Description
EXTENDED RELEASE FORMULATION OF METFORMIN
Technical Field
[1 The present invention relates to a dry ready to use modi fied release dosage fo r
mulation for Metformin dosage forms and its salts and derivatives thereof, a process
for preparing extended release tablet using JN'STAMODEL (A43 D0004 1 and
A43D00042) manufactured by Ideal Cures Private Limited Mumbai India thereof also
use thereof as additive to animal feeds, foods and food supplements and also cosmetic
and pharmaceutical compositions. Invention also relates to ready-to-use modi ied
release compositions capable of regulating release of Metformin at various dosage
strength, a process for production thereof and also use thereof as formulated pharma
ceutical compositions.
Background Art
[2] In general Metformin has been widely prescribed for lowering blood glucose in
patients with diabetes. However, being a short acting drug, metformin requires nv or
three times-a-day dosing. Adverse events associated with metformin use are often gas
trointestinal e.g. anorexia, nausea, vomiting and occasionally diarrhea, etc. These
adverse effects may be partially avoided by reducing the initial and/or maintenance
dose or using an extended-release dosage form.
[ Metformin has intrinsically poor permeabi lity in the lower portion o the gastroi n
testinal tract, leading to absorption from the upper part of the tract. It has very h igh
solubility in water (>300mg/ml at 25°C). These parameters can lead to difficu lty in
providing a sustained release of the drug from a formulation and the concomitant
problems associated with controlling the initial burst from such a formu lation. The rate
of dissolution of such high solubility drugs may be reduced by embedding the drug i
a polymeric matrix or surrounding it with a polymeric barrier membrane through )
which the drug must diffuse o be released for absorption.
[4] Metformin is administered through solid dosage ranges from 100 mg to 75 mg
daily. In standard doses of 100 ing is taken i daily. Prescription of Metformin
recommend that it should be taken with meals if possible and daily. Dosage generally
should not exceed 100 mg dai ly.
[5] In state of the art modified release compositions are developed to provide relatively
constant drug plasma levels and sustained efficacy for longer period of time. In
principle aim of extended and modified release composition is to get required
therapeutic concentration of the active in the blood stream and mainta in its therapeutic
concentration without deviation from strength during spec ified period .
[6] In state of art various grades of cellulosic polymers are used in the modified release
compositions e.g. HPMC polymer. WO 20 060256, WO 2003039527 and WO
2005 23 134 disclose the use of hydrophilic polymers like hypromellose for extended
release of drug like metformin. These polymers extend the release of drug by showing
osmosis nature in aqueous conditions. Cellulosic matrix based system work by the
swelling and gelling function i.e. these polymer swell through influx of liquids and a
gel like physical structure is formed which provides extended release effect facilitated
by diffusion of the Metformin. Some patents that disclose matrix based systems for
slow release of metformin include WO 2007 1 6 1 1 and US 5955 106.
n theory it is known that with high viscosity grade polymer after attaining gell ing
effect drug release is lower but as time progresses drug release is increased. On the
contrary with low viscosity grade polymer after attaining gelling effect drug is released
at faster speed due to larger pore sized and concentration of drug decrease as time
progresses.
n order to minimize difficulties associated in ratios of polymers, batch to batch
variations, formulating, storing and preserving many loose components of differently
textured a d sized ingredients means have been desired in industry to make ready to
use extended release or modified release composition which are convenient to handle.
The object of the present invention is to provide a ready-to-use matrix system and
method of preparation for Metformin extended release or modi fied release fo r
mulation.
Disclosure of Invention
Summary of Invention
Accordingly, the present invention provides hydrophilic matrix system based read
to use technology for Modified or Extended Release Formulation of Metformin Hy
drochloride using INSTAMODEL (A43 D0004 1 and A43 D00042) manufactured by
Ideal Cures Private Limited Mumbai India.
Accordingly, the present invention also provides method for making ready to use
Metformin modified or extended release formulation, involving steps of aqueous
granulation, drying, lubrication and punching of tablets.
In another aspect, present invention also provides Twice a day Metformin table
dosage form.
