The present invention relates to a process for
preparation of a controlled release formulation for water
soluble drugs comprising, a water soluble active pharmaceutical
ingredient, such as herein described, a polysaccharide gum, a
lipophilic ingredient, an inert carrier and pharmaceutically
acceptable excipients, diluents and additives.
This application has been divided out of patent
application No.97CAL2001.
The novel combination of xanthan gum and glyceryl
behenate or other lipophilic ingredients provides the distinct
release profile of the present invention and reduces the
initial immediate release of the active pharmaceutical
ingredient.
Isosorbide -5- mononitrate is a vasodilator used for the
long term treatment of cardiac insufficiency. The development
of a controlled release dosage form is desirable as it
provides a uniform plasma concentration and avoids peak
plasma levels and the side effects associated with it.
However , isosorbide -5- mononitrate exhibits some typical
drawbacks such as high water solubility, the tendency to
generate high static electricity when processed alone in a
dry form and sublimation, which make it difficult to
formulate as a controlled release product.
US Patent No. 5,453,283 describes a solvent free orally
administered pharmaceutical preparation containing isosorbide
-5- mononitrate in delayed release form wherein the drug is
melt blended with water insoluble matrix former like
polyvinyl acetate and water soluble substances like lactose
as carrier, together with water insoluble substances like
silicon dioxide and talcum, wherein the talcum acts as a
mechanical obstacle, prolonging the diffusion path and
resulting in a slowing down of the active substance released.
US Patent No. 4,812,316 discloses stabilized isosorbide
-5- mononitrate tablets in retard form where the drug is
formulated in a stable solid solution with polyvinyl
pyrrolidone and retard effect is obtained by using Hydroxy
propylmethylcellulose, namely, methocel, either singly or in
various combinations.
WO 98/05306 discloses a controlled release tablet
formulation of isosorbide -5- mononitrate where the active
ingredient is granulated with a solution of a polyvinyl
pyrrolidone and the drug granules are blended with cellulose
based controlled release agent like Hydroxypropylmethyl
cellulose. The tablet formed can be placed in capsules along
with a second active ingredient such as aspirin.
US Patent No. 4,855,143 refers to a method of preparing
a controlled long acting pharmaceutical tablet containing a
drug and cellulose ether carrier base. The method discloses
mixing the drug and the cellulose ether base material such as
Hydroxypropylraethylcellulose and allowing the mixture to
stand for a period of time so as to allow bonding of the drug
and Hydroxypropylraethylcellulose and compressing portions of
the mixture into tablets.
US Patent No. 5,334,393 reveals a sustained release
tablet in which isosorbide -5- mononitrate in powder form
having different particle sizes is added to hydrophilic
swelling component such as Hydroxypropylmethylcellulose,
natural gums, alginic acid derivatives, etc. and at least one
diluent component.
US Patent No. 5,851,555 discusses controlled release
dosage forms for water soluble drugs containing the active
agents such as isosorbide -5- mononitrate, niacin, etc. inert
carrier, cellulosic polymer and a lipophilic ingredient. The
drug was processed using either solid dispersion or melt
blended with a lipophilic ingredient, milling the mass into a
granulate and then blending the granulate with a cellulosic
polymer such as Hydroxypropylmethylcellulose.
EP Patent No. 234670 discloses that xanthan gum has also
been used in controlled release tablet formulation.
US Patent NOS. 4,994,276, 5,728,143 and 5,135,757
describe the use of xanthan gum in combination with other
gums such as locust bean gum as controlled release agent.
Hence, various polysaccharide gums and cellulosic ethers
such as, Hydroxypropylmethylcellulose, carboxy methyl
cellulose, methyl cellulose, alginates, xanthan gums, etc.
are known and they have all been used as controlled release
agents. However, the "cellulosics" are Newtonian at low
shear rates and become pseudoplastic as the shear rate
increases, that is, they exhibit shear thinning.
Xanthan gun on the other hand is characterized in being
extremely pseudoplastic and having a high at rest viscosity,
displaying four tines higher viscosity conpared to
Hydroxypropylnethylcellulose at low shear rates, making it
alnost ideal as a controlled release agent. Xanthan gun also
displays viscoelasticity with high elastic modulus, which
provides erosion resistance to hydrated layer.
