pharmaceutically acceptable salts, hydrophilic substance and / or hydrophobic
substance (2) coating with an copolymers of acrylic acid and methacrylic acid esters.
The formulation of the present invention provides controlled release of metformin
hydrochloride with no burst release which is commonly associted with highly water
soluble drug along with sustained action for extended period. The present formulation
also provides a maximum plasma concentration less than the commercially available
formulations and along with it shows an extended Tmax.
Active ingredient means metformin or pharmaceutically acceptable salts or
derivatives or prodrug or metabolites there of.
"Sustained release," means drug delivery system releasing the drug at a predetermined
rate, locally or systemically, for a specified period of time. Sustained release can be
used interchangeably with prolonged release, programmed release, timed release,
extended release, controlled release, and modified release, slow release and other such
dosage forms.
By "pharmaceutically acceptable" is meant a carrier comprised of a material that is
not biologically or otherwise undesirable.
Cmax " as used herein, means maximum plasma concentration
"Cmin " as used herein, means minimum plasma concentration
"Cavg " as used herein, means the average concentration within the 24-hour interval.
"Tmax " as used herein, means time to the maximum observed plasma concentration.
"AUC24" as used herein, means area under the plasma concentration-time curve over
the complete 24-hour interval for all the formulations.
"Adverse effects" as used herein, means those physiological effects to various systems
in the body, which cause pain, and discomfort to the individual subject.
Degree of Fluctuation (DFL)" as used herein, is expressed as: DFL=(Cmax -Cmjn)/Cavg
Pharmaceutically acceptable excipients include but are not limited to binders,
diluents, lubricants, disintegrating agents, glidants and surface-active agents.
6

The dosage form according to present invention may be tablet, capsules, pellet, bead,
spheroids, microcapsules, minitablet, powder, granules and others.
The present invention is a controlled release metformin hydrochloride formulation
that comprises of core comprising metformin hydrochloride, a hydrophilic substance
and/ or hydrophobic substance and a permeable coating.
It has been observed that although it is possible to produce controlled release
formulation comprising metformin hydrochloride, hydrophilic substance and/ or
hydrophobic substance, such a formulation provides a burst release since metformin
hydrochloride is highly soluble active ingredient.
It has been found that when such a core formulation is further coated with copolymers
of acrylic acid and methacrylic acid esters which are commercially known as
Eudragits® or mixture of copolymers of acrylic acid and methacrylic acid esters, the
burst release of the active ingredient is avoided.
Further the formulation of the present invention provides a sustained release of
metformin and its pharmaceutically acceptable salts over extended period of time. The
dosage form of the present invention has a significantly lower Cmax and longer Tmax
compared to the commercially available metformin hydrochloride formulation. This
reduces the systemic exposure of the drug. The pharmacokinetics of commercially
available is shown in table 1.
Table 1: Pharmacokinetics of Commercially available Metformin Hydrochloride
formulation:

Commercial
Formulations AUC (0-36)
ng.hr/ml Cmax (ng/ml) Tmax(hr)
Glumetza® (2x500mg) 14182±2415 1301.4±285.7 7.5±1.2
Glucophage XR®
(lOOOmg) 12587±3164 1080±259 7
Fortamet (lOOOmg) 11900±2763 1424±319 6.3±1.4
7

With respect to embodiments of the present invention it has been found that drugs
such as metformin provide substantially linear pharmacokinetics up to a level of about
2 grams per day. Therefore, it is contemplated for purposes of the present invention
that a given plasma level (e.g., Cmax) of metformin per specified dose will be directly
proportional to other doses of metformin. Such proportional doses and plasma levels
are contemplated to be within the scope of the invention and to be within the scope of
the appended claims.
The pharmaceutical composition of the present invention contain, for example, from
about 0.1% to about 90% of metformin.
Hydrophilic substance which may be used in the present invention includes
hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, vinyl
acetate copolymers, polysaccharides as alginates, xanthan gum, Chitosan,
carrageenan, dextran and the like, polyalkylene oxides as polyethylene oxide and the
likes, methaacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers,
carbomer (Carbopol(TM)), guar gum, locust bean gum, poly vinyl acetate, polyvinyl
alcohol and the like.
Hydrophobic substance include acrylates, cellulose derivatives as ethylcellulose,
cellulose acetate and the likes, methaacrylates, high molecular weight polyvinyl
alcohols, waxes , hydrogenated vegetable oil, purified grades of beeswax; fatty acids;
long chain fatty alcohols, such as cetyl alcohol, myristyl alcohol, and stearyl alcohol;
glycerides such as glyceryl esters of fatty acids like glyceryl monostearate, glyceryl
distearate, glyceryl esters of hydrogenated castor oil and the like; oils such as mineral
oil and the like, or acetylated glycerides; stearic acid , paraffin, carnauba wax, talc;
and the stearate salts such as calcium, magnesium, zinc and other materials known to
one of ordinary skill in the art.
The formulation of the present invention may further include other excipients such as
binders, diluents, lubricants, disintegrating agents, glidants, stabilzers, and surface-
active agents.
8