Extended release or modified release tablet formulation can be in the form of
single or multilayer tablets, capsule shaped oral dosage form, caplei, granules, disc,
pellets, granules in capsule, mini-tablets in oral dosage form and other possible oral
dosage form mean thereof.
In yet. another embodiment, the solid oral dosage form can optionally include one
or more pharmaceutically acceptable excipients.
The details of one or more embodiments in the practice of the inventions are set
forth in the description below. Other features, objects and advantages of the inventions
will be apparent from the appended examples and claims.
Detailed Description
Below description specify various scientific terms unless stated with context, all
technical and scientific terms used herein have the same meaning as commonly un
derstood by one of ordinary skill in the art, to which this invention belongs. Although
any methods and materials similar or equivalent to those described herein can be used
in the practice or testing of the present invention, the preferred methods and materials
are described.
Unless stated to the contrary. The feature 'ready-to-use', in the context of the
present invention, is taken to mean the property that the composition according to the
invention can be used directly for its purposes by the user by simply dispersing it in
required quantity of water.
The term 'modified release' is in context of the invention as a way of active drug
delivery where the rate of release of the active drug from the composition is not ex
clusively dependent on the concentration of active drug remain ing in the dosage form
and / or the solubility of the active drug in the liquid surrounding the composition, and
where the time course with or without respective location of release of active drug
from an oral dosage form are chosen to accomplish therapeutic or convenience o b
jecti ves not offered by conventional dosage forms. For the purpose of invention active
drug is selected from Aceclofenac, its intermediates and derivatives thereof.
The term 'Aceclofenac' is in context of the invention includes ts polymorphic
forms, the pharmaceutically acceptable salts, including salts esters and pother chemical
derivatives or intermediates etc. The solid pharmaceutical composition comprises Ace
clofenac from 1 to 80 w/w % of dosage form.
The term 'dosage', 'solid pharmaceutical composition' may include one or more of
tablet, capsule, powder, disc, caplet, granules, pellets, granules in capsule, minitablets,
minitablets in capsule, pellets in capsule, sachet and the like. The solid pharmaceutical
composition also includes multilayer tablets. The solid pharmaceutical compositions
are meant for oral administration.
The term 'tablet' includes pharmaceutical compositions of a ll shapes and sizes,
whether coated or uncoated.
The .term 'Lubricant' in the context of the present invent ion, is taken to mean that
an ingredient added to prevent the adhesion of tablet materials to the punches and dies,
reduce inter-particle friction and facil itate the ejection of oral dosage forms from the
die cavity, .Lubricant of present invention includes but not limited to talc, magnesium
stearate, stearic acid, sodium stearyl fumarate and there derivatives thereof.
The term 'Glidant' in the context of the present invention, is taken to mean that a
ingredient which enhance product flow by reducing inter-particulate friction. Glidant
can be used in present invention includes but not limited to silicon di-oxide, colloidal
silicon dioxide and there derivatives thereof. t is available under several brand names
like AEROSIL® and CAB-O-SIL®.
The term 'Solvent' in the context of the present invention, is taken to mean in
gredient that facilitate mixing of components in wet granulation process. Solvent can
be used in present invention includes but not limited to Acetone, ethanol, methylene d i
chloride, isopropyl alcohol, water or their mixture thereof.
The term 'Binder' or 'Binding agent' in the context of the present invention, is taken
to mean ingredient that facilitate binding of components in wet granulation process.
Solvent can be used in present invention includes but not limited to dextrin and their
derivatives, inaltodextrin, polyvinyl polymers, Polyvinyl pyrrol idone 30 (PVP K..30)
and there derivatives thereof.
The ready to use polymeric composition Instamodel A43D00045 for extended and
modified release formulation was supplied by Ideal Cures Private Limited, Mumbai,
www.idealcures.co.in . This product was used to create inventive dosage form having
ideal modified release profile for twice a day administration.
According to inventors i was surprisingly found that extended release solid oral
dosage form for Aceclofenac can be created with ready to use Instamodel
(A43D00045) system and dosage fo m have advantageous modified release properties.