Lipophilic ingredients are used as a processing aid for
preparations involving a solid dispersion, or hot melt blend
technique and also act as sustained release agents. The
lipophilic ingredient generally used are fatty acid esters
such as glyceryl behenate, waxes, hydrogenated castor oil,
hydrogenated vegetable oil, cetyl alcohol, etc. Combinations
of cellulosic polymer such as Hydroxypropylmethylcellulose
together with lipophilic ingredient glyceryl behenate are
known (US 5,851,555).
The "cellulosic" based controlled release formulations
suffer from drawbacks such as a relatively fast drug release
profile of 10 to 12 hours for 60 rag isosorbide -5-
roononitrate tablet and immediate release within the first
hour of more than 25% which is normally associated with
Hydroxypropylmethylcellulose based formulations. The tablets
are also relatively large due to a large amount of matrix
forming material required.
The object of the invention is to provide a controlled
release formulation wherein the dose dumping of the drug
during the initial 60 minutes following administration is
minimized.
A further object of the invention is to provide a
controlled release formulation which exhibits a sustained
drug release profile over a longer period of time of 10 to 24
hours.
A still a further object of the invention is to provide
a controlled release dosage form wherein ratio of drug to
controlled release matrix agent is maintained below 1:2.55 and
wherein dosage form weight thereby size is kept relatively
small, thus making the formulation economical and easy to
swallow. The ratio of drug to controlled release matrix agent
in the prior art US 585155 is 1:2.75.
The present invention thus provides a controlled
release formulation for a water soluble drug comprising, a
water soluble active pharmaceutical ingredient, a
polysaccharide gum, a lipophilic ingredient, an inert
carrier and pharmaceutically acceptable excipients, diluents
and additives. The controlled release formulation for oral
administration includes matrix formulations such as matrix
tablets granules or pellets, or coated formulations such as
coated tablets granules or pellets, caplets, soft chews, gel
capsules and microcapsules.
Accordingly the present invention provides a process for
the preparation of controlled release formulation for a water
soluble drug comprising a water soluble active pharmaceutical
ingredient such as herein described (5 to 50% by weight), a
polysaccharide gum (5 to 50% by weight) , a lipophilic
ingredient (5 to 50% by weight) , an inert carrier and
pharmaceutically acceptable excipients, diluents and
additives comprising the steps of :
(a) mixing a water soluble active pharmaceutical ingredient,a
lipophilic ingredient and part or all of a polysaccharide
gum with diluents;
(b) hot melting of the mixture to form aggregates;
(c) cooling and granulating the aggregates;
(d) blending the granulates with the remaining polysaccharide
gum if any,and pharmaceutically acceptable excipients and
additives;
and
(e) compressing either alone or as a bilayer matrix
formulation with a second active pharmaceutical
ingredient or as a coated formulation or optionally as
caplets, soft chews, gel capsules and microcapsules.
The invention deals with controlled release formulations
and processes for making orally deliverable dosage forms
containing water soluble active pharmaceutical ingredients,
which processes overcome the processing difficulties
encountered with these active pharmaceutical ingredients, and
which controlled release formulations exhibit a sustained
drug release profile over a longer period of time of 10 to 24
hours wherein the immediate rapid release of the drug ( dose
dumping) during the initial 60 minutes following administration
is minimized. Further, the size is kept relatively small,thus
making the formulation economical and easy to swallow.
The present invention provides a controlled release
formulation for a water soluble active pharmaceutical
ingredient comprising, a water soluble active pharmaceutical
ingredient,a polysaccharide gum,a lipophilic ingredient
an inert carrier and pharmaceutically acceptable excipients,
diluents and additives.
Preferably, the formulations of the invention contain,
as essential ingredients, a water soluble active
pharmaceutical ingredient in the range 5 to 50%;
polysaccharide gum in the range 5 to 50%; and lipophilic
ingredient in the range 5 to 50%. Preferred ranges of the
essential ingredients are a water soluble active
pharmaceutical ingredient in the range 20 to 40%;
polysaccharide gum in the range 10 to 40%; and lipophilic
ingredient in the range 10 to 40%.
The novel combination of xanthan gum and glyceryl
behenate or other lipophilic ingredients provides the
distinct release profile of the present invention and reduces
the initial immediate release of the active pharmaceutical
ingredient.
Polysaccharide gum is selected from the group comprising
xanthan gum, gelIan gum, locust bean gum, gum caraya, etc.
The preferred polysaccharide gum is xanthan gum.