The amount of excipients employed will depend upon how much active agent is to be
used. One excipient can perform more than one function.
Binders include, but are not limited to, starches such as potato starch, wheat starch,
corn starch; microcrystalline cellulose celluloses such as hydroxypropyl cellulose,
hydroxyethyl cellulose, hydroxypropylmethyl cellulose (HPMC), ethyl cellulose,
sodium carboxy methyl cellulose; natural gums like acacia, alginic acid, guar gum;
liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone,
poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth,
combinations there of and other materials known to one of ordinary skill in the art and
mixtures thereof.
Fillers or diluents, which include, but are not limited to confectioner's sugar,
compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose,
starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate,
calcium phosphate dibasic or tribasic, calcium sulphate, and the like can be used.
Disintegrating agents, which may be used, includes crospovidone, croscarmellose,
sodium starch glycolate and the likes.
Lubricants may be selected from, but are not limited to, those conventionally known
in the art such as Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate,
mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and talc.
Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate,
powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate,
magnesium silicate, colloidal silicon dioxide, silicon hydrogel and other materials
known to one of ordinary skill in the art.
The present formulations may optionally contain a surface-active agent. The preferred
agent is poloaxmer. However, other agents may also be employed such as dioctyl
sodium sulfosuccinate (DSS), triethanolamine, sodium lauryl sulphate (SLS),
polyoxyethylene sorbitan and poloxalkol derivatives, quaternary ammonium salts or
other pharmaceutically acceptable surface-active agents known to one ordinary skilled
in the art.
9

The present invention further comprise of coating. The coating over the core is a
permeable coating. The coating is permeable in that water can penetrate the coating
and the active agent can be released there through. The polymers may be cross-linked
polyvinyl alcohol, poly (lactic acid) (PLA), poly (lactic-co-glycolic acid) (PLGA),
poly (caprolactone) (PCL), polyolefms, polyvinyl chlorides, cross- linked gelatins,
insoluble and non-erodable cellulose, acylated cellulose, esterified celluloses,
cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate,
cellulose acetate diethylaminoacetate, polyurethanes, polycarbonates, acrylic polymer,
cellulose ethers, and microporous polymers formed by co-precipitation of a
polycation and a polyanion modified insoluble collagen. The coating is preferably
comprised of an acrylic polymer. Within the invention, an"acrylic polymer" means a
pharmaceutically acceptable copolymer of methacrylic acid or a salt thereof and an
acrylic or methacrylic acid, acid ester, and/or salt thereof. The amount of coating is
usually within about 1% to about 10%. The appropriate amount will depend on the
core, the active agent, and the kind of materials in the coating and the desired
modification of the release.
The coating need not be in physical, direct contact with the core as intervening layers
may instead be present, so long as the coating surrounds or envelops the core.
Preferably the water insoluble coating is disposed on the core.
Thus the present invention comprise of coating compriding copolymers of acrylic acid
and methacrylic acid esters. The coating helps to avoid the burst effect associated with
high solubility active ingredient as metformin hydrochloride. The commercially
available copolymers of acrylic acid and methacrylic acid esters are called as
Eudragit®. Eudragit is available in various grades.
All EUDRAGIT® polymers for sustained-release formulations release the drug by
diffusion.
The most preferred copolymers of acrylic acid and methacrylic acid esters are
EUDRAGIT® RL 100 or RL PO or RL 30D or RL12.5 and EUDRAGIT® RS 100 or
RS PO or RS 30D or RS12.5. They are copolymers of acrylic and methacrylic acid
esters with a low content in quaternary ammonium groups. The ammonium groups are
10