The ready to. use composition in accordance with present invention comprise IN
STAMODEL (A43D00045). In one of the embodiment of present invention Ace
clofenac is formulated with ready to use composition o prepare modi fied release
dosage form. In accordance with present invention different sails, derivatives,
polymorphs of Aceclofenac could be combined to achieve ready-to-use composition to
achieve extended or modified release dosage form.
In a dosage form according to the invention Aceclofenac is blended with the ready
to use polymer and aqueous granulated further the granulated mixture is compressed to
produce a solid formulation. The ingredients are blended to form a uniform powder
and then compressed with means generally known to skilled in the art.
In yet another embodiment of present invention Aceclofenac and INSTA MODEL
are blended together with binding agent and thereafter wet granulated and dried. These
dried granules are then processed in presence of lubricant and g lidant, and thereafter
compressed to form appropriate dosage form and final ly coated.
In yet another embodiment of present invention Aceclofenac and INSTAMODEL
are blended together with binding agent and thereafter wet granulated and dried. These
dried granules are then processed in presence of lubricant and glidant, and thereafter
compressed to form appropriate dosage form and optional y coated.
This system of formulation uses simple and economic polymers hence cost
effective to the customer. Another advantage of the present formulation is its robust
and reproducible results for extended release dose form without batch to batch
variations. Further by using aqueous solvent system for granulation dosage form does
not have any residual solvent or hazardous effect found in many organic solvent based
formulations.
Inventive dosage form may be prepared by blending Aceclofenac, their derivatives
or combination thereof along with ready to use composition. Therefore inventive forr
mulation preparation comprise steps as:-
Below description specify various scientific terms unless stated with context, all
technical and scientific terms used herein have the same meaning as commonly u n
derstood by one of ordinary skill in the art, to which this invention belongs. Although
any methods and materials similar or equivalent to those described herein can be used
in the practice or testing of the present invention, the preferred methods and materials
are described.
Unless stated to the contrary, The feature 'ready-to-use , in the context of the
present invention, is taken to mean the property that the composition according to the
invention can be used directly for its purposes by the user by simply dispersing it in
required quantity of water.
The term 'modified release' is in context of the invention as a way of active drug
delivery where the rate of release of the active drug from the composition is not e x
clusively dependent on the concentration of active drug remaining i the dosage form
and / or the solubility of the active drug in the liquid surrounding the composition, and
where the time course with or without respective location of re lease of act ive drug
from an oral dosage form are chosen to accomplish therapeutic or convenience ob
jectives not offered by conventional dosage forms. For the purpose oi invention active -
drug is selected from Metformin, its intermediates and derivati ves thereof.
The term 'Metformin' is in context of the invention includes its polymorphic forms,
the pharmaceutically acceptable salts, including salts esters and pother chemical
derivatives or intermediates etc. The solid pharmaceutical composi tion comprises
Metformin from 1 to 90 w/w % of dosage form.
The term 'dosage', 'solid pharmaceutical composi tion' may include o e or more o
tablet, capsule, powder, disc, caplet, granules, pellets, granules in capsule minitablets,
minitablets in capsule, pellets in capsule, sachet and the like. The sol i pharmaceutical
composition also includes multilayer tablets. The solid pharmaceutical composi tions
are meant for oral administration.
. The term 'tablet' includes pharmaceutical compositions of all shapes and sizes,
whether coated or uncoated.
The term 'Lubricant' in the context of the present invention, is taken to mean that
an ingredient added to prevent the adhesion of tablet materials to the punches and dies,
reduce inter-particle friction and facilitate the ejection of oral dosage forms from the
die cavity. Lubricant of present invention includes but not limited to talc, magnesium
stearate, stearic acid, sodium stearyl fumarate and there derivatives thereof.
The term 'Glidant' in the context of the present invention, is taken to mean that an
ingredient which enhance product flow by reducing inter-particulate friction. Glidant
can be used in present invention includes but not limited to sil icon di-oxide, colloida l
silicon dioxide and there derivatives thereof. It is available under several brand names
like AEROS1L® and CAB -O-SIL®.
The term 'Solvent' in the context of the present invention, is taken to mean in
gredient that facilitate mixing of components in wet granulation process. Solvent can
be used in present invention includes but not limited to Acetone, ethanol, methylene di
chloride, isopropyl alcohol, water or their mixture thereof.