Xanthan gum exhibits a high affinity for water and
hydrates rapidly forming a gel layer around the formulation
thus minimizing the immediate rapid release of the drug
during the initial 60 minutes following administration, which
is a characteristic of Hydroxypropylmethylcellulose.
Isosorbide -5- mononitrate and the lipophilic ingredient
such as glyceryl behenate are melted together, when the
molten drug gets dispersed in the wax phase. The molten wax
is cooled, and the isosorbide -5- mononitrate crystalizes
first due to its high melting point (90°C). The isosorbide -
5- mononitrate crystals formed are surrounded by molten wax.
On further cooling, this molten wax forms a uniform coating
on the isosorbide -5-raononitrate crystals.
The invention provides drug release sustained over a
longer period of time of 10 to 24 hours upon oral
administration.
Further, as xanthan gum has a faster hydration rate and
is highly pseudoplastic and viscoelastic as compared to
cellulose, hence, less xanthan gum is required and the dosage
form weight and thereby size is kept relatively small with
less matrix forming ingredient, making the oral dosage form
of the formulation economical and easy to swallow.
The lipophilic ingredient is selected from a fatty acid
ester such as glyceryl behenate, hydrogenated castor oil,
hydrogenated vegetable oil, wax and cetyl alcohol either
alone or in combination with the fatty acid ester.
The preferred carriers are lactose, mannose, etc. The
ratio of the active agent to the carrier is in the range of
4:1 to 2:1.
Examples of water soluble active pharmaceutical
ingredients are isosorbide -5- mononitrate, isosorbide
dinitrate, venlafaxine hydrochloride, propranolol
hydrochloride, metformin hydrochloride, diltiazem
hydrochloride their combinations and other pharmaceutically
acceptable water soluble active ingredients thereof.
Lubricants such as stearic acid, magnesium stearate, etc. nay
be used.
Colorants such as pigments, lakes, iron oxide, etc. may
be used.
The formulation thus prepared may be compressed alone as
a tablet or may be compressed as a bilayered tablet along
with a second active ingredient. One of the suitable second
active ingredients is Aspirin. Aspirin in the form of
"Encapsulated Aspirin" (available under the brand name
"Gattaprine" from Gattafosse) may also be used which
minimizes the side effect such as gastric irritation
associated with Aspirin. It also enhances the stability of
Aspirin.
The following examples are included by way of
illustration and do not in any way restrict the scope of the
invention.

The ingredients are mixed in a planetary mixer for 30
minutes. Heated to 70 to 100°C and mixed for 30 minutes. The
hot mass is cooled and milled to get a particle size of # 16.

The tablet was compressed at 247.2 rag using 8.7 mm round
punches. The hardness may be in the range of 50 to 150 N,
preferably between 75 to 110 N.
The in vitro drug release of the tablets was studied by
employing standard dissolution techniques in a USP Apparatus
(type 1) at 75 rpm with 1000 ml of distilled water at 37.5*C.
The results are as follows:

The results indicate that the tablets made according to
the invention, reduce dose dumping during the initial hour as
well as provide drug release over 10 to 15 hours.
The dissolution studies compared the properties of the
hot melt blend tablets of the present invention to the
isosorbide -5- mononitrate controlled release tablets
prepared using Hydroxypropylmethylcellulose as controlled
release agent.
The isosorbide -5- mononitrate controlled release
tablets using Hydroxypropylmethylcellulose as controlled
release agent were prepared as per formulation given below:
Ingredients mg/tablet
Isosorbide -5- mononitrate: 75 mg
Lactose preraix (4:1)
Lactose 175 mg
Methocel - K4M (Hydroxypropylmethylcellulose K4M) 85 mg
Methocel E15LV (Hydroxypropylmethylcellulose E15LV) 15 mg
Magnesium Stearate 6 mg
Talc 4 mg
The isosorbide -5- mononitrate controlled release
tablets using hydroxypropylmethylcellulose as controlled
release agent were prepared as given below:
1. Sift isosorbide -5- mononitrate, lactose and Methocel
K4M (Hydroxypropyl methylcellulose K4M) through # 40 mesh and
mix in a planetary mixer.
2. Dissolve Methocel E 15LV (Hydroxypropy1 methylcellulose
E15LV) in suitable solvent (isopropyl alcohol: methylene
chloride 1:1) and granulate the powder mix in step 1 with the
resulting solution.
