Form 2
THE PATENTS ACT, 1970
COMPLETE SPECIFICATION
(Section 10)
NOVEL DOSAGE FORM

TORRENT PHARMACEUT1CALS LTD., a company incorporated under the Companies Act, 1956,

of Torrent House, Off Ashram Road, Near Dinesh Hall, Ahmedabad-380 009, Gujarat, India

The following specification particularly describes and ascertains the nature of the invention and the
manner in which it is to be perfomed;

FIELD OF INVENTION
This invention reiates to a dosage form comprising of a high'dose, high solubility
active ingrediënt as modified release and a low dose active ingrediënt as immediate release
where the-weight ratio of immediate release active ingrediënt and modified release active
ingrediënt is from 1:10 to 1:15000 and the weight of modified release high dose high
soiubility active ingrediënt per unit is from 500 mg to 1500 mg and the weight of
immediate release active ingrediënt is up to 50 mg; a process for preparing the
formulation. .
BACKGROUND OF THE INVENTION
Combining two active ingredients in one pharmaceutical unit to improve patiënt
compliance is known in literature. It can be eiiher in the form of two or more active
ingredients in immediate release form or a combination of immediate release and modified
release form. There are various techniques by which the combination of immediate
release and modified release is formulated in single dosage form.
Several examples of formulations having combination of immediate release active
ingrediënt and modified release active ingrediënt are described below.
Shoichi Higo and Kazuo Igusa describes in US patent no. 5,985,843 various types
of pharmaceutical fonnulations, which consists of a delayed release of sucralfate and an
immediate release fraction of another active ingrediënt. The pharmaceutical dosage forms
are a tablet formulation containing immediate release and delayed release grauules; a two
or three layer tablet; a tablet with delayed release core surrounded by immediate release
shell; a delayed release tablet / granule coated with a film of immediate release active
ingrediënt.
Similarly Jurgen Zeidler et.al describes in US patent No. 6,001,391 a process for
producing solid combination tablets, which have atleast two phases. The one of the two
phases is processed by melt extrusion technique and contains a water soluble or swellable
binder.
A compressed V-shaped center scored doublé layer tablet is disclosed by George
M. Krause et. al in US patent no. 3,336,200, one layer of which contains immediate
release Active Ingrediënt and the other layer contains sustained release Active Ingrediënt.
The tablet is divisible in two equal halves.
2

Similarly Jacob A. Glassman described in US Patent No. 4,503,031 a super fast
starting, slow release medicina! tablet, wherein the tablet is comprised of two layers of
compressed matrix that are fused together by means of readily dissolvab!e adhesive
substance.
Allan A. Rubin describes in US patent no. 6,238,699 B1 a pharmaceutica! dosage
torm of carbidopa and levodopa where both the Active Ingredients are present as
immediate release and sustained release. The formulation is in the form of inlay tablet or
bilayered tablet or a capsule containing pellets.
Block Jurgen et. al. describes in PCT application No. WO 01/72286 Al a formulation of
vitamin composition whereas a beadlet comprises a slow release core coated by a
controlted release coating. The sustained release core is coated with an immediate release
layer.
Richard Ting and Charles Hscao describes in US patent No. 6,372,254 BI a press
coated, pulsatile active ingrediënt delivery system which comprises a core of immediate
release, enveloped by au extended release compartment
The need to use active ingredients with different and complementary mechanisms
of action frequently arises in treatment of diabetes. There are several reasons to do tuis,
namely, the disease itself is progressive, with deterioration of glycemic control over time;
mono-therapèutic attempts to achieve and maintain glycemic control often fail in the long
run; multiple defects in the disease and consequentiy primary drug faüures (1,2,3).
Current guidelines for combination therapy advise the use of agents with differing
and complementary mechanisms of action in order to maximize therapeutic activity and
reduce toxicity. Earlier introduction of combination therapy is increasingly being
recommended. The commonly combined active ingredients include biguanides
(metformin) + sulphonylureas, biguanides + PPARγ agonists(thiazolidinediones),
sulphonylureas + thiazolidinediones, non-sulfonylurea secretagogues (repaglinide) +
biguanides etc.
Fixed dose combinations of many of the above mentioned co-administer active
ingredients have also been approved by the FDA. Most of these combinations are
conventional formulations combined together into a single tablet. However, because of
the disparity in the duration of action (half-life), these combinations are given twice or
thrice a day.
To reduce this clisparity in the duration of action, a novel strategy would be to
combine a sustained release formulation of one active ingrediënt (shorter duration of
3

action) with conventional formulation (long duration of action) of another active
ingrediënt. This would make it possible to give the active ingredients in same dosing
frequency.
This type of combination will give better compliance and a relaüve freedom from
mealtime drug administration, thus, improving the quality of life. More importantly,
because of prolonged duration of action, it shall produce a stricter control of blood glucose
and consequently Less diabetic complications.
The techniques described above do nol work well when the difference in the dose
of active ingredients are high for example where the weight ratio of active ingredients in
immediate release and modifïed release is from 1:10 to 1: 15000 and the dose of modified
release.active ingrediënt per unit is from 500 mgto 1500 mg. The techniques described in
the prior art do not give good results when the active ingrediënt is highly soluble. The
weight of the dosage form becomes very high, or complicated process for manufacturing
is requiredr or accurate dosing of low dose active ingrediënt is difficult when the
techniques reported in the prior art are utilized to make formulation with high dose, high
solubiliry active ingrediënt in the form of modified release and small dose active
ingrediënt into immediate release form where the weight ratio of immediate release active
ingrediënt and modified release active ingrediënt is from 1:10 to 1:15000 and the weight
of modified release active ingrediënt per unit is from 500 mg to 1500 mg and also it is
inconvenient to swallow due to large size.
Accordingly a need exists for a dosage form providing combination of immediate
release and modified release active ingredients and providing soiution to problems
associated with dosage forms described in prior art. Further, the dosage form should be
simple and economical to produce.
Therefore an object of the present invention is a dosage form of combination of a
high dose, high solubility active ingrediënt as modified release and a low dose active
ingrediënt- as immediate release where the weight ratio of immediate release active
ingrediënt and modified release active ingrediënt is from 1:10 to 1:15000 and the weight
of modified release active ingrediënt per unit is from 500 mg to 1500 mg.
Another object of the present invention is a dosage form, which is suitable for
swallowing for humans containing two active ingredients one of which is in modified
release form and other in immediate release form.
Accordingly, an object of the present invention to provide a dosage form, which
uses dual retard technique to control the release of the high dose, high solubility active
4

ingrediënt and significantly reduce the amount of release controlling agents which are
otherwise required in very high quantity and make the dosage form very bulky and
therefore pose difficulty in swallowing,
A further object of the present invention is to provide d dosage form, containing
one active ingrediënt in an immediate release form and another active ingrediënt as
modirïed release and the release or disintegration of the immediate release active
ingrediënt is not hindered by the modified release ingrediënt.
Another object of the present invention is to provide a dosage form, which
effecrively avoids the problem of separation of layers of multilayered tablets.
A further object of the present inventioa is a formulation, which gives accurate
dosing and is prepared by conventional and simple processes.
A further object of the present invention is to provide a dosage form, which can be
given twice a day or more preferably can be given once a day.
SUMMARY OF THE INVENTION
The above objects are realized by a dosage form, which is comprised of an inner
portion and an outer portion. The inner portion is surrounded by the outer portion in such
a manner that only one surface of the inner portion is exposed. The inner portion contains
a low dose active ingrediënt in immediate release form and the outer portion contains a
high dose, high solubility active ingrediënt as modified release. The weight of the
immediate release Jow dose active ingrediënt and high dose, high solubility modified
release active ingrediënt is from l:10 to 1:15000 and the weight of modified release active
ingrediënt per unit is from 500 mg to 1500 mg,
"the present invention also provides solid oral dosage form comprising a
composition according to the invention.
The present invention also teaches the use of dual retard technique to effectively
control the release rate of modified release active ingrediënt by using small quantity of
release controlling agents. This dual retard technique thüs sufficiently reduces the size of
the dosage form, which is convenient for swallowing.
The present invention further teaches the use of hydrophobic release controlling
agents, which do not hinder the release of the immediate release active ingrediënt.
The present invention further provides the dosage form that effectively prevents
the problem of separation of the layers of the multilayered tablets.
The present invention also provides a novel process for preparing the novel
formulations of the invention.
5

-The present invention further provides a method of treating an animal, particularly
a human in need of treatment utilizing the active agents, comprising administering a
therapeutically effective amount of composition or solid orai dosage form according to the
invemion to provide administration of two active ingredients one in immediate release and
other in modified release form.
DETAILED DESCREPTION OF THE INVENTION
This invention relates to a novel dosage form of combination of high dose high
soiubiiity active ingrediënt, as modified release and low dose active ingrediënt as
immediate release, suitable for swallowing comprising dual retard technique to control the
retease öf-the high dose high soiubiiity active ingrediënt, with suffïcient reduction in the
amount of release controlling agent, without interfering the release of each other.
The term "modified release" as used herein in relation to the composition
according to the invention or a rate controlling polymer or used in any other context means
release, which is not immediate refease and is taken to encompass controlled release,
sustained release, prolonged release, timed release, retarded release, extended release and
delayed release. The term "modified release dosage fonn" as used herein can be described
as dosage forms whose drug-release characteristics of time course and/or location are
chosen to accomplish therapeutic or convenience objectives not offered by conventional
dosage forms such as a solution or an immediate release dosage form. Modified release
solid orai dosage forms include both delayed and extended release drug products (as per
US FDA guideline for 'SUPAC-MR: Modified Release Soüd Oral Dosage Forms').
The term "immediate release" as used herein in relation to composition according
to the invention or used in any other context means release which is not modified release
and releases more than 70% of the active ingrediënt within 60 minutes. The term
"immediate release dosage form" as used herein can be described as dosage form which
allows the drug to dissolve in the gastrointestinal contents, with no intention of delaying or
prolonging the dissolution or absorption of the drug' (as per US FDA guideline for
'SUPAC-MR: Modified Release Solid Oral Dosage Forms').
The term "dosage form" denotes any form of the formulation that contains an
amount suffïcient to achieve a therapeutic effect with a single administration.
The term "active ingrediënt" refers to an agent, active ingrediënt compound or
other substance, or compositions and mixture thereof that provide some pharmacological,
often beneficial, effect. Reference to a specific active ingrediënt shall include where
appropriate the active ingrediënt and it's pharmaceutically acceptable salts,
6