The term 'Binder' or 'Binding agent' in the context of the present invention, is taken
to mean ingredient that facilitate binding of components in wet granulation process.
Solvent can be used in present invention includes but not limited to dextrin and their
derivatives, maltodextrin, polyvinyl polymers, Polyvinyl pyrrol idone 30 (PVP .30)
and there derivatives thereof.
The ready to use polymeric composition Instamodel A43D0004 1 and A43 D00042
for extended and modified release formulation was supplied by Idea l Cures Private
Limited, Mumbai, www.idealcures.co. in . This product was used to create inventive
dosage form having ideal modified release profi le for Once a day administration.
According o inventors it was surprisingly found that extended release solid oral
dosage form for Metformin can be created with ready to use Instamodel (A4 D0004
and A43D00042) system and dosage form have advantageous modi fied release
properties, The ready to use composition in accordance with present invention
comprise INSTAMODEL (A43D0004 1 and A43 D00042 ) . Instamodel blends com
bination can be used in plurality of layers and combinations including but not limited
to various combinations and orders of mixings or granulations. In one of the em
bodiment of present invention Metformin is formulated with ready o use composition
to prepare modified release dosage form. n yet another embodiment metformin is
formulated with ready to use composition with different grades and orders of mixing
and granulations. n accordance with present invention different salts, derivat ives,
polymorphs of Metformin could be combined to achieve ready-to-use composit ion to
achieve extended or modified release dosage form.
In a dosage form according to the invention Metformin s blended with th ready to
use polymer and aqueous granulated further the granulated mixture is compressed to
produce a solid formulation. The ingredients are blended to form a uniform powder
and then compressed with means generally known to skilled in the art.
In yet another embodiment of present invention Metformin and INSTAMODEL
are blended together with binding agent and thereafter wet granulated and dried. These
dried granules are then processed in presence of lubricant and glidant, and thereafter
compressed to form appropriate dosage form and finally coated.
In yet another embodiment of present invention Metformin and INSTAMODEL
are blended together with binding agent and thereafter wet granulated and dried. These
dried granules are then processed in presence o f lubricant and glidant, and thereafter
compressed to form appropriate dosage form and optionally coated .
This system of formulation uses simple and economic polymers hence cost
effective to the customer. Another advantage of the present formulation is its robust
and reproducible results for extended release "dose form without batch to batch
variations. Further by using aqueous solvent system for granulation dosage form does
not have any residual solvent or hazardous effect found in many organic solvent based
formulations.
Inventive dosage form may be prepared by blending Metformin, their deri vati ves
or combination thereof along with ready to use composition. Therefore inventi ve fo r
mulation preparation comprise steps as:-
. Blending of ready to use formulation Instamodel (A43 D0004 1) with
Metformin.
2 . Thorough mixing to form dry powder
3. Wet granulation with active drug and solvent
4 . Sieving through appropriate size
5. Tray drying or fluidized bed drying
6 . Again blending with ready to use formulation instamodel (A43 D00042)
7. Optionally addition of lubricant
S. Final tablet compression
9. Optional film coating-
According to one of the embodiment inventive dosage form is prepared by
blending ready to use composition (Instamodel A43D0004 1 and A43 D00042 ), process
blending is performed by conventional dry blender or a food processor or 'V-blender
or a similar function device. Further Metformin are processed using aqueous solvent
with binder through wet granulation or a similar wet mixing method to generate
dosage formulation. Dosage formulation is further dried, sieved and compressed op- .
tionally with addition of lubricant, binder, glidant to form modified release ora dosage
form.
n one of the embodiment of present invention, inventive dosage formulations are
prepared by blending Metformin along with Instamodel (A43D0004 1 and
A43D00042). Initially all components are blended by conventional dry blending in a
food processor or 'V-blender' or a similar function device. Other solid oral dosage for
mulation components like binders, lubricants, glidants, detackifier,. excipients can be
added to create inventive formulation. Further mixture is then processed with ap
propriate quantity of aqueous solvent with binder and wet granulated. Obtained sieved
granulated is then uniformly mixed with premeasured amount of the lubricant to
improve industrial acceptability and oral dosage compression quality. Subsequently
uniform mixed inventive formulation is compressed in standard pharmacopoeial
equipment to get a controlled release oral dosage formulation of the correct desired
weight and strength.