present as salts and make the polymers permeable. EUDRAGIT® RL 100 and
EUDRAGIT® RS 100 are colourless, clear to cloudy granules with a faint amine-like
odour. EUDRAGIT® RL PO and EUDRAGIT® RS PO are white powders with a
faint amine-like odour.
EUDRAGIT® RL 100 / RL PO has 8.85 - 11.96 % ammonio methacrylate units on
dry substance (DS) having an alkali value of 23.9 - 32.3 mg KOH per g dry substance
and EUDRAGIT® RS 100 / EUDRAGIT® RS PO has 4.48 - 6.77 % ammonio
methacrylate units on dry substance and an alkali value: 12.1 - 18.3 mg KOH per g
DS
EUDRAGIT® RL and EUDRAGIT® RS are water-insoluble, swellable film formers
based on neutral methacrylic acid esters with a small proportion of
trimethylammonioethyl methacrylate chloride. With EUDRAGIT® RL, the molar
ratio of the quaternary ammonium groups to the neutral ester groups is 1:20
(corresponding to about 50 meq./ 100 g), with EUDRAGIT® RS this ratio is 1:40
(corresponding to roughly 25 meq./100 g). Since quaternary ammonium groups
determine the swellability and the permeability of the films in aqueous media,
EUDRAGIT® RL, which contains more of these groups, forms more permeable films
with little delaying action. By contrast, and owing to the reduced content in
quaternary ammonium groups, films of EUDRAGIT® RS swell less easily and are
only slightly permeable to active ingredients. Given coherent film coatings and an
adequate layer thickness, it is therefore possible to slow down drug diffusion very
noticeably. EUDRAGIT® RS and RL polymers can be mixed in any ratio to produce
films with different permeability.
For the present invention the coating solution is prepared by mixing Eudragit® RL
PO 100 and RS PO100 in different ratio to prepare permeable coating which controls
the release of metformin hydrochloride and also avoid burst effect.
The pharmaceutical composition of the invention can be formed by various methods
known in the art such as by dry granulation, wet granulation, melt granulation, direct
compression, double compression, extrusion spheronization, layering and the like.
11

Compaction of the blend into coprimate may be carried out using a slugging
technique or roller compaction. The milling of the granules may be carried out
according to conventional milling methods.
The process of wet granulation includes aqueous or non-aqueous granulation. The wet
granulation process comprises the admixing of the active ingredient with diluent(s)
and/or rate controlling polymer, and granulation of the blend with the binder mass to
form the wet mass followed by drying and sizing. The binder may optionally be
admixed with the dry blend and granulation performed with aqueous or non-aqueous
solvent. The solvent for the non-aqueous granulation may be selected from ethanol,
isopropyl alcohol, dichloromethane and the like.
The following examples are illustrative of the present invention, and the example
should not be considered as limiting the scope of this invention in any way, as these
examples and other equivalents thereof will become apparent to those versed in the
art, in the light of the present disclosure, and the accompanying claims.
A person skilled in the art may make variations and modifications without deviating
from the spirit and scope of the invention. All such modifications and variations are
intended to be included within the scope of the invention.
Example:
Matrix Tablet with 70% drug granulated with HPMC and 30% drug melt granulated
with Hydrogenated Vegetable Oil (Sterotex) and coated with Eudragit RLPO and
RSPO100.
Table 2: Exemplary formulation

Sr. No. Ingredients %
1. Metformin Hydrochloride 60
2. SLS 1.0
3. HPMC K 100 M 24
6. Hydrogenated Vegetable Oil (Sterotex) 8.0
7. MCC PH 102 3.0
8. PEG 6000 1.0
12

9. Aerosil 200 0.5
10. Magnesium Stearate 0.5
Coating up to 2% to 5% weight gain
Mfg. Procedure:
(1) Metformin hydrochloride, SLS and HPMC K 100 M passed through sieve and
granulated and granules were sifted.
(2) Required quantity of hydrophobic vegetable oil was melted along with PEG
6000 and Metformin HC1 was added to it under stirring. Mass cooled and milled.
(3) Mix step 1 and 2 and lubricated with MCC 102, Aerosil and Magnesium
Stearate and compressed using compression machine and coated with E-udragits till a
weight gain of 2% to 5%.
(4) The resulting formulation and the commercially available formulation
(fortamet®) were than tested according to USP dissolution test, type (1) at 100 rpm at
37lC in 1000ml of pH 6.8 phosphate buffer and found to be equivalent in release
profile (Table 3, Figure 1).
Table 3: Dissolution profile

Time
(Hrs) Test Formulation
% release
u A
u
1 7.1
2 21.6
3 36.6
4 46.1
5 55.8
6 63
7 71.8
8 74.6
10 81.2
12 93.9
Pharmacokinetic study-Determination of serum concentrations of Metformin
A randomized open label single dose two treatment, two period, two sequence,
crossover study was carried out for the test tablets of the present invention and
13

compared with Fortamet® 1000mg in 12 healthy human subjects. Table 4
summarizes the pharmacokinetics result. Fig 2 discloses the time versus
concentration graph (μgm/ml) for exemplary formulation and commercially
available formulation Fortamet®.
Table 4: Pharmacokinetics of exemplary formulation

Formulation AUG ng.hr/ml Cmax ng/ml Tmax hrs
Test formulation 10370(%20.14) 750(%23.20) 12(%27.02)
Commercial
formulation
(Fortamet®) 8270 (%33.89) 1060(%34.10) 7.5(%15.6)
While the invention has been described above with reference to specific embodiments
thereof, it is not restricted there in any way whatsoever. On the contrary, as will be
understood by those skilled in the art, various changes, modifications, substitutions
and omissions can be made without departing from the basic concept of the invention
as defined in the claims, which follow. Thus, for example, other sustained release
formulations may be used.
14