In the dosage form of the present invention, the inner portion may optionally
contain more than one low dose antidiabetic active ingrediënt.
The low dose active ingrediënt is in the form of immediate release and has dose of
50 mg or less.
The low dose active ingredients are comprises of the following therapeutic classes
but not limited to antidiabetic agents, anti-histamines, anti-depressants, anti-viral agents,
anesthetics, antacids, anti-arththriics, antibiotica, anti-psychotics, anti-spasmodics,
aaxiolytic agents, 'appetite suppressants, cardiovascular agents, cough suppressants,
emollients, gastro-intestinal agents, growth regulators, respiratory stimulants, vitamins,
angiotensin converting enzyme inhibitors, anti-asthmatics, anti-cholesterolemics, anti-
convulsarits, anti-depressants, anti-diarrhea preparations, anti-infective, anti-inflammatory
agents, anti-nauseants, anti-stroke agents, anti-tumor drugs, anti-tussives, anti-uricemic
drugs, amino-acid preparations, antiemetics, antiobesity drugs, antiparasitics, antipyretics,
appetite stimulants, celebral dilators, chelating agents, cholecystokinin antagonists1
cognition activators, deodorants, dermatological agents, diuretics, erythropoietic drugs,
fertility agents, synthetic hormones, laxatives, mineral supplements, neuroleptics,
neuromuscular agents, peripherai vaso-dilators, prostaglandins, vaginal preparations, vaso-
constrictors, vertigo agents, sulphonylurease, meglitinides, PP AR gama agonist [inslin
sensitisers "(thiazolidinedione)], PPAR alpha and gamma agonist, alpha-glucosidase
inhibitors and the active ingredients described ui united states patent numbers 2968158,
3097242, 3454635, 3654357, 3668215, 3669966, 3708486, 3801495, 5104888, 5232945,
5264451, 5478852, 6296874, and European patent publication numbers EP0008203,
EP0032128, EP0139421, EP0155845, EP0177353, EP0208420, EP0257881, EP0306228,
EP0319189, EP0332331, EP0332332, EP0428312, EP0489663, EP0508740, EP0528734,
EP0533933, EP0833933, EP87112480.6 and Japanese patent number 05271204 and
United Kingdom patent numbers 5504078, GB2088365A and PCT patent application
numbers WO91/19702, W092/03425, W092/18501; WO93/02079, W093/21166,
W093/22445, W094/01420, WO94/05659.
Examples of low dose active ingredients comprises of but not limited to
zafirlukast, quinapril hydrochloride, isofretinoin, rabeprazole sodium, estradiol(e2),
norethindrone acetate, risedronate sodium, pioglitazone HC1, amphetamine, anagrelide
hydrochloride, biperiden HC1, mephalan, alprazolam, ramipril, naratriptan hydrochloride,
ieflunomide, anastrozole, exemestane, paroxetine mesylate, candesartan cilexetil,
almotriptan, cerivastatin, betaxolol hydrochloride, bisoprolol fumarate, deloratadine,
8

clonazepara, clorazepate dipotassium, clozapine, methylphenidate HC1, carvedüol,
warfarin sodium, norgestrei, ethinyl estradiol, cyclophosphamide, pemoline, liothyronine
sodium, misoprostol, tolterodine tartrate, dextroamphetamine sulfate, dicyclomine
hydrochloride, digoxin, oxybutynin chloride, doxazosin mesylate, ethacrynate sodium,
venlafaxine HCl, enalapril maleate, estradiol, estropipate, famotidine, letrozole,
fludrocortisone acetate,- fluoxetine, dexmethylphenidate hei, alendronate sodium,
ziprasidone} glipizide, glyburide, migütol, guanabenz acetate, haloperidol, doxercalciferol,
zalcitabine, hydrochiorothiazide, iiydromorphoae HCl, indapamide, estradiol, nitric oxide,
ketorolac tromethamine, clonazepam, granisetron, iamotrigine, fluvastatin sodium,
levonorgestrel, ievothyroxine sodium, atorvastatin calcium, lisinopril, minoxidü,
loperamide, loratidine, lorazepam, lovastatin, pravastatin sodium, fluvoxamine maleate,
acetaminophen, acyclovir, aminocaproic acid, pitavastatin, rosuvastatin, dalvastatin,
sertraline,pitavastatin,rosuvastatin,dalvastatinescetalopram,sartaline celecoxib,parecoxib
valdecoxib, glibenclamide (glyburide),glipizide, gliclazide, glimepiride, tolaxamide,
tolbutamide, clorpropamide, gliquidone, nateglznido, glyburide, glisoxepid, glibornuride,
phenbutamide, tolcyclamide, repaglinide, troglitazone, ciglitazone, pioglitazone,
englitazone, acarbose, voglibose, eroiglitate, miglitol, farglitazar, (S)-2-ethoxy-3-[4-(2-{4-
methanesulfonyloxypheny 1} ethoxy)phenyJ]propanoic acid, 3 - {4-[2-(4- tert-
butoxycarbonylaminophenyl)etlioxy]pheiiyl}-(S)-2-ethoxy propanoic acid and L-6766892.
Further examples of low dose, antidiabetic active ingredients comprises of but not limited
to JTT-501 (PNU-182716) (Reglita2ar),AR-H039242ï MCC-555 (Netogütazone), AR-
H049020 , Tesaglitazar), CS-011 (CI-1037), GW-409544X, KRP-297, RG-12525, BM-
15.2054, CLX-0940, CLX-0921, DRF-2189, GW-1929, GW-9820, LR-90, LY-510929,
NIP-221, NIP-223, JTP-20993, LY 29311 Na, FK 614, BMS 298585, R 483, TAK 559,
DRF 2725 (Ragaglitazar), L-686398, L-168049, L-805645, L-054852, Demethyl
asteriquinone BI (L-783281), L-363586, KRP-297, P32/98, CRE-16336 and EML-16257.
As indicated above the inner portion of the' present invention may comprise
auxiliary excipients such as for example diluents, binders, lubricants, surfactants,
disintegrants, plasticisers, anti-tack agents, opacifying agents, pigments, and such like. As

vvill be appreciated by those skilled in the art, the exact choice of excipient and their
relative amounts will depend to some extent on the final oral dosage form.
Suitable diluents include for example pharmaceutically acceptable inert fillers such
as microcrystalline cellulose, lactose, starch, dibasic calcium phosphate, saccharides,
and/or mixtures of the foregoing. Examples of diluents include microcrystalline celluloses
9

such as those sold under the Trade Mark Avicel PH 101, Avicel PH 102, Avicel PH 112,
Avicel PH 200, Avicel PH301 and Avicel PH 302; lactose such as lactose monohydrate,
lactose anhydrous and Pharmatose DCL21 (Pharmatose is a Trade Mark), including
anhydrous, monohydrate and spray dried forms; dibasic calcium phosphate such as
Emcompress (Emcompress is a Trade Mark); mannitol; Pearlitol SD 200 (Pearlitol SD 200
is a trade mark); starch; sorbitol; sucrose; and glucose.
Suitable binders include for example starch, povidone,
hydroxypropylmethylceüulose, pregelatinised starch, hydroxypropylcellulose and/or
mixtures of the foregoing.
Suitable lubricants, including agents that act on the flowability of the powder to be
compressed are, for example, colloidal slilcon dioxide such as Aerosil 200 (Aerosil is a
Trade Mark); talc; stearic acid, magnesium stearate, calcium .stearate and sodium stearyl
fumarate.
Suitable disintegrants include for example lightly crosslinked polyvinyl
pyrrolidone, corn starch, potato starch, maize starch and modified starches, croscarmellose
sodium, cross-povidone, sodium starch glycolate and combinations and mixtures thereof.
(ii) Outer Portion: The outer portion comprises of a) Micro matrix particles containing
high dose, high solubility active ingrediënt and one or more hydrophobic release
controlling agent, b) Coating of Micro matrix particles with one or more hydrophobic
release controlling agents. The outer portion may also include one or more commonly
used excipients in oral pharmaceutical formulations. The release of the high dose, high
solubility active ingrediënt is controlled through dual retard technique. The dual retard
technique is a combination of matrix formulations and reservoir formulations. First the
micro matrix particles of high dose, high solubility dose active ingrediënt and one or more
hydrophobic release controlling agents are formed and then these are further coated with
one or more release controlling agents, Thus the dual retard release technique presents the
doublé barriers and efïectively controis the diffusion of the high dose, high solubility
active ingredients from the present invention in predictable manner and also significantly
reduces the amount of release controlling agents which are otherwise required in very high
quantity and make the dosage form very bulky and therefore pose difficulty in swallowing.
The other advantages of the present invention are such as it reduces the chances of
dose dumping, unnecessary burst effects and failure of the system, which are otherwise
usuaily associated with simple matrix or reservoir systems.
10

Further advantages of present invention include the disintegration of inner portion
is not hindered as nonswellable release controliing agents are used which do not swell and
maintain. the shape during operation and it effectively prevents tïie separation of the layers
of the multilayered tablets which is normally associated with normal niultilayered tablets.
The high dose, high solubility active ingrediënt can be present in the form of a free
base or in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts
forming part of this invention are intended to define but not limited to salts of the
carboxylic acid moiety such as alkali metal salts like Li, Na and K salts; alkaline earth
metal salts like Ca and Mg salts; salts of organic bases such as lysine, arginine, guanidine,
diethanolamine, choiïae, and the like; ammonium or substituted ammonium salts and
alumininm salts. Salts may be acid addition salts "Walen defines but not ümited to
sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates,
maleates, citrates, succinates, palmoates, methanesulfonates, benzoates, salicylates,
hydcoxyrtsphthoates, benzensulfonates, ascorbates, glucerphosphates, ketagoglutarates and
the like.
Further, the high dose, high solubility active ingrediënt, where applicable, may be
present either in the form of one substantially optically pure enantiomer or as a mixture of
enantiomers or polymorphs thereof.
The high dose, high solubility active ingrediënt is in the form of modified release
and has dose from 500 mg to 1500 mg.
The high dose, high solubility active ingrediënts are comprises of the following
therapeutic classes but not limited to antidiabetic agents, anti-histamines, anti-depressants,
anti-viral agents, anesthetics, antacids, anti-arthritis, antibiotics, anti-psychotics, anti-
spasmódics, anxiolytic agents, appetite suppressants, cardiovascular agents, cough
suppressants, emollients, gastro-intestinal agents, growth regulators, .respiratory
stimulants, vitamïns, angiotensin converting enzyme inhibitors, anti-asthmatics, anti-
cholesterolemics, anti-convulsants, anti-depressants, anti-diarrhea preparations, anti-
infective, anti-inflammatory agents, anti-nauseants, anti-stroke agents, anti-tumor drugs,
anti-tussives, anti-uricemic drugs, amino-acid preparations, antiemetics, antiobesity drugs,
antiparasitics, antipyretics, appetite stimuiants, cerebral dilators, chelating agents,
cholecystokinin antagonists, cognition activators, deodorants, dermatological agents,
diuretics, erythropoietic drugs, fertility agents, synthetic hormones, laxatives, mineral
suppleraents, neuroleptics, neuromuscular agents, periphfcral vaso-dilators, prostaglandins,
vaginal preparations, vaso-constrictors,vertigo agents, biguanides and the active
11

ingredients described in united States patent numbers 3957853, 4080472, 3174901,
4835184,6031004.
Examples of high dose, high solubility active ingredients comprises of but not
limited to potassium chloride, metformin hydrochloride, phenformin, buformin,
clindamycin, hydroxyurea, erythromycin, lactobionate, vancomycin hydro chloride,
balsalazide disodium, sodium valproate, niacin, aminocaproic acid, acetaminophen,
Ciprofloxacin, quetiapine. Other drugs suitable for use and meeting the solubility and dose
criteria described above will be apparent to those skilled in the art.
In the dosage form of the present invention, the outer portion may optionally
contain more than one high dose high solubility active ingrediënt.
In the dosage form of the present invention, the outer portion may optionally
contain more than one high dose high solubility antidiabetic active ingrediënt.
As indicated above the outer portion of the present invention may comprise
auxiliary excipients such as for example lubricants, plasticisers, anti-lack agents,
opacifying agents, pigments, and such like. As will be appreciated by those skilled in the
art, the exact choice of excipient and their relative amounts will depend to some extent on
the fmal oral dosage form.
Suitable lubricants, including agents that act on the flowability of the powder to be
compressed are, for example, colloidal silicon dioxide such as Aerosil 200 (Aerosü is a
Trade Mark); talc; stearic acid, magnesium stearate.. calcium stearate and sodium stearyl
fumarate.
In micro matrix particles, the active ingrediënt and one or more hydrophobic
release controlling agents are preferably present in a ratio of from 100:1 to 100:75, more
particularly from 100:2.5 to 100:50, still more preferably fromlOO:2.5 to 100:30 and most
preferably from 100:2.5 to 100:20.
. 1-n outer portion, micro matrix particles and coating of one or more hydrophobic
release controlling agents are preferably present in a ratio of from 100:0.5 to 100:75, more
particularly from 100:2.5 to 100:50, still more preferably fromlOO:2.5 to 100:30 and most
preferably from 100:2.5 to 100:20.
According to one embodiment the release controlling agents are pharrnaceutically
excipients, which are hydrophobic in nature.
The polymers that can be used to form the rate-controiling membrane or
micromatrix are described in greater detail herein below.
12

