FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION
(See section 10]
1. Title of the invention: "Supersaturated soft gelatin capsule formulation and
Process for preparation thereof
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashta, India.
3. The following specification describes the invention:

FIELD OF THE INVENTION
The invention relates to soft gelatin capsule formulation for oral administration comprising supersaturated drug matrix obtained using solubilizer, viscosity enhancing agent and optionally at least one pharmaceutically acceptable excipient The formulation is devoid of any stabilizing agent. The invention further relates to process of preparation for such supersaturated soft gelatin capsule formulation which exhibits desired physical and chemical stability, BACKGROUND OF THE INVENTION
Pharmaceutical compositions are available in many forms including liquid and solid pharmaceutical formulations. But soft gelatin capsules provide dosage forms that are superior to conventional oral dosage forms in terms of improved bioavailability and better patient compliance. Soft gel capsules get easily dissolved and absorbed in stomach, thus offer attractive means of administering medicaments. Soft gel capsules are better than other liquid dosage forms because liquid formulation containing medicament may have unacceptable or unpleasant taste. They are further advantageous because of ease of administration, accuracy of dosage and avoid the spillage during traveling situations. Especially pharmaceutical compositions meant for treating common ailments such as symptoms of the moderate to severe pain (migraine, Rheumatoid) can be administered in the form such as soft gelatin capsules for the purpose.

Stability of such formulations is a major concern while formulating the compositions. There exists prior art outlining soft gelatin capsules comprising a hydrophilic suspension fill that contains pharmaceutically active agent along with a stabilizing agent to achieve physical and chemical stability.
US Patent Application US2005/0249802 is directed to pharmaceutical compositions which comprise highly concentrated pharmaceutical active and a stabilizing agent suspended in a solvent. These pharmaceutical compositions are suitable for encapsulation within soft gelatin capsules having improved stability and used to treat cold and/or influenza-like symptoms.
Research article by Karunakar S. et al; entitled "Effect of acetaminophen concentration, as a hydrophilic suspension fill, on the stability of soft gelatin capsules" teaches that soft gelatin capsules comprising a high dose of acetaminophen can exhibit deteriorating physical changes such as seam widening, softening, sticking, and increase in the gelatin shell weight.
Another US Patent No US7029698 provides for an oral pharmaceutical composition adapted for use in capsular dosage forms comprising about 42% acetaminophen and a lactate salt alone or in combination with an acetate salt. Compositions of the invention exhibit improved solubility characteristics of the active ingredient per given fill volume, thereby permitting the use of smaller capsule sizes to deliver a given effective dose of the active ingredient. However, such formulation is

comprised of less than 50% of the active and is not patient compliant with respect to frequency of administration for desired therapeutic effect.
European Patent Application EP0152292 describes a gelatin capsule for oral administration comprises a gelatin shell substantially encapsulating a physiologically compatible fill material, the fill material comprising an effective dosage amount of acetaminophen, a vehicle for acetaminophen, a surfactant and a modifier for the vehicle, the drug being substantially evenly distributed through the vehicle; (b) the surfactant is of a type that is physiologically solubile and is in solution in the vehicle; and (c) the viscosity modifier is present in an amount equal to or greater than the amount necessary to gel the vehicle. In this type of composition, around 50% of acetaminophen is encapsulated in soft gelatin capsule with respect to total weight of the formulation.
Soft gelatin capsule formulation containing a suspension of active is disclosed in US Patent No. 5002777. This patent relates to the encapsulation of calcium carbonate suspension particles of specific size and shape, wherein the capsules are suitable for use as an antacid. Drug suspension is compatible with gelatin shell and thus results into stable antacid formulation.
US Patent No. 5071643 relates to a solvent system for enhancing the solubility of an acidic, basic, or amphoteric pharmaceutical agent to produce solution suitable for soft gel filling or two piece encapsulation. The solvent system comprises polyethylene glycol containing 0.2-1.0 mole equivalents of an ionizing agent per

mole equivalent pharmaceutical agent and 1-20% water. Glycerin or
polyvinylpyrrolidone may be added to further enhance the solubility of certain drugs.
Although this invention describes highly concentrated soft gel formulations
containing from 20 to 80% of the active, these formulation contain a stabilizing
agent or preservative like benzyl alcohol.
US Patent No 5484606 describes process for reducing precipitation of difficultly
soluble pharmaceutical active in a mixture of polyethylene glycol, polyvinyl
pyrrolidone and propylene glycol. However, by this process only about 1 to 40 % of
active is incorporated in the soft gelatin capsule form.
WO 2009066146 relates to a stable pharmaceutical soft gelatin capsule formulation
containing at least one sparingly soluble active (25 to 50%) and a solvent system
which is comprised of solvent, co-solvent, solubilizer, surfactant, aqueous solution of
alkali and crystal growth inhibitor. This composition makes use of aqueous alkali
solution which imparts stability to the formulation. But use of such alkali solution
gives rise to impurities with certain actives.
Despite the state of the art in describing soft gelatin capsules filled with liquid
pharmaceutical compositions comprising concentrated active ingredients, there is
still a need to design the stable formulation, free of stabilizer, which will be safe for
administration and exhibits enhanced patient compliance.
Jt has been found by present inventors that the supersaturated drug matrix, which
incorporates more than 55% of the active, can be encapsulated within the soft gelatin