In yet another embodiment Metformin is formulated comprising steps of mixing
Instamodel with Metformin with solvents, granulating and drying to granulation which
is subsequently sifted using appropriate mesh screen. Further generated granules can
be again blended with instamodel to generate plurality of layers. Finally generated
granules are sifted and blended with lubricants.
According to one of the main embodiment wherein hardness of tablets produced is
in range of 5 Kg/cm 2 to 30 Kg/cm 2. In one of the embodiment oral dosage forms
produced by inventive composition having human administrable active ingredient is
suitable for human use. Alternatively drug suitable for veterinary purpose formulated
in accordance with present composition will be suitable for veterinary use.
According to the objective of present invention Metformin is formulated i oral
dosage form for modified or extended release delivery. Inventi ve composition
comprising 250, 500, 750, 800, 1000 mg or 1500 mg of Metform in in plurality of
dosage formulations. Controlled release formulation can have combination of one or
more additional drugs.
Suitable APIs that can be used with the present invention include, but are not
limited to: andrenergic blocking agent; acetyl-cholin-esterase inhibitor; analgesic or
antipyretics; angiotensin modulator; anthelmintic agents; ant! anxiety agent; an¬
tibacterial; antibiotic; anticoagulant; anticonvulsant; antidepressant; anti fungal ; an ihistamine;
antimalarial; antimicrobial agent; antipsychotic agent; Antiviral agents;
blood glucose lowering drug; calcium channel modulator; diuretic; erectile dys
function; gastric acid secretion inhibitor; histamine H2-receptor antagonist; inh ibitor of
steroid Type II 5 alpha - reductase including; lipid regulating agents; selective Hlreceptor
antagonist; vasodilator; vitamins. . . .
Following examples are offered to more fully illustrate the invention, but are not to
be construed as limiting the scope thereof.
Mode for invention
Example 1 .
Preparation of Metformin Hydrochloride modified release tablets (500 mg)
The dosage formulation for 100,000 (86.00 kg) Tablets of Metformin is prepared
using composition as stated in table:- 1 wherein Metformin is 50.0 kg and 1.20 kg of
Instamodel (A43D0004 1) are weighed, sifted in rapid mixture granuiator accordingly,
subsequently sieved to get uniformly granulated powder through 40 mesh screen. It is
noted that other size screen could be used to get simi lar results. Sieved Metformin with
above ingredients is granulated using water as granulating solvent .in rapid mixture
granuiator (RMG) . t is recommended that RMG should be at slow speed for min
fol lowed by high speed for 3-5 mins. Granulation step requires proper optimization of
water quantity and continuous monitoring to avoid heavy granulation. If required extra
water can be added gradually under continuous observation (to avoid heavy wet mass).
Generated wet mass is sieved using 2 screen (Multi-mill/ Fitzmi ll) dried in tray drier
(or Fluidized. bed dryer) at temperature not more than 50 C-5 5 C keeping loss on
drying at -2%. Subsequently sift the dried granule using #30 mesh sieve on vibratory
sifter and again sift on 1.0 mm screen at slow speed.
Further Mix the dried granule with 23.90 kg of Instamodel blend II (A43 D00042)
for 10 min in a suitable blender (octagonal blender).
Table 1
[63]
Coating ingredients
Instacoat Universal (ICU- 2.580 kg incl de 20 % extra v>compensate p or s
20 
3849) white H . losses
Purified water 20.S7 kg
Total 880J0
To promote efficient tablet punching further 0.50 kg of magnesium stearate and
0.40 kg of colloidal silicon dioxide sieved through 40 mesh screen is added to above
dried blended formulation in blender for subsequent 5 minutes. Final screened granules
are compressed using using 18.0 mm x 9.0 mm, capsule shaped, standard concave
punches (for 860 mg average weight) circular, standard concave circular punches using
Karnavati Tablet Compression M/C- 17 Stn. GM.P machine at hardness not less than
5-25 kg/cm 2. 7. The tablets are subjected to film coating using suitable film coating
system. Film coating is done with normal immediate release film coating system i.e.