The hydrophobic release controlling agents are selected from but are not limited to
Ammonio methacrylate copolymers type A and B as described in USP, methacrylic acid
copolymer type A, B and C as described in USP, Polyacrylate dispersion 30% as described
in Ph. Eur.,Polyvinyl acetate dispersion, ethylcellulose, cellulose acetate, cellulose
propionate (lower, medium or higher molecular weight), cellulose acetate propionate,
cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl
methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl
mechacryiate), and poiy (hexyl methacrylate). Poly(isodecyl methacrylate), poly (lauryl
methacrylate), poly(phenyl methacrylate), poly (methyl acrylate), poly (isopropyl
acrylate), poly (isobutyl actylate), poly (octadecyl acrylate), waxes such as beeswax,
carnauba wax, microcrystalline wax, and ozokerite; fatty alcohols such as cetostearyl
alcohol, stearyl alcohol; cetyl alcohol and myristyl alcohol; and fatty acid esters such as
glyceryl monostearate, glycerol distearate; glycerol monooleate, acetylated
monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl
behenate, and hydrogenated castor oil.
According to an especially preferred embodiment the release controüing agents
contains ammonio methacrylate co-polymers and fatty acid esters as hereinafter described.
The suitable hydrophobic agents are polymers sold under the Trade Mark Eudragit
RS (Ammonio Methacrylate Copolymer type B USP), ( Eudragit NE 30D (Polyacrylate
dispersion 30% Ph. Eur.), Eudragit RL (Ammonio Methacryiate Copolymer type A USP)
and Kollicoat SR 30 D and fatty acid esters such as glyceryl behenate, glycerol distearate
and hydrogenated castor oil. Eudragit polymers are polymeric lacquer substances based on
acrylate and/or methacrylates.
The outer portion can also include one or more commonly used excipients in oral
pharmaceutical formulations.
Representative commonly used excipients in oral pharmaceutical formulations
include talc, fumed silica, glyceryl monostearate, magnesium stearate, calcium stearate,
kaolin, colloidal silica, gypsum, Tween 80, Geleol pastiles (trade mark), micronised silica
and magnesium trisilicate.
The quantity of commonly used excipients in oral pharmaceutical formulations
used is from about 0.5% to about 200% by weight, preferably from 2 to 100% more
particularly 10 to 60% based on the total dry weight of the polymer.
The outer portion can also include a material that impróves the processing of the
release controlling agents. Such materials are generally referred to as "plasticisers" and
13

include, for example, adipates, azelates, benzoates, citrates, isoebucaes, phthalates,
sebacates, stearates, tartrates, polyhydric alcohols and glycols.
Representative plasticisers include acetylated monoglycerides; butyl phthalyl butyl
gylcolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate,; etbyl phthalyl ethyl
giycolate; glycerin; ethylene glycol, propylene glycol; Triethyl citrate; triacetin;
tripropinoin; diacetin; dibutyl phthalate; acetyl monoglyceride; polyethylene glycols;
castor oil; triethyl citrate; polyhydric alcohols, acetate esters, glycerol triacetate, acetyl
triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl
phthalate, butyl octyl phthalate, dioctyl azelate, epoxidised tallate, triisoctyl trimellitate,
diethylexyl phthalate, di-n-octyl phthalate, di-I-octyl phthalate, di-I-decyl phthaiate, di-n-
undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylexyl trimellitate, di-2-ethylexyl
adipate,- di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate, glyceryl
monocaprylate, glycerol distearate and glyceryl monocaprate.
The amount of pfasticiser to be used is rrom about 1% Co 50% based on the weigat
of the dry release controüing agent(s).
The amount of release controlling agent(s) to be used in fonning the outer portion
wil! be determined based on various parameters such as the desired delivery properties,
including the amount of active ingrediënt to be delivered, the active ingrediënt release rate
desired, and the size of the micro matrix particles.
The novel dosage form of the present invention can be manufactured by the
following procedure:
A) Inner Portion
The granules of the inner portion can be manufactured in accordance with usual
techniques in which the active ingrediënt and other excipients are mixed and granulated by
adding solution of binder in a low or high shear mixer or by fluidized bed granuiation. The
granulate is dried, preferably in a fluidized bed dryer. The dried granulate is sieved and
mixed with lubricants and disintegrants. Alternatively the manufacture of granules of inner
portion can be made by direct mixing of the directly compressible excipients or by roller
cornpaction.
B) Outer Portion
The micro matrix particles of the outer portion can be manufactured in accordance
with usual techniques in which the active ingrediënt and one or more hydrophobic release
controlling agents are mixed and granulated by adding solvent in a Jow or high shear
mixer or by fluidized bed granulator. The granulate is dried, preferably in a fluidized bed
14

dryer. The dried granuiate is sized. The sizing of the micromatrix particles can be done
using oscillating granulator, comminuting mill or any other conventional method. The
sieve used for the sizing can have openings frora 0.25 mm to 5 mm. Alternatively the
micro matrix particles can be made by extrusion, spheronization or by roller compaction.
The micro matrix particles can be coated by a solution of one or more hydrophobic
release controlling agents by any known method, including spray application. Spraying
can be carried out using a fluidized bed coated (preferably Wurster coating), or in a pan
coating system. Alternatively the coating of the micro matrix particles with oae or more
rate controlling agents can be done by hot meJt process using a granulator or fluidized bed
coated (preferably Wurster coating), or in a pan coating system.
C) Tablet Compression
The compression of tablets is carried out on usual press coaters (e.g. machines of
the Manesty, Cadmach or Kilian) with slight modification. The device such as feed frame
and hoppers making top ïayer are eliminated. The granules of the inner layer are charged
in the hopper of the machine compressing first layer and the granules of the outer layer are
charged in the hopper of the machine compressing the coating. On operation only the
bottom layer of the coating (outer portion) is deposited into the die and the first layer is
placed on it. The compression wheels then embed the first layer in the granules of the
outer layer, displacing some of latter to form sides, and finally press the whole into the
tablet. The resultant tablet has inner portion covered by the outer portion from all the sides
except top surface that remains uncovered and the level of the inner portion and the outer
portiori is same. The tablets can be made of various sizes and shapes. The present
invention uses round punch tooiing with upper flat bottom punches and lower flat bottom
beveled edges lower punches for the compression of inner portion and oblong shaped flat
bottom beveled edges punches for the compression of the outer portion.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. l is a plan view of the dosage form described in the present invention;
F1G. 2 is an edge view of the dosage form described in the present invention;
FIG. 3 is a transverse section view as seen along the line 3-3 of Fig. 1;
FIG. 4 (a) is a cross section of coated micro matrix particles prepared by
spheronization and coating for the purpose of illustration only.
FIG. 4 (b) is a cross section of coated micro matrix particles prepared by
granulation and coating for the purpose of illustration only.
15

FIG. 5 is a plot of % active ingrediënt versus time for immediate release and
modified release active agent;
FIG. 6 is a plot of % active ingrediënt versus time for modified release active agent
prepared using dual retard technique as described in the present invention and prepared
- without retard release technique as per examples l and 3;
FIG. 7 is a plot of % active ingrediënt versus time for modified release active agent
prepared using dual retard technique as described in the present invention and prepared
without retard release technique as per examples 2 and 4,
FIG. 8 is a plot of metformin plasma concentration versus time for test (a) and
reference (b) formulation;
FIG. 9 is a plot of rosiglitazone plasma concentration versus time for test (a) and
reference (b) formulation;
FIG. 10 is a plot of metfomin plasma concentration versus time for test (a and b)
and reference (c)formulation;
FIG. 11 is a plot of metformin plasma concentration versus time for test (a)and
reference (b)formulation;
PIG. 12 is a plot of rosiglitazone plasma concentration versus time for test (a) and
reference (b) formulation;
Referring to FIGS. l to 3, a dosage form 4 as described in the present invention
having an inner portion l containing low dose active ingrediënt as immediate release and
outer portion 2 containing high dose, high solubility active ingrediënt as modified release.
FIG. 4(a) & 4(b) show the cross section of the coated micro matrix particles 5 and
having 6 a high dose, high solubility active ingrediënt, 7 hydrophobic release controlling
agent and 8 a coating of hydrophobic release controlling agent. FIG. 5 shows the release
profile of a low dose active ingrediënt as immediate release 9 and the release profile of a
high solubility active ingrediënt as modified release 10. FIG. 6 and 7 show release of high
dose, high solubility active agent 11 & 12 and 15 & 16'as per example l & 2 respectively
from a dosage form prepared using dual retard technique as described in the present
invention and release of high dose, high solubility active agent 13 & 14 and 17 & 18 as per
example 3 & 4 respectively from a dosage form prepared without using dual retard release
technique. The total quantity of the hydrophobic release controlling agent is same in all the
dosage forms inspite of that the figures clearly shows that dual retard technology
signiflcantly reduces the burst effect and effectively controls the release rate of the high
dose, high solubility active ingrediënt for prolonged period.
16

DISCRIPTION OF THE PREFERRED EMBODEMENTS
The following examples further illustrate but by no means limit the present
invention.
The dissolution of novel dosage fonn of the present invention was determined by
following method.
For sodium valproate-
Instrument - Apparatus I, USP (basket)
Revolution - 60 / min.
Temperature - 37±0.5°C
Dissolution medium - 1000 ml pH 6.8 buffer
For niacin-
Instrument - , Apparatus I, USP (Basket)
Revolution - 100 / min.
Temperature - 37±0.5°C
Dissolution medium - 900 ml 0. l N HC1
For lamotrigine-
Instrument - Apparatus ïï, USP (Paddie)
Revolution - 100 / min.
Temperature -. 37±0.5°C
Dissolution medium - 1000 mlO.OOl N HC1
For pravastatin sodium-
Instrument - Apparatus II, USP (Paddie)
Revolution - 100 / min.
Temperature - 37±0.5°C
Dissolution medium - 900 ml pH 6.8 buffer
For metformin hydrochloride-
Instrument - Apparatus II, USP (paddle)
Revolution - 50 / min.
Temperature - 37±0.5°C
Dissolution medium - 900 ml 0. l N HC1
For rosiglitazone maleate-
Instrument - Apparatus II, USP (Paddle)
Revolution - 100 / min.
Temperature - 37±0.5°C
17