3. Mill the resulting wet mass through 12.6 mm sieves and
dry.
4. Size the dried granules to get # 20 mesh granules.
Lubricate the granules with magnesium stearate and talcum.
5. Compress the granulate on a rotary tablet compression
machine using 10.3 mm round punches at 360 mg/ tablet weight.
The in vitro release profile of the hot melt blend
tablets of the present invention was compared to the
isosorbide -5- mononitrate controlled release tablets
prepared using hydroxypropylmethylcellulose as controlled
release agent (as per formulation given above).
The results are as given below:

From the result it is apparent that the invention
reduces the drug release during the first hour, sustains drug
release upto 24 hours and provides for a smaller size.
Example 2
The granulate from Example 1 may be compressed as a
bilayered tablet with a second active pharmaceutical
ingredient such as Aspirin.
I. Isosorbide - 5- mononitrate fraction:
All ingredients of the Aspirin fraction are sifted and.
blended together. Isosorbide -5- mononitrate fraction
(Average weight: 247.2 ng) and Aspirin fraction (Average
weight: 180.0 mg) are compressed as bilayered tablet using
9.56 nun round punches on a Press Kota Cadmach machine.
WE CLAIM :
1. A process for the preparation of controlled release formulation for a
water soluble drug comprising a water soluble active pharmaceutical
ingredient such as herein described (5 to 50% by weight), a polysaccharide
gum (5 to 50% by weight), a lipophilic ingredient (5 to 50% by weight), an
inert carrier and pharmaceutically acceptable excipients, diluents and
additives comprising the steps of:
(a) mixing a water soluble active pharmaceutical ingredient, a
lipophilic ingredient and part or all of a polysaccharide gum
with diluents;
(b) hot melting of the mixture to form aggregates;
(c) cooling and granulating the aggregates;
(d) blending the granulates with the remaining polysaccharide gum if
any, and pharmaceutically acceptable excipients and additives;
and
(e) compressing either alone or as a bilayer matrix formulation with a
second active pharmaceutical ingredient or as a coated
formulation or optionally as caplets, soft chews, gel capsules and
microcapsules.
2. The process as claimed in claim 1, wherein the active pharmaceutical
ingredient is selected from the group consisting of isosorbide -5-mononitrate,
isosorbide dinitrate, venlafaxine hydrochloride, propranolol hydrochloride,
metformin hydrochloride and diltiazem hydrochloride.
3. The process as claimed in any of the preceding claims, wherein the
percentage range by weight of the water soluble active pharmaceutical
ingredient in said composition is 20 to 40%.
4. The process as claimed in any of the preceding claims, wherein the
percentage range by weight of the lipophilic ingredient in said composition is
10 to 40%.
5. The process as claimed in any of the preceding claims, wherein the
lipophilic ingredient is the fatty acid ester glyceryl behenate.
6. The process as claimed in any of the preceding claims, wherein the
polysaccharide gum is selected from the group consisting of xanthan gum,
gellan gum, locust bean gum and gum caraya.
7. The process as claimed in any of the preceding claims, wherein the
percentage range by weight of the polysaccharide gum in said composition is
10 to 40%.
8. The process as claimed in any of the preceding claims, wherein the
lipophilic ingredient is selected from the group consisting of a fatty acid ester,
hydrogenated castor oil, hydrogenated vegetable oil, wax and cetyl alcohol.
9. The process as claimed in any of the preceding claims, wherein aspirin
is used as the second active pharmaceutical ingredient.
10. A process for the preparation of a controlled release formulation for a
water soluble drug substantially as herein described particularly with reference
to the examples.

The present invention discloses for a process for preparation of a controlled
release formulation for water soluble drugs comprising, a water soluble active
pharmaceutical ingredient, a polysaccharide gum, a lipophilic ingredient, an inert
carrier and pharmaceutically acceptable excipients, diluents and additives;
comprising the steps of (a) mixing a water soluble active pharmaceutical ingredient,
a lipophilic ingredient and a part or all of the polysaccharide gum with diluents;
(b) hot melting of the mixture to form aggregates; (c) cooling and granulating the
aggregates; (d) blending the granulates with the remaining polysaccharide gum
and pharmaceutically acceptable excipients and additives; and (e) compressing
either alone or as a bilayer matrix formulation with a second active pharmaceutical
ingredient or as a coated formulation or optionally as caplets, soft chews, gel
capsules and microcapsules.