We claim:
1. A controlled release oral pharmaceutical dosage form comprising (1) a core
comprising an active ingredient metformin or its pharmaceutically acceptable
salts, hydrophilic substance and/or hydrophobic substance (2) permeable
coating, wherein the dosage form provides a mean time to maximum plasma
concentration (Tmax) of metformin hydrochloride of more than about 7.5
hours after administration.
2. A controlled release oral pharmaceutical dosage form according to claim 1
wherein Tmax is about 12 hours.
3. A controlled release oral pharmaceutical dosage form according to claim 1
wherein hydrophilic substance may be cellulose derivatives, dextrins, starch,
carbohydrate based polymers, natural or hydrophilic gums, alginates, gelatin,
and the likes
4. A controlled release oral pharmaceutical dosage form according to claim 3
wherein, the hydrophilic substance is hydroxypropylmethyl cellulose.
5. A controlled release oral pharmaceutical dosage form according to claim 1
wherein hydrophobic substance may be ethyl cellulose, hydrogenated
vegetable oil, hydroxyethyl cellulose, ammmonio methacrylate copolymers,
waxes, fatty alcohols, fatty acid csters and the like.
6. A controlled release oral pharmaceutical dosage form according to claim 5
wherein the hydrophobic substance is hydrogenated vegetable oil.
7. A controlled release oral pharmaceutical dosage form according to claim 1
wherein permeable coating comprise of copolymers of acrylic acid and
methacrylic acid esters.
8. A controlled release oral pharmaceutical dosage form according to claim 7
wherein copolymers of acrylic acid and methacrylic acid esters may comprise
mixture of copolymers of acrylic acid and methacrylic acid esters type A and
Type B with low content in quaternary ammonium groups.
15

9. A controlled release oral pharmaceutical dosage form comprising (1) a core
comprising an active ingredient metformin or its pharmaceutically acceptable
salts, hydrophilic substance and/or hydrophobic substance (2) a permeable
coating, wherein the dosage form provides Cmax of metformin hydrochloride
of less than about 1000ng/ml after administration.
10. A controlled release oral pharmaceutical dosage form comprising an active
ingredient metformin or its pharmaceutically acceptable salts, said dosage
form providing an in vivo plasma profile for 1000 mg metformin
hydrochloride dosage form selected from:
a. Mean Tmax of about 7.5 hours or more
b. Mean Cmax less than about 1000ng/ml
c. Mean AUC24 of more than about 7000 ng.hr/ml
11. The controlled release pharmaceutical dosage form of claim 10 where in said
mean Cmax is less than about 800ng/ml.
12. The controlled release pharmaceutical dosage form of claim 10 where in said
mean Tmax is about 12 hrs.
13. The controlled release pharmaceutical dosage form of claim 10 where in said
mean AUC is about 10000ng.hr/ml
13. A method of preparing controlled release oral pharmaceutical dosage form
providing no burst effect comprising (1) preparing granules comprising
metformin hydrochloride and hydrophilic substance (2) preparing granules
comprising metformin hydrochloride and hydrophobic substance (3) Mixing
granules of (1) and (2) and lubricating and then compressing. (4) Compressed
core was then coated with copolymers of acrylic acid and methacrylic acid
esters type A and Type B.
15. A controlled release oral pharmaceutical dosage form according to claim 14
wherein hydrophilic substance may be cellulose derivatives, dextrins, starch,
carbohydrate based polymers, natural or hydrophilic gums, alginates, gelatin,
and the likes
16

16. A controlled release oral pharmaceutical dosage form according to claim 15
wherein, the hydrophilic substance is hydroxypropylmethyl cellulose.
17. A controlled release oral pharmaceutical dosage form according to claim 14
wherein hydrophobic substance may be ethyl cellulose, hydrogenated
vegetable oil, hydroxyethyl cellulose, ammmonio methacrylate copolymers,
waxes, fatty alcohols, fatty acid esters and the like.
18. A controlled release oral pharmaceutical dosage form according to claim 17
wherein the hydrophobic substance is hydrogenated vegetable oil.
Dated this 5th day of February 2008

17

A controlled release oral pharmaceutical dosage form comprising (1) a core comprising
an active ingredient metformin or its pharmaceutically acceptable salts, hydrophilic
substance and/or hydrophobic substance (2) permeable coating, wherein the dosage form
provides a mean time to maximum plasma concentration (Tmax) of metformin
hydrochloride of more than about 7.5 hours after administration.