Dissolution medium - 500 ml 0,01 N HC1
For glimepiride-
Instrument - Apparatus II, USP (Paddie)
Revolution - 75 / min.
Temperature - 37±0.5°C
Dissolution medium - 500 ml 0.5% sodium lauryl sulfate in water
The composition of outer portion in the dosage form comprising high dose high
solubility antidiabetic active ingrediënt is as follows-
Micro matrix particles-
Metformin hydrochloride 75%w/w to 99%w/w
Eudragit RS l%w/w to 25%w/w
Coated micro matrix particles
Micro matrix particles 70%wAv to 99%w/w
Hy drogenated castor oil l %w/w to 3 0%w/w
Magnesium stearate 0%w/w to 2%w/w
The dissolution of high dose high solubility ingrediënt of the formulation of the
present invention is achieved not more than 45% in l hour and from 25 to 90% in six
hours.
The dissolution of metfonnin hydrochloride is achieved not more than 50% in l
hour, and from 30 to 90% is in four hours and notless than 65% in 12 hours.
After oral administration of a dosage form of the present invention the maximum
plasma concentration can be achieved between 700 ng/ml and 2500 ng/ml, preferably
from 900 ng/ml to 2400 ng/ml and more preferably from 1000 ng/ml to 2350 ng/ml. The
invivo mean dissolution time (MDT) of the dosage form of the present invention is 4 to 6
hours. The minimum plasma concentration (at 24 hours)of the said dosage form ranges
between O to 450 ng/ml after oral administration.
EXAMPLES
EXAMPLË l
i) Production of inner portion
11.71 %w/w of pravastatin sodium is mixed with 52.62 %w/w of lactose
monohydrate and 22.22 %w/w starch and the mixture is granulated in a binder of 2.22 v
povidone in water and then dried. The granules are sieved and mixed with 1,11 %w/w
magnesium stearate, 9.0 g sodium starch glycolate, 0.11 %w/w lake of sunset yellow. This
mixture is compressed to 90 mg weight tablets having a diameter of 6.35 mm.
18

2)Production of outer portion
A) Micro matrix particles- 90.91 %w/w of niacin is mixed with 9.09 %w/w of
Eudragit RSPO (Ammonio Methacrylate Copolymer type B USP) and the mixture is
granulated with a solvent mixture of acetone and methylene chloride and then dried. The
granules are sized.
•L-*
B) Coating of Micro matrix particles- 85.84 %w/w of micro matrix particles is
charged in fluidized bed processor. 13.61 %w/w of hydrogenated castor oil is dissolved in
acetone aad tuis coating solution is sprayed to coat the micro matrix particles. The coated
micro matrix particles are sieved and mixed with 0.86 %w/w magnesium stearate.
3) Compression of tablets
Tablet (A)- 90 mg granules of inner portion are pressed to tablets(equal to 10 mg
pravastatin) using 6.35 mm round punches and 643 mg granules of outer portion (equal to
500 mg niacin)are compressed using 14.95 X 8.35 mm oblong punches.
Tablet (B)- 90 mg granules of inner portion are piessed to tablets(equal to \0 mg
pravastatin) using 6.35 mm round punches and 1286 mg granules of outer portion (equai
to 1000 mg niacin)are compressed using 20.3 X 9.8 mm oblong punches.
The compression is done on press coater machine in such a manner that the
resultant tablet has inner portion covered by the outer portion from all the sides except top
surface that remaïns uncovered and the level of the inner portion and the outer portion is
on the same surface.
The dissolution rate of the novel dosage form was determined (Table I and 2)
Table 1: Dissolution profile of tablet (A)

Niacin Pravastatin sodium
Time (hour) % Released Time (min) % Released
1 12.4 45 83.8
2 19.1 60 84.1
4 29.4
6 37.4

8 41.9
10 47.1
12 50.6
14 54.6
. 24 67.7
19

Table 2: Dissolution profile of tablet (B)

Niacin Pravastatin sodium
Time (hour) % Released Time (min) % Released
1 .9.8 45 84.1
2 15,3 60 85.6
4 24.7

6 28.7
8 31.4
10 35.7
12 39.1
14 41.9
24 51.5
EXAMPLE 2
1) Production of inner portion
38.47 %w/w of lamotrigine is mixed with 2.71 %w/w of crosspovidone and 0.1$
%w/w colloidal silicon dioxide and the mixture is granulated in a binder of 0.71 %w/w
povidone in water and then dried. The granules are sieved and mixed with 28.70 %w/w of
Mannitol (Pearlilol SD 200 R.T.M.), 12:31 %w/w of crosspovidone, 2.31 %w/w of
magnesium stearate, 6.15 %w/w aspartame, 2.31 %w/wtalc, 5.0 %w/w flavour and 1.15
%w/w of colloidal silicon dioxide. This mixture is compressed to 65 mg weight tablets
having a diameter of 5.55 mm.
2) Production of outer portion
A) Micro matrix particles- 90.91 %w/w of sodium valproate is mixed with 9.09
%w/w of Eudragit RSPO (Ammonio Methacrylate Copolymer type B CTSP) and the
mixture is granulated with a solvent mixture of acetone and methylene chloride and then
dried. The granules are sized.
B) Coating of Micro matrix particles- 85.84 %w/w of micro matrix particles is
charged in fluidized bed processor. 13.61 %w/w of hydrogenated castor oil is dissolved in
acetone and this coating solution is sprayed to coat the micro matrix particles. The coated
micro matrix particles are sieved and mixed with 0.86 %w/w magnesium stearate.
l) Compression of tablets
- 20

Tablet (A)- 65 mg granules of inner portion are pressed to tablets(equal to 25 mg
lamotrigine) using 5.55 mm round punches and 643 mg granules of outer portion (equal to
500 mg sodium valproate)are compressed using 14.95 X 8.35 mm oblong punches.
Tablet (B)- 65 mg granules of inner portion are pressed to . tablets(equal to 25 mg
lamoirigine) using 5.55 mm round punches and 1286 mg granules of outer portion (equal
to 1000 mg sodium valproate)are compressed using 20-3 X 9.8 mm oblong punches. The
compression procedure is same as Example 1.
The dissolution rate of the novel dosage form was determined (Table 3 and 4)
Table 3; Dissolution profile of tablet (A)

Sodium valproate Lamotrigine
Time (hour) % Released Time (min) % Released
1 23.3 15 83.5
2 36.3 30 S8.6
4 55.1 45 91.6
6 67.5 60 92.8
8 77.0
10 83.8
12 88.9
14 92.5
24 104.6
Table 4: Dissolution profile of tablet (B)

Sodium valproate Lamotrigine
Time (hour) % Released Time (min) % Released
1 19.0 15 90.3
2 29.5 30 95.6
4 45.2 45 98.3
6 55.9
' 8 65.0
10 71.9
12 77.8
21

14 82.4
24 95.8
Dosage forms described in the examples 3 and 4 are prepared by not coating the
micro matrix particles of the outer portion but the hydrophobic release controlling agent is
mixed vvith the micro matrix particles. The sole purpose of these examples is to
demonstraie the usefulness of the present invemion as described earlier. The examples
clearly show that the rate of release of the modified release active ingrediënt is
significantly faster than the present invention.
EXAMPLE 3
1) Production of inner portion
Same as for Example l
2) Production of outer portion
77.76 %w/w of niacin is mixed with 7.78 %w/w of Eudragit RSPO (Ammonio
Methacrylate Copolymer type B USP) and the mixture is granulated with a solvent
mixture of acetone and methylene chloride and then dried. The granules are sized and
mixed with 13.61 %w/w of hydrogeaated castor oil and 0.86 %w/w of magnesium
stearate.
2) Compressionoftablets
Tablet (A)- Same as for Example l
Tablet (B)- Same as for Example l
The dissolution rate of the novel dosage form was determined (Table 5 and 6)
Table 5: Dissolution profile of tablet (A)

Niacin Pravastatin sodium
Time (hou r) % Released Time (min) % Released
1 30.1 45 75.9
2 43.6 60 80.9
4 61.6
6 74.1
S 83.9
10 92.1
12 99.4
22

24 102.6
Table 6: Dissolution profile of tablet (B)

Niacin Pravastatin sodium
Time (hour) % Released Time (min) % Released
1 29.9 45 89.6
2 36.3 60 90.0
4 52.8
6 63.4
8 73.5
10 77.8
12 84.5
24 90.5
EXAMPLE 4
1) Production of inner portion
Same as for Example 2
2) Production of outer portion
77.76 %w/w of sodium valproate is mixed with 7.78 %w/w of Eudragit RSPO
(Ammonio Methacrylate Copolymer type B USP) and the mixture is granulated with a
soivent mixture of acetone and methylene chloride and then dried. The granules are sized
and mixed with 13.61 %w/w of hydrogenated castoc oil and 0.86 %w/w of magnesium
stearate.
3) Compression of tablets
Tablet (A)- Same as for Example 2
Tablet (B)- Same as for Example 2
The dissolution rate of the novel dosage form was determined (Table 7 and 8)
Table 7: Dissolution profile of tablet (A)

Sodium valproate Lamotrigine
Time (hour) % Released Time (min) % Released
1 58.3 15 81.8
2 79.9 30 89.8
23

4 98.5 45 91.7
6 101.6 60 97.4
Table S: Dissolution profile of tablet (B)

Sodium valproate Lamotrigine
Time (hour) % Released Time (min) % Released
1 50.2 15 S6.1
2 69.1 30 87.3
4 91.0 45 92.6
6 101.3 60 98.3
EXAMPLE 5
1) Production of inner portion
5.89 %w/w of rosiglitazone raaleate is mixed with 55.89 %w/w of lactose
monohydrate and 22.22 %w/w starch and the mixture is granulated in a binder of 2.78
%w/w povidone and 2.78 %w/w starch in water and then dried. The granules are sieved
and mixed with 0.28 %w/w magnesium stearare, 10.00 %w/w sodium starch
glycolate,0.17 %w/w ferric oxide yellow. This mixture is compressed to 90 mg weight
tablets having a diameter of 6.35 mm.
2) Production of outer portion
A) Micro matrix particles- 90.91 %w/w of metformin hydrochloride is mixed with
9.09 %w/w of Eudragit RS (Ammonio Methacrylate Copolymer type B USP) and the
mixture is granuiated with a solvent mixture of acetone and methylene chloride and then
dried. The granules are sized.
B) Coating of Micro matrix panicles- 85.54 %w/w of micro matrix particles is
charged in fluidized bed processor. 13.61 %w/w of hydrogenated castoroil is dissolved in
acetone and this coating solutioais sprayed to coat the micro matrix particles. The coated
micro matrix particles are sieved and mixed with 0.86 %w/w magnesium stearate.
3) Compression of tablets
Tablet (A)- 90 mg granules of inner portion are pressed to tablets(equal to 4 mg
rosiglitazone) using .6.35 mm round punches and 643 mg granules of outer portion (equal
to 500 mg metforniin hydrochloride)are compressed using 14.95 X 8.35 mm oblong
punches.
24