Instacoat Universal (1CU - 3849 White) for weight gain of 2.0 - 2.5 % w w. Generated
dosage form tablets are then subjected to film coating using Instacoat Universal.
Coating composition is weighed in accordance with table 1 and 1% coating sus
pension is prepared in water with stirrer and mixed for about 45 minutes subsequently
it is passed through 80 mesh screen. Coating is preformed on dosage form using
INS TACOAT Pharma nD coater (6' pan) at 25 rpm with inlet temperature being 53
°C and bed temperature at 40 °C. coating was done using Imm nozzle sprayer with
peristaltic pump injecting coating suspension at the rate of Iml/min. Coated tablets are
then dried and packed as per pharmacopoieal guidelines.
Example 2
Dissolution Profile Evaluation of Metformin tablet
Metformin dose form dissolution study was performed. Drug dissolution profiles
of tablet prepared are measured by USP 35 dissolution test of rotating basket method
<7 1>. t is evident from standard state of the art that active ingredient may have its
own dissolution testing parameters which can be found in their respective monographs.
The active ingredient content for present invention is standardized for sustained release
profile is as per table 2:-
Medium: Phosphate buffer p 6.8; 1000 ml
Time interval: 1, 2, 3, 6 and 10 hour ( Test 1 & Test 2 of USP/NF 35, 20 12.)
Table 2
The mea values are shown Sample size is of 0 tablets
It was observed that it shows maximum absorbance at 284 n on Double Beam
UV-VIS.Spectrophotometer (UV 2700- Thermo Fisher Scientific).
METFORMIN IN VITRO %DRUG RELEASE USING INSTAMODEL
A43D00 41 AND A43D00042) DISSOLUTION COMPARISON
[75]
Citapin X 500 mg .N . 0712042 (Aug )
Metformin HC ER tab 500 mg using Instamodel Blend B.No RDIM BM038 (Avg )
6 10
Time in t
The drug dissolved profi le of the Reference products and Metform in ha ving dos -
strength of 500 mg using instamodel (A43D0004 1 and A43 D00042 ) formulations are
compared. The release exponents for the Reference and formulated Metformin is found
to be having similar modified release profile indicating a predominantly diffusion
based drug release mechanism.
Claims
A modified release solid pharmaceutical composition comprising Metformin, In
stamodel (A43D0004 1 and A43D00042), solvent, binder, lubricant, glidant op
tionally opacifiers, colorants.
The solid pharmaceutical composition of claim l , wherein Metformin can be in
form of salt, polymorphic form, its derivatives or mixture thereof.
The solid pharmaceutical composition of claim 1, wherein binder is selected
from polyvinyl polymers, Polyvinyl pyrrolidone 30 (PVP 30) and like.
The solid pharmaceutical composition of claim i , wherei n sol vent is selected
from water, isopropyl alcohol and like.
The solid pharmaceutical composition of claim 1, wherein lubricant is selected
from talc, magnesium stearate, stearic acid, sodium stearyl t n arate and com
bination thereof.
The solid pharmaceutical composition of cla im 1, wherein g lidant is selected
fro silicon di-oxide, colloidal sil icon dioxide a d there derivatives thereof.
A process for preparing Metformin tablet according o claim 1 comprising
a . Blending Instamodel (A43 D0004 ) with Metformi .
. . . b.. Thorough mixing and Wet granulation with binder and solvent
c . Sieving and drying
d . Again Blending with Instamodel (A43 D00042)
. e.. Addition of lubricant and glidant
. .. Final tablet compression
g . Optional film coating.
The solid pharmaceutical composition prepare using process for preparing
Metformin tablet according to claim 1 comprising
... a . Blending Instamodel (A43 0 0 ) with Metform in
b. Thorough mixing and Wet granu lation with binder and sol vent
c . Sieving and drying
d . Again Blending with Instamodel (A4 D00042)
e. Addition of lubricant and glidant
f. Final tablet compression
g . Optional film coating.