Tablet (B)- 90 mg granules of inner portion are pressed to tablets(equal to 4 mg
rosiglitazone) using 6.35 mm round punches and 1286 mg granules of outer portion (equal
to 1000 mg metforarin hydrochlorïde)are compressed using 20.3 X 9.8 mm oblong
punches.
The compression is done on press coater machine in such a manner that the
resultam tablet has inner portion covered by the outer portion from all the sides except top
surface that remams uncovered and the level of the inner portion and the outer portion is
on the same surface.
The dissolution rare of the novel dosage form was determined (Tabte 9 and 10)
Table 9; Pissolution profile of tablet (A)

Metformin hydrochloride Rosiglitazone
Time (hour) % Released Time (min) % Released
1 42.5 15 84.88
2 58.0 30 99.02
4 74.09 45 101.20
6 86.1 60 104.4
8 97.8
10 101.9
12 103.7
Table 10; Dissolution profile of tablet (B)

Metformixv hydrochloride Rosiglitazone
Time (hour) % Released Time (min) % Released
1 38.2 45 96.79
2 53.4 60 99.32
4 .69.5
6 78.1
8 86.8
10 93.6
12 97.65
EXAMPLE 6
l) Production of inner portion
25

Same as for Example 5
2) Production of outer portion
A) Micro matrix particles- 86.96 %w/w of metformm hydrochloride is mixed with
13.07 %w/w of Eudragit RS (Ammonio Mettiacrylate Copolymer type B USP) and the
mixture is granulated with a solvent mixture of acetone and methylene chloride and then
dried. The granules are sized.
B) Coating of Micro matrix particles- 86.40 %w/w of micro matrix particles is
charged in fiuidized bed processor. 13.15 %w/w of hydrogenated castor oil is dissolved in
aceione and this coating soluüon is sprayed to coat the micro matrix parücles. The coated
micro matrix particles are sieved and mixed with 0.45 %w/w magnesium stearate.
3) Compression of tablets
90 mg granule of inner portion are pressed to tablets (equivalent to 4 mg
rosiglitazone) using 6.35 mm round punches and 1331 mg granules of outer porüon
(equivalent to 1000 mg metformin hydrochioride) are compressed using 20.3 X 9.S mm
oval punches. The compression procedure is same as Example 5.
The dissolution rate of the novel dosage form was determined (Table 11)
Table 11: Dissolution profile

Metformin Hydrochloride Rosiglitazone Maleate
Time (hour) % Released Tirne (min) % Reieased
1 32.10 15 75.63
2 41.65 30 88.35
4 59.05 45 103.49
6 63.90 60 105.70
8 73.63
10 79.35
12 84.21
24 94.91
EXAMPLE 7
1) Production of inner portion
Same as for Example 5
2) Production of outer portion
A) Micro matrix particles-
Same as for Example 5
26

6) Coating of Micro matrix particles- 89.36 %w/w of micro matrix particles is charged in
fluidized bed processor. 10.15 %w/w of glycerol distearate type l Ph. Eur. (Precirol ATO
5 R.T.M.) is dissolved in acetone and this coating solution is sprayed to coat the micro
matrix particles. The coated micro matrix particles are sieved and mixed with 0.49 %w/w
magnesium stearate.
3) Compression of tablets
90 mg granule of inner portion are pressed to tablets (equal to 4 mg rosiglitazone
maleate) using 6.35 mm round punches and 1231 mg granules of outer portion (equal to
1000 mg metformin hydrochloride) are compressed using 20.3 X 9.8 mm oval punches.
The compression procedure is same as Example 5.
The dissolution rate of the novel dosage form was determined (Table 12)
Table 12: Dissolution profile

Metformin Hydrochloride Rosiglitazone Maleate
Time (hour) % Reieased Time (min) % Released
1 39.9 15 78.32
. 2 51.7 30 89.15
4 69.2 45 97.13
6 82.5 60 100.57
8 83.8
10 91.2
12 94.9
24 99.8
EXAMPLE 8
1) Production of inner portion
2.94 %w/w of rosiglitazone maleate is mixed with 87.80 %w/w of Mannitol
(Pearlitol SD 200 R.T.M.), 6.67 %w/w of crosspovidone, 2.0 %w/w of magnesium
stearate, 0.56 %w/w of colloidal silicon dioxide and 0.03 %w/w ferric oxide' red. This
mixture is compressed to 90 mg weight tablets having a diameter of 6.35 mm.
2) Production of outer portion
Same as of Example 5.
3) Compression of tablets
27

90 mg granule of inner portion are pressed to tablets(equal to 2 mg rosiglitazone
maleate) using 6.35 mm round punches and 1281 mg granules of outer portion (equal to
1000 mg metformin hydrochloride)are compressed using 20.3 X 9.8 mm oval punches.
The compression procedure is same as Example 5.
The dissolution rate of the novel dosage form was deiermined (Table 13)
Table 13: Dissolution profile

j Metformin Hydrochloride Rosiglitazone Maleate
Time (hour) % Released Time (min) % ReLeased
1 38.29 15 80.2
2 53.40 30 96.1
4 69.51 45 103.4
6 78.11
8 86.86
10 93.60
12 97.65
24 100.17
EXAMPLE 9
1) Production of inner portion
1.11 %w/w of glimepiride is mixed with 63.28 °/ow/w of lactose monohydrate and
22.22 %w/w staren and the mixture is granulated in a binder of 2.22 %w/w povidone in
warer and then dried. The granules are sieved and mixed with 1.11 %w/w magnesium
stearate, 10.0 %w/w sodium starch glycolate,0.06 %w/w lake of brilliant blue. This
mixture is compressed to 90 mg weight tablets having a diameter of 6.35 mm.
2) Production of outer portion
A) Micro matrix particles- 83.33 %w/w of metformin hydrochloride is mixed with
16.67 %w/w of Eudragït RS (Ammonio Methacrylate Copolymer type B USP) and the
mixture is granulated with a solvent mixture of acetone and methylene chloride and then
dried. The granules are sized.
B) Coating of Micro matrix particles- 86.46 %w/w of micro matrix particles is charged in
fluidized bed processor.
12.61 %w/w of hydrogenated castor oil is dissolved in acetone and this coating
solution is sprayed to coat the micro matrix, particles. The coated micro matrix particles
are sieved and mixed with 0.91 %w/w magnesium stearate.
28

3) Compression of tablets
90 mg granule of inner portion are pressed to tablets(equal to l mg glimepirlde)
using 6.35 mm round punches and 694 mg granules of outer portion (equal to 500 mg
metformin hydrochlonde)are compressed using 14.95 X 8.35 mm oblong punches. The
compression procedure is same as Example 5.
The dissolution rate of the novel dosage form was determined (Table 14)
Table 14: Dissolution profile

Metformin Hydrochloride Glimepiride
Time (hour) % Released Time (min) % Released
1 28.0 15 69.4
2 40,5 30 91.87
4 57.8 45 99.64
6 65.8 60 103.87
8 73.2
10 80.3
12 S5.0
24 101.8
EXAMPLE 10
1) Production of inner portion
Same as for Example 5
2) Production of outer portion
C) Micro matrix particles-
Same as tbr Example 5
B) Coating of Micro matrix particles- 91.21 %w/w of micro matrix parücles and 8,29
%w/w of hydrogenated castor oil is mixed and charged in planetary mixer which is heated
fröm outside to maimain the temperature approximately 80°C with the help of a water
bath. The above blend is mixed by running the planetary i;iixer for l hour to coat the
micro matrix particles. The coated micro matrix particles are sieved and mixed with 0.50
%w/w magnesium stearate.
3) Compression of tablets
90 mg granule of inner portion are pressed to tablets (equal to 4 mg rosiglitazone maleate)
using 6.35 mm round punches and 1206 mg granules of outer portion (equal to 1000 mg
29

metformin hydrochloride) are compressed using 20.3 X 9.8 mm oval punches. The
compression procedure is same as Example 5.
The dissolution rate of the novel dosage formwas determined (Table 15)
Table 15: Dissolution profüe

Metformin Hydrochloride Rosiglitazone Maleate
Time (hour) % Released Time (min) % Released
1 25.7
- 30 85.9
2 36.6 45 100.3
4 49.1 60 104.9
6 57.5
8 66.5
10 71.3
12 76.0
14 90.7
Dosage forms described in the example 11 are prepared by not coating the micro
matrix: particles of the outer portion but the hydrophobic release controlling agent is mixed
with the micro matrix particles. The sole purpose of these examples is to demonstrate the
usefulness of the present invention as described earlier. The examples clearly show that
the rate of release of the modified release active ingrediënt is significantly faster than the
present invention.
EXAMPLE 11
1) Production of inner portion
Same as for Example 5
2) Production of outer portion
77.76 %w/w of metformin hydrochloride is mixed with 7.780 %w/w of Eudragit
RS (Ammonio Methacrylate Copolymer type B USP) and the mixture is granulated with a
solvem mixture of acetone and methylene chloride and then dried. The granules are sized
and mixed with 13.61 %w/w of hydrogenated casto: oil and 0.86 %w/w of magnesium
stearate.
3) Compression of tablets
Tablet (A)- Same as for Example 5
Tablet (B)- Same as for Example 5
The dissolution rate of the novel dosage form was determined (Table 16 and 17)
30

Tabie 16: Dissolution profile of tablet (A)

Metformin hydrochloride Rosiglitazone
Time (hour) % Reieased Time (min) % Released
1 63.9 15 100.08
2 85.5 30 106.41
3 102.1 45 109.77
Table 17: Dissolution profile of tablet (B)

Metformin hy dr o chloride Rosiglitazone
Time (hour) % Released Time (min) % Released
1 50.3 15 99.22
2 70.5 30 105.26
4 88.0 45 107.53
6 100.9 60 107.53
EXAJVIPLE 12
1) Production of inner portion
Same as for Example 7.
2) Production of outer portion

A) Micro matrix particles- 93.02 °/ow/w of metformin hydrochloride is mixed with 6.98%
w/w of Eudragit RS (Ammonio Methacrylate Copolymer type B USP) and the mixture is
granulated with a solvent mixture of acetone and methylene chloride and then dried. The
granules are sized.
B) Coating of Micro matrix particles- 85.18 %w/w of micro matrix particles is charged in
fluidized bed processor. 13.87 %w/w of hydrogenated castor oil is dissolved in acetone
and tliis coating solution is sprayed to coat the micro matrix particles. The coated micro
matrix panicles are sieved and mixed with 0.95 %w/w magnesium stearate.
3) Compression of tablets
90 mg granule of inner portion are pressed to tablets(equal to 4 mg rosiglitazone) using
6.35 mm round punches and 1262 mg granules of outer portion (equal to 1000 mg
metformin hydrochloride)are compressed using 20.3 X 9.8 mm oblong punches. The
compression procedure is same as Example 5.
The dissolution rate of the novel dosage form was determined (Table 18)
31

Table 18; Dissolution profile

Metformin Hydrochloride Rosiglitazone
Time (hour) % Released Time (min) % Released

1 40.9 45 89.68
i 2 52.2 60 91.42
4 68.4
6 79.2
S S8.6

10 99.9
12 101.5
EXAMPLE 13
1) Production .of inner portion
Same as for Example 7.
2) Production of outer portion

A) Micro matrix particles- Same as for Example 12.
B) Coating of Micro matrix particles- 88.70 %w/w of micro matrix particles is charged in
fïuidized bed processor. 10.31 %w/w of hydrogenated castor oil is dissolved in acetone
and this coaring solution is sprayed to coat the micro matrix particles. The coated micro
marrix panicles are sieved and mixed with 0,99 %w/w magnesium stearate.
3) Compression of tablets
90 mg granule of inner portion are pressed to tablets(equal to 4 mg rosiglitazone) using
6.35 mm round punches and 1212 mg granules of outer portion (equal to 1000 mg
metformin hydrochloride)are compressed using 20.3 X 9.8 mm oblong punches. The
compression procedure is same as Example 5.
The dissolution rate of the novel dosage form was determined (Table 19)
Table 19: Dissolution profile

Metformin Hydrochloride Rosiglitazone
Time (hour) % Released Time (min) % Released
1 44.50 15 79.9
2 58.90 30 89.9
4 76.90 45 95.8
6 91.40 60 100.6
8 102.40
32

EXAMPLE 14
l) Production of inner portion
Same as for Example 11.
1) Production of outer portion
.A) Micro matrix particles- Same as for Example 12.
B) Coating of Micro matrix pardcies- 90.56 %w/w of micro matrix particles is charged in
flüidized bed processor. 8.42 %w/w of hydrogenated castor oil is dissolved in acetone and
rhis coating solution is sprayed to coat the micro matrix particles. The coated micro matrix
parades are sieved and mixed with 1.01 %w/w magnesium stearate.
3) Compression of tablets
90 mg granule of inner portion are pressed to tablets(equal to 4 mg rosiglitazone)
usiag 6.35 mm round punches and 1187 mg granules of outer portion (equal to 1000 mg
metformin hydrochloride)are compressed using 20.3 X 9.8 mm oblong punches. The
compressiou procedure is same as Ex.ample 5.
The dissoluüon rate of the novel dosage form was determined (Table 20)
Table 20: Dissolution profile

Metformin Hydrochloride Rosiglitazone
Time (hour) % Released Time (min) % Released
1 42.40 45 86.05
2 58.1 60 90.73
4 75.9
6 86.5
8 94.5
10 99.0
EXAMPLE 15
1) Production of inner portion
Same as for Example 7.
2) Production of outer portion
A) Micro matrix particles- 90.91 %w/w of metformin hydrochloride is mixed with 4,55 %
w/w of Eudragit RS (Ammonio Methacrylate Copolymer type B USP) and 4.55 %w/w of
Eudragit RL (Ammonio Methacrylate Copolymer type A USP) and the mixture is
33

granulated with a solvent mixture of acetone and methylene chloride and then dried. The
granuies are sized.
B) Coating of Micro matrix particles- 85.47 %w/w of micro matrix particles is charged in
nuidized bed processor. 13.60 %w/w of hydrogenated castor oü is dissolved in acetone
and this coating solution is sprayed to coat the micro matrix particles. The coated micro
man ix particles are sieved and mixed with 0.93 %w/w magnesium stearate.
3) Compression of tablets
90 mg granule of inner portion are pressed to tablets(equai to 4 mg rosiglitazone)
using 6.35 mm round punches and 1287 mg granuies of outer portion (equal to 1000 mg
metformia hydrochloride)are compressed using 20.3 X 9.8 mm oblong punches. The
compression procedure is same as Example 5.
The dissolution rate of the novel dosage form was determined (Table 21)
Table 21: Dissolution profïle

Metformin Hydrochloride Rosiglitazone
Time (hour) % Released Time (min) % Released
1 34.8 45 92.65
2 48.3 60 97.02
4 66.2
6 79.3
8 85.9
10 92.6
12 97.6
EXAiMPLE 16
1) Production of inner portion
Same as tbr Example 7.
2) Production of outer portion

A) Micro matrix particles- Same as for Example 15.
B) Coating of Micro matrix particles- 94.66 %w/w of micro matrix particles is charged in
fluidtzed bed processor. 4.30 %w/w of hydrogenated castor oil is dissolved in acetone and
this coating solution is sprayed to coat the micro matrix panicles. The coated micro matrix
particles are sieved and mixed with 1.03 %w/w magnesium stearate.
3) Compression of tablets
34

90 mg granule of inner portion are pressed to tablets(equal to 4 mg rosiglitazone)
using 6.35 mm round punches and 1162 mg granules of outer portion (equal to 1000 mg
metformin hydrochloride)are compressed using 20.3 X 9.8 mm oblong punches. The
compression procedure is same as Example 5.
The dissolution rate of the novel dosage fonn was determined (Table 22)
Table 22: Dissolution profile

Metformin Hydrochloride Rosiglitazone
Time (hou r) % Release d Time (min) % Released
1 47.56 45 92.94
2 61.93 60 96.70
4 82.42
6 96.0 .
8 100.0
EXAMPLE 17
1) Production of inner portion
Same as for Example 7.
2) Production of outer portion

A) Micro matrix particles- Same as for Example 5.
B) Coating of Micro matrix particles- 88.92 %w/w of micro matrix particles is charged in
fluidized bed processor. 10.11 %w/w of hydrogenated castor oil is dissolved in acetone
and tthis coating solution is sprayed to coat the micro matrix particles. The coated micro
matrix particles are sieved and mixed with 0.97 %w/w magnesium stearate.
3) Compression of tablets
90 mg granule of inner ponion are pressed to tablets(equal to 4 mg rosiglitazone)
using 6.35 mm round punches and 1237 mg granules of outer portion (equal to 1000 mg
metformin hydrochloride)are compressed using 20.3 X 9.8 mm oblong punches. The
compression procedure is same as Example 5.
The dissolution rate of the novel dosago form was determined (Table 23)
Table 23: Dissolution profile

Metformin Hydrochloride Rosiglitazone
Time (hour) % Released Time (min) % Released
1 35.0 15 69.2
35

2 47.3 30 79.5
4 60.8 45 85.7
6 72.5 60 90.4
S 81.8
10 89.2
12 94.1
24 98.2
EXAiVlPLE 18
1) Production of inner portion
Sa me as for Example 7.
2)Production of outer portion
A) Micro matrix particles- Same as for Example 5.
B) Coating of Micro matrix particles- 87.09 %w/w of micro matrix particles is charged in
fiuidized bed processor. 11.88 %w/w of hydrogenated castor oil is dissolved in acetone
and this coating solütion is sprayed to coat the micro matrix particles. The coated micro
matrix particles are sieved and mixed with 1.03 %w/w magnesium stearate.
3)Compression of tablets
90 mg granule of inner portion are pressed to tablets(equal to 4 mg rosiglitazone)
using 6.35 mm round punches and 1263 mg granules of outer portion (equal to 1000 mg
metformin hydrochloride)are compressed using 20.3 X 9.8 mm oblong punches. The
compression procedure is same as Example 5.
The dissolution rate of the novel dosage form was determined (Table 24)
Table 24: Dissolution profile

Metformin Hydrochloride Rosiglitazone
Time (hour) % Released Time (min) % Released
1 38.7 30 78.66
52.9 45 83.47
4 71.6 60 88.06
6 82.3
8 91.3
10 97.3
12 101.1
36

EXAMPLE 19
1) Production of inner portion
2.22 %w/w of glimepiride is mixed with 62.17 %vv/w of lactose monohydrate and 22.22 %
w/w suarch and the mixture is granulated in a binder of 2.22 %w/w povidone in water and
then dried. The granules are sieved and mixed with 0.56 %w/w magnesium stearate, 10.0
°/ów/w sodiuni staren glycolate,0.06 %w/w lake of erythrocine and 0.56 %w/w colloidal
siücon dioxide. This mixture is compressed to 90 mg weight tablets having a diameter of
6.35 mm.
2) Production of outer portion- same as for example 18.
3) Compression of tablets
90 mg granule of inner portion are pressed to tablets(equal to 2 mg gümepiride)
using 6.35 mm round punches and 1263 mg granules of outer portion (equal to 1000 mg
metformin hydrochloride) are compressed using 20.3 X 9.8 mm oblong punches. The
compression procedure is same as Example 5.
The dissolution rate of the novel dosage form was detennined (Table 25)
Table 25: Dissolution profile

Metformin Hydrochloride Gümepiride
Time (hour) % Released Time (min) % Released
1 38.79 45 100.7
2 54.12 60 102.2
4 69.54
6 82.04
8 89.78
10 95.06
12 100.48
lixamplc 20
Dcteriniaation of rehitive bioavavaibility of Metformin sustained release formulation
with respect to metformin immediate release tablet.
The study was carried out to demonstrate the sustained release characteristic of
metformin in the combmaüon formulation and to evaluate the relative bioavaüability of
combination formulation of sustained release Metformin hydrochloride and Rosiglitazone
maleate versus metformin immediate release tablet 2x500mg (marketed as Glycomet® by
37

USV Ltd., India.) and rosiglitazone immediate release tablets 4mg (marketed as Enselin®
by Torrent pharma Ltd.; India.).
Methodology:
The biostudy had an open label, randomized two period, two-treatment, two way
sinüle dose crossover study with 7 days washout period between treatment days.
Non-compartmental Pharmacokinetic assessment was based on the plasma levels
of Metformin and Rosiglitazone measured by blood sampiing. Blood samples were
obtained before dosing and at the following times after administration of test and reference
formulations;
Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0, 15.0, 18.0,
and 24.0 hours.
Number of subjects and study population:
Twelve (12) volunteers were enrolled and all óf them completed the study. All 12
volunteers were included in the Pharmacokinetic and safety analyses.
Criteria for inclusion:
Healthy male volunteers aged between 18 to 45 years.
Test formulation, Dose and Mode of Administration:
Test Formulation: 4mg/1000mg Rosiglitazone/Metformin SR prepared as per the
invention disclosed in. the examples.
Volunteers received a single oral dose of above products with 200ml of water
following high calorie diet (~800Kcai).
Reference Product, Dose and Mode of Administration:
Reference: Immediate release 4mg Enselin ® plus Glycomate (2 x 500mg)
Volunteers received a single oral dose of above products with 200ml of water
following high calorie diet (~800Kcal).
Pharmacokinetics:
The following Pharmacokinetic parameters were calculated using non
compartments methods: the area under the drug plasma concentration curve from time of
dosing to the time of last sampiing poir.t (AUC(0-1); the area under the drug plasma
concentration versus time curve extrapolated to infmity (AUC (o-inf)); the maximum
measured concentration of the drug in the plasma (Cmax) and the time at which this
concentration was measured (W); the concentration at 24 hours (C24h); the time taken for
drug plasma concentration to decrease by 50% (t1/2); and the terminal first-order
elimination rate constant (Kei).
38

Area Under the curve (AUC) is the integral part of drug blood level over time
from zero to infinity and is a raeasure of quantity of drug absorbed and in the body.
AUC(O-t) represents area under the curve from zero to time t, where t represents
the cime at which last bJood sample was taken.
AUC (O- inf) represent s area under the curve from zero to infinity.
Elimiiiation hïtlf life of a drug is the time in hours necessary to reduce the drug
concemraiion in the blood, plasma or serum to 1/2 after equilibrium is reached.
Cmax is the peak plasma concentration achieved after the administration of the drug,
Tmax is the time to reach peak plasma concentration.
Statistical Methods:
Descriptive statisücs of relevant Pharmacokinetic parameters were perfomed. An
analysis of variance (ANOVA) was used to assess treatment differences.
Methods used for analysis of Metformin and Rosiglitazone in plasma samples:
Analysis of Metformin:
Estimation of Metformin in plasma samples was carried out by High Performance
Liquid Chromatography and UV detection at 234 nm. Brïefly 0.5 ml of plasma sample
was precipitated with 2.0 ml acetonitrile. Samples were centrifuged and supernatant
aliquot was washed with dichioromethane. After ceatrifugation , aqueous layer was
injected on HPLC.
Analysis of Rosiglitazone :
Estimation of Rosiglitazone in plasma samples was carried out by LC-MS/MS.
Briefly O, l ml of plasma sample was precipitated with 0.25 ml acetonitrile , Samples were
centrifuged and supernatant aliquot was analyzed by LC-MS/MS.
Pharmacokinetic results:
The summary of the statistical analysis and confidence intervals of the
Pharmacokinetic parameters is contained in Tables 26 & 27. The mean plasma
concentration versus time curve is depicted in Figure 8 (metformin) & Figure 9
Rosiglitazone) vvherein curve a represents Test Formulation and curve b represents
Reference Formulation.

Tabie: 26 Bioavailability Summary and Anaïysis - Metformin SR (lOOOmg)
Parameters Unit Test Reference
39

A UCo-inf ng*hr/ml
CJ 15980 ±3456 19551+4265
AUCo-t ng*hr/ml 14983 ± 2930 19091+4200
C lll:lX n g/ml 1737.61 ±249.09 2558.37 + 623.05
C2-4h n g/ml 113.87 + 91.05 56.44 + 37.94
Tmax Hr 5,42 + 0.68 4.42 + 0.88
T t/2 Hr 4.71 ±1.36 4.26± I.I4

Table: 27 Bioavaiïability Summai*y and Analysis - Rosiglitazone (4mg)
Parameters Unit Test Reference
AUCo-inf ng*hr/ml 1851 ±414 1730 ±465
AUC0-t ng*hr/ml 1795 ±401 1676 + 438
Cmax
Ng/ml 243.48 + 40.78 247.48 ±45.38
C2-4h Ng/ml 6.36 + 5.19 3.37 + 4.36
Tmax hr 3.75 ±1.03 3.25 + 1.66
tl/2 hr 3.73 + 0.60 3. 63 ±0.79
Conclusion.
Metformin in test formulation has shown sustained release characteristics with
lower Cmax and prolonged W (FigureS). The relative bioavailabiüty of both the
componems was studied.
Example 21
Determination of relative bioavailability of t\vo Formulations with different release
pro tïlcs:
A biostudy was carried out with the preliminary objective of comparing the
relative bioavailability of the lOOOmg metformin sustained release formulations (A & B)
relative to immediate release metformin tablets 2x500mg (marketed as Glycomet by
USV Ltd.; India.). A secondary objective was to characterize the plasma concentration
proüle of metfornün in the sustained release formulation relative to immediate release
formulation i. e. Glycomet® 2x500mg tablets.
40

Methodology:
The biostudy had an open label, randomized, three periods, three treatment, three
ways single dose crossover design with 7 days washout period between treatment days.
Non-companmemal Pharmacokinetic assessment was based on the plasma levels
of metformin measured by blood sampling. Blood samples were obtained before dosing
and at the tbllowing limes after admmistration of test and reference formulations;
Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0, 15.0, 18.0,
and 24.0 hours.
Number of subjects and study population:
Twelve (12) voluiueers were enrolied and 11 of them completed the study. All 12
volunteers were included in the Pharmacokinetic and safety analyses.
Criteria for ïnclusïon:
Healthy male volunteers aged between 18 to 45 years.
Test product, Dose and Mode of Admmistration:
Formulation A: 4mg/lOOOmg Rosiglitazone/Metformin dosage form prepared as
per the invention disclosed in the examples.

Formulation B; 4mg/1000mg Rosiglitazone/Metformin SR dosage form prepared
as per the invention disclosed in the examples.
In the moming, volunteers received a single oral dose of above products with
200ml of water following high calorie diet (~800Kcal).
Reference Product, Dose and Mode of Administration:
Formulation C: Immediate release 4mg Enselin ® plus Glycomate® (2 x 500mg)
In the morning, volunteers received a single oral dose of above products with 200ml of
water following high calorie diet (~800Kcal).
Pliarmacokinetics:
Same as for example 20.
Statistical Methods:
Same as for example 20.
Methods used for analysis of Metformin and Rosigtitazone in plasma samples:
Same as for example 20.
Pharmacokinetic results:
The summary of the Statistical analysis and confidence intervals of the
Pharmacokinetic parameters is contained in
41

Table 28. The mean plasma concentratie n versus time curve is depicted in Figure 10.
wherein curve a represents Formulation A, curve b represents Formulation B and curve c
represents the Formulation C.

Table: 28 Bioavaiïability Summary and Analysis - Metformin SR (lOOOmg)
Paranieters Unit Formulation A Formulation B Formulation C
AUC0-inf ng*hr/ml 16508 + 3655 17762 + 5113 15985 + 2886
AUC0-t ng*hr/ml 15899 + 3270 14989 + 3196 15558+2930
Cmax n g/ml 1801.72 + 264.82 1551.01+337.49 2121.96 + 405.95
C24h n g/ml 79.58 + 75.10 204.96 + 151.02 45.48 + 37.99
Tmax Hr 5.36 ±0.51 5,46 + 0.78 4.00 + 0.74
T1/2 Hr 4.08 ±1.32 7.23 + 3.45 4.6Ï + 1.54
Conclusion:
Both the formulations according to the invention tested had reduced Cmas
compared to that of the reference product (Glycomet tablets), with Formulation B being
significantly reduced. The W of both the formulations according to invention were
prolonged relative to that of Glycomet® tablets. The concentration at 24 hours (C24h) of
Formulation B was almost 4.5 times higher than Glycomet® tablets and almost 2.6 times
higher than Formulation A.
Example 22
Determination of relative bioavailability of Metformin sustained release formulations
The study was carried out to assess the effect of night time administration and to
cvaluate the relative bioavailability of combination formulation of sustained release
Metformin and Rosiglitazone (prepafed as per the invention disclosed in the examples)
versus metformin sustained release tablet (marketed as Glucophage XR® by
Bristol Myers Squibb; USA.) and rosiglitazone immediate release tablet (marketed
as Avandia^by Glaxo Smithkline; United Kingdom.).
Methodology:
The biostudy had an open label, randomized two period, two treatment, two way
single dose crossover study with 7 days washout period between treatment days.
42

Non-compartmental Pharmacokinetic assessment was based on the plasma levels
of Metformin and Rosiglitazone measured by blood sampling. Blood samples were
obtained before dosing and at the following times after administration of test and reference
formulatïons;
Pre-dose, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0, 15.0, 18.0,
and 24.0 hours.
Number of subjects and study population:
Sixteen (16) volunteers were enrolled and 15 of mem completed the study. All 15
volunteers were included in the Pharmacokinetic and safety analyses.
Criteria for inclusion:
Healthy male volunteers aged between 18 to 45 years.
Test product, Dose and Mode of Administration:
Test Formulation: 4mg/1000mg Rosiglitazone/Metformin sustained release dosage
foYm prepared as pei the invention disclosed in the examples. Volunteeis received a single
oral dose of above products with 200ml of water following high calorie dinner
(~1400KCal).
Reference Product, Dose and Mode of Administration:
Reference: 4mg Avandia® plus Glucophage XR® (2 x 500mg)
Volunteers received a single oral dose of above products with 200ml of water
following calorie dinner (-HOOKcal).
Pharmacokinetics:
Same as for example 20.
Statistical Methods:
Descriptive statistics of relevant Pharmacokinetic parameters were performed. An
analysis of variaace (ANOVA) was used to assess treaunent diffetences,
Westlake's 90% confidence interval for the ratio of two formulations for log
transformed data were calculated, and to test that the difterence between two formulations
are within the (80 to 125%) limits.
Methods used for analysis of Metformin and Rosiglitazone in plasma samples:
Same as for example 20.
Pharmacokinetic results:
The summary of the Statistical analysis and confidence intervals of the
Pharmacokinetic parameters is contained in Table 29 & 30. The mean plasma
concentration versus time curve is depicted in Figure 11 (Metformin) & 12 (Rosiglitazone)
43

wherein curve a represents Test Formulation and curve b represents Reference
Formulation.

Table: 29 Bioavailability Summary and Analysis - Metformin SR (lOOOmg)
Parameters unit Test Reference 90% Westlake Interval

Upper Lower
AUC0-inf
ng*hr/ml 16939 + 2323 16396 ±3791 ! 83.84 116.16
AUC0-t
ng*hr/ml . 16I07 + 21Ï4 15951 ±3543 87.33 112.67
Cmax
ng/ml 1515.29 +
225.97 1558.78 +
364.23 90.89 109.11
C24h
ng/ml 120.10 +
74.01 79.63 ± 60.22 - -
Tmax
hr 7.64 ±1.65 8. 86 ±1.03 - -
T1/2
hr 4. 12 ±1.34 3.36 + 0.70 - -

Table: 30 Bioavailabüity Summary and Analysis - Rosiglitazone (4mg)
Parameters Unit Test Reference 90% Westlake Interval

Upper Lower
AUC0-inf
i ng*hr/ml 1308 + 432 1258 ±331 85.73 114.27
AUC0-t
ng*hr/ml 1266 ±400 1234 + 324 86.61 113.39
Cmax ng/ml 145.70 ±
48.90 161.83 + 55.43 80.88 119.12
C24h ng/ml 6.07 + 7.46 1.80 + 3.11 - -
Tmax
hr 5.07 ±2.63 4.13 ± 1.91 - -
T 1/2 hr 3.59 + 0.71 3.32±0.59 - -
Conclusion;
The relative bioavailability study shown that bioequivalance was achieved between
the 4mg/1000mg combination formulation and the respective components, for both AUC
and Cmax parameters (Table 29 & 30). Moreover, in the test formulation, the concentration
of Metformin at 24 hrs was almost 1.5 times more than Glucophage XR® (Figure 11)
44

wherein curve a represents Test formulaüon and b represents Reference formulation
(Table 29). Similarly Rosiglitazone component of the test formulation also shown higher
concentration at 24 hrs as that of Avandia® (Figure 12; wherein curve a represents Test
Formulation and curve b represents Reference Formulation and Table 30).

45

We claim:
1. A dosage form of combination of high dose high solubility active ingrediënt, as
modified release and low dose active ingrediënt as immediate release suitable for
swallowing comprising of dual retard technique to control the release of high dose,
high solubility active ingrediënt, wherein said dosage form comprising of an inner
portion having a low dose active ingrediënt as immediate release and an outer portion
having a high dose, high solubility active ingrediënt as modified release, in which the
outer portion comprises a) micro matrix particles and b) coating on micro matrix
particles and wherein the weight ratio of immediate release active ingrediënt and
modified release active ingrediënt is from l: l O to l: 15000.
2. A dosage form as claimed in claim l, in the form of a tablet, wherein said inner portion
is covered by the outer portion from all the sides except top surface that remains
uncovered.

3. A dosage form as claimed in claim l, wherein the micro matrix particles comprises
one or more hydrophobic release controlling agents.
4. A dosage form as claimed in claim 3, wherein the hydrophobic release controlling
agents are selected from the group comprising of ammonio methacrylate copolymers
type A and B as described in USP, methacrylic acid copolymer type A. B and C as
described in USP, polyacrylate dispersion 30% as described in Ph. Eur., "polyvinyl
acetate dispersion, ethylcellulose, cellulose acetate, cellulose, propionate (lower,
medium or higher molecular weight), cellulose acetate propionate, cellulose acetate
butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate),
poïy(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly
(hexyl methacrylate), poly(isodecyl methacrylate), poly (lauryl methacrylate),
poly(phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly
(isobutyl actylate), poly (octadecyl acrylate), waxes such as beeswax, carnauba wax,
microcrystalline wax, and ozokerite; fatty alcohols such as cetostearyl alcohol, stearyl
alcohol;- cetyl alcohol and myristyl alcohol; and fatty acid esters such as glyceryl
monostearate, glycerol distearate, glycerol monooleate, acetylated monoglycerides,
tristearin, tripalmïtin, cetyl esters wax, glyceryl palmitostearate. glyceryl behenate and
hydrogenated castor oil.
5. A dosage form as claimed in claim 3, wherein in micro matrix particles, the active

ingrediënt and one or more hydrophobic release controlling agents are present in a
46

ratio of from 100:1 to 100:75, preferably in ratio of from 100:2.5 to 100:50; more
preferably in ratio of from 100:2.5 to 100:30 and most preferably in ratio of from
100:2.5 to 100:20.
6. A dosage form as claimed in claim l, wherein said coating of micro matrix particles
comprises one or more hydrophobic release controlling agents.
7. A dosage form as claimed in claim 6, wherein the hydrophobic release controlling
agents are selected from the group comprising of ammonio methacrylate copolymers
type A and B as described in USP, methacrylic acid copolymer type A, B and C as
described in USP, polyacrylate dispersion 30% as described in Ph. Eur., polyvinyl
acetate dispersion, ethylcellulose, cellulose acetate, cellulose propionate (lower,
medium or higher molecular weight), cellulose acetate propionate, cellulose acetate
butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate),
poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly
(hexyl methacrylate). poly(isodecyl methacrylate). poly (lauryl methacrylate).
poly(phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly
(isobutyl actylate), poly (octadecyl acrylate), waxes such as beeswax, carnauba wax,
microcrystalline wax, and ozokerite; fatty alcohols such as cetostearyl alcohol, stearyl
alcohol; cetyl alcohol and myristyl alcohol; and fatty acid esters such as glyceryl
monostearate, glycerol distearate, glycerol monooleate, acetylated monoglycerides,
tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate
glycerol distearate, and hydrogenated castor oil.

8. A dosage form as claimed in claim l, wherein in outer portion, micro matrix particles
and coating of onc or more hydrophobic release controlling agents are present in a
ratio of from 100:0.5 to 100:75, preferably in a ratio of from 100:1 to 100:50, more
preferably present in a ratio of from 100:2.5 to 100:20.
9. A dosage form as claimed in claim l, wherein the low dose active ingrediënt
comprises dose less than or equal to 50 mg.
10. A dosage form as claimed in claim l, wherein the low dose active ingrediënt is
selected from the group comprising of antidiabetic agents, anti-histamines, anti-
depressants, anti-viral agents, anesthetics, antacids, anti-arththriics, antibiotics, anti-
psychotics, anti-spasmodies, anxiolytic agents, appetite suppressants, cardiovascular
agents, cough suppressants, emollients, gastro-intestinal agents, growth regulators,
respiratory stimulants, vitamins, angiotensin, converting enzyme inhibitors, anti-

asthmatics. anti-cholesterolemics, anti-convulsants, anti-depressants. anti-diarrhea
47

preparations, anti-infective, anti-inflammatory agents, anti-nauseants, anti-stroke
agents, anti-tumor drugs, anti-tussives, anti-uricemic drugs, amino-acid preparations,
antiemetics, antiobesity drugs, antiparasitics, antipyretics, appetite stimulants,
cerebral dilators, chelating agents, cholecystokinin antagonists, cognition activators,
deodorants, dermatological agents, diuretics, erythropoietic drugs, fertility agents,
synthetic hormones, laxatives, mineral supplements, neuroleptics, neuromuscular
agents, peripheral vaso-dilators, prostaglandins vaginal preparations, vaso-
constrictors, vertigo agents, sulphonylurease, tneglitinides, PPAR gama agonist
[insulin sensitisers (thiazolidinedione)], PPAR alpha and gamma agonist, alpha-
glucosidase inhibitors and the like.
11. A dosage form as claimed in claim 10, wherein the low dose active ingrediënt is
selected from the group comprsing of zafirlukast, quinapril hydrochloride,
isotretinoin, rabeprazole sodium, estradiol(e2), norethindrone acetate, risedronate
sodium, pioglitazone HC.l, amphetamine, anagre]jde hydrochloride, biperiden HC1,
mephalan, alprazolam, ramipril, naratriptan hydrochloride, leflunomide, anastrozole,
exemestane, paroxetine mesylate, candesartan cilexetil, almotriptan, cerivastatin,
betaxolol hydrochloride, bisoprolol fumarate, delcyclotadine, clonazepam, clorazepate
dipotassium, clozapine, methylphenidate hei, carvedilol, warfarin sodium, norgestrel,
ethinyl estradiol, cyclophosphamide, pemoline, üothyronine sodium, misoprostol,
tolterodine tartrate, dextroamphetamine sulfate, dicyclomine hydrochloride, digoxin,
oxybutynin chloride, doxazosin mesylate, ethatrynate sodium, venlafaxine HC1,
enalapril maleate, estradiol, estropipate, famotidine letrozole, fludrocortisone acetate,
fluoxetine, dexmethylphenidate hei, alendronate sodium, ziprasidone, glipizide,
glyburide, miglitol, guanabenz acetate, haloperidol, doxercalciferol, zalcitabine,
hydrochlorothiazide, hydromorphone HC1, indapamide, estradiol, nitric oxide,
ketorolac tromethamine, clonazepam, granisetron, lamotrigine, fluvastatin sodium,
levonorgestrel, levothyroxine sodium, atorvastatin calcium, lisinopril, minoxidil,
loperamide, loratidine, lorazepam, lovastatin, pravastatin sodium, fluvoxamine
maleate, acetaminophen, acyclovir, aminocaproic acid, pitavastatin,
rosuvastatin,dalvastatin,escetalopram,sertraline,celecoxib,parecoxib; valdecoxib,
glibenclamide (glyburide),glipizide, gliclazide, glimepiride, tolazamide, tolbutamide,
clorpropamide, gliquidone, nateglinide, glyburide, glisoxepid, .glibornuride,
phenbutamide, tolcyclamide, repaglinide, troglitazone, ciglitazone, pioglitazone,
englitazone, acarbose, voglibose, emiglitate, miglitol, farglitazar, (S)-2-ethoxy-3-[4-
48

(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid, 3-{4-[2-(4- tert-
butoxycarbonylaminophenyl) ethoxyjphenyi) -(S)-2-ethoxy propanoic acid, L-
6766892 and pharmaceutically acceptable salts therof.
12. A dosage form as claimed in any preceding claim wherein the high dose. high
solubility active ingrediënt comprises dose from 500 mg to 1500 mg.
13. A dosage form as claimed in any preceding claim wherein the high dose, high
solubility active ingrediënt is selected from the group comprising of antidiabetic
agents, anti-histamine s, anti-depressants, anti-viral agents, anesthetics, antacids, anti-
arththriics, antibiotics, anti-psychotics, anti-spasmodics, anxiolytic agents, appetite
suppressants, cardiovascular agents, cough suppressants, emollients, gastro-intestinal
agents, growth regulators, respiratory stimulants, vitamins, angiotensin converting
enzyme inhibitors, anti-asthmatics, anti-cholesterolèmics, anti-convulsants, anti-
depressants, anti-diarrhea preparations, anti-infective, anti-inflammatory agents, anti-
nauseants. anti-stroke agents. anti-tumor drugs, anti-tussives, anti-uricemic drugs,
amino-acid preparations, antiemetics, antiobesity drugs, antiparasitics, antipyretics,
appetite stimulants, celebral dilators, chelating agents, cholecystokinin antagonists,
cognition activators, deodorants, dermatological agents, diuretics, erythropoietic
drugs, fertility agents, synthetic hormones, laxatives, mineral supplements,
neuroleptics, neuromuscular agents, peripheral vaso-dilators, prostaglandins, vaginal
preparations, vaso-constrictors, biguanides, vertigo agents and the like.
14. A dosage form as claimed in claim 13, wherein the high dose, high solubility active
ingrediënt is selected from the group comprising of metformin hydrochloride,
phenformin, buformin, potassium chloride, clindamycin, hydroxyurea, erythromycin,
lactobionate, vancomycin hydrochloride, balsalazide disodium, sodium valproate,
niacin, aminocaproic acid., acetaminophen ciprofloxacin, quetiapine and
pharmaceutically acceptable salts thereof.
15. A dosage form as claimed in claim l, wherein said inner portion optionally contains
more than one low dose active ingredients.

16. A dosage form as claimed in claim l, wherein outer portion optionally contains
more than one high dose high solubility active ingredients.
17. A dosage form as claimed in any preceding claim wherein said active ingredients
comprise antidiabetic active ingrediënt such as herein described.
18. A dosage form as claimed in claim 17 ,wherein the low dose antidiabetic active
ingrediënt is selected from the group comprsing of sulphonylurease, meglitinides,
49

PPAR gama agonist [insulin sensitisers (thiazolidinedione)], alpha-glucosidase
inhibitors, PPAR alpha and gama agonist.
19. A dosage form as claimed in claim 17, wherein the low dose antidiabetic active
ingrediënt is selected from the group comprsing of glibenclamide
(glyburide),glipizide, gliclazide, glimepiride, tolazamide, tolbutamide, clorpropamide,
gliquidone, nategünide, glyburide, glisoxepid, glibornuride, phenbutamide,
tolcyclamide, repaglinide, troglitazone, ciglitazone, pioglitazone, englitazone,
acarbose, voglibose, emiglitate, miglitol, farglitazar, (S)-2-ethoxy-3-[4-(2-{4-
rnethanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid, 3-{4-[2-(4- tert-
butoxycarbonylaminophenyl) ethoxy]phenyl}-(S)-2-ethoxy propanoic acid and
pharmaceutically acceptable salts thereof.
20. A dosage form as claimed in claim 17, wherein the high dose high solubility
antidiabetic active ingrediënt is selected from biguanides.
21. A. dosage form as claimed in claim 17, wherein the .high dose high solubility
antidiabetic active ingrediënt is selected from the group comprsing of metformin
hydrochloride, phenformin and buformin
22. A dosage form as claimed in claim 17, wherein the composition of outer portion is as
follows-
Micro matrix particles-
Metformin hydrochloride 75%w/w to 99%w/w
Eudragit RS l%w/w to 25%w/w
Coated micro matrix particles
Micro matrix particles 70%w/w to 99%w/w
Hydrogenated castor oil l%w/w to 30%w/w
Magnesium stearate 0%w/w to 2%w/w

Dated this the 18th day of February 2004
50