capsules. Such highly concentrated active ingredients encapsulated within soft gelatin capsules can, however, have a tendency to exhibit physical and chemical instability in the form of hydrolyzation, premature dissolution, seam widening, softening, sticking, increase shell weight, and/or tanning (hardening). Further higher strength of active ingredients may require their incorporation into large size of the capsules, affecting ease of administration.
With rigorous experimentation, the researchers of the present invention have formulated soft gelatin capsules which incorporate more than 55% of active in supersaturated hydrophilic matrix. It has been found that the higher strength of active in the present invention provides for highly stable supersaturated drug matrix encapsulated within the soft gelatin capsules with the acceptable capsules size. The formulation does not make use of any stabilizing agent, still renders the formulation physically and chemically stable. The process for preparation of such formulation is simple, robust, economically viable and makes use of conventional equipments. SUMMARY OF THE INVENTION
The present invention is directed to a pharmaceutical composition that comprises (a) from about 55% to about 80% by weight of a active in the form of supersaturated matrix; (b) from about 18% to about 35% by weight of a low molecular weight hydrophilic solubilizer; and (c) from about 1.0% to about 5% by weight of a cosolvent; (d) from about 1.0% to about 5% by weight of a viscosity enhancing agent

with about 0.1% to 0.5% of pharmaceutically acceptable excipient wherein the composition is encapsulated within a soft gelatin capsule. DETAILED DESCRIPTION OF THE INVENTION
The pharmaceutical compositions of the present invention are soft gel capsule formulations, wherein supersaturated drug matrix is encapsulated within a soft gelatin shell. These soft gelatin capsules are especially effective in the prevention and/or treatment of pain-like symptoms.
The terms "formulation", "dosage form" and "composition" are used interchangeably herein and denote soft gel capsule formulation for oral administration of the present invention comprising a therapeutically effective amount of active agent, or a pharmaceutically acceptable salt thereof, which is dispersed in a matrix of solubilizer and viscosity enhancing agent along with at least one pharmaceutically acceptable excipient. The term "therapeutically effective amount" as used herein refers to a nontoxic but sufficient amount of the active agent required to provide the desired therapeutic, preventive and/or beneficial effect. The amount of active agent that is "effective" will vary from subject to subject, depending on the age, type of disorder and general condition of the individual, and the like. Thus, it is not always possible to specify an exact "effective amount." However, an appropriate "effective amount" in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

The term "supersaturated drug matrix" is to refer to highly viscous solutions comprising pharmaceutical active (more than 55% by weight of composition) along with viscosity enhancing agent and one more pharmaceutically acceptable excipient, wherein the active agent is dispersed and dissolved partially. Further this drug matrix is free of any stabilizing agent.
The term "treatment of pain-like symptoms" as used herein refers to treating the onset, duration, and/or after-effect of migraine, rheumatoid like symptoms. In other words, "treatment of pain-like symptoms" includes preventing the onset of migraine and rheumatoid like symptoms, and alleviating pain-like symptoms. As used herein "pain-like symptoms" refer to symptoms typically associated with mild to severe pains. These symptoms include, but are not limited to head and joints and also fever, body aches and other known pain-like symptoms. Pharmaceutical Active
The pharmaceutical compositions of the present invention comprise a pharmaceutical active. The pharmaceutical active can be included in the compositions either as an individual active ingredient or the mixture of more than one active. The pharmaceutical active is preferably effective in the prevention and treatment of painlike symptoms.
The pharmaceutical active is included in the pharmaceutical compositions of the present invention as a supersaturated matrix.

As per one of the embodiments of the present invention, "supersaturated drug matrix" is obtained by dissolving high concentration of pharmaceutical active at high temperature in matrix of solubilizer, viscosity enhancing agent and at least one pharmaceutically acceptable excipient, to get highly viscous solution. According to one more embodiment of the invention, the pharmaceutical composition is comprised of the active concentration from about 50% to about 85%, more preferably from about 55% to about 80%, by weight of the pharmaceutical composition.
Specific non-limiting examples of analgesics, antipyretics, and anti-inflammatory agents suitable for use as a highly concentrated pharmaceutical active herein include acetaminophen, aspirin, sodium salicylate, salicylamide, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, ketorolac, nabumetone,
naproxen, piroxicam, caffeine, ketorolac, indomethacin, meclofenamic acid, COX-2 inhibitors such as valdecoxib, celecoxib and rofecoxib, and the like or mixtures
thereof.
Solubilizer
Examples of solubilizer suitable for use herein include polyethylene glycols - PEG
400 and PEG 600, propylene glycols. Polyethylene glycols are the preferred
solubilizer materials.
Specific examples of preferred polyethylene glycols include those polyethylene
glycols which corresponds to the general formula: H(OCH2CH2)n OH wherein n has

an average value of from 4 to 35, preferably from 5 to 30, more preferably from 5 to 20. These materials are polymers of ethylene oxide, and are also known as polyethylene oxides, polyoxyethylenes, and PEGs. The polyethylene glycols are typically designated by both their average molecular weight range and their average "n" value as specified in the above general formula. For example, polyethylene glycol 400, which is also known by the CTFA designation of PEG-8, has a number average molecular weight range (Mn) of from about 380 to about 420 and an average n value of between 8.2 and 9.1. The number average molecular weight (Mn) of the polyethylene glycols can be determined by known titration procedures used to determine the number of molecules having hydroxy-end groups wherein the Mn is calculated based on the weight of a given polyethylene glycol divided by the number of hydroxy-end group-containing molecules within the polyethylene glycol polymer. Specific examples of polyethylene glycols suitable for use herein include those polyethylene glycols designated as PEG-5, PEG-6, PEG-8, PEG-12 and mixtures thereof. Preferred are those polyethylene glycols which have a number average molecular weight of from about 190 to about 700, most preferably 400 and 600. Specific examples of the most preferred polyethylene glycols include, PEG-8 wherein n has an average value of about 8; PEG-12 wherein n has an average value of about 12.

Viscosity enhancing agent
This agent is used for enhancing viscosity of the solubilizer system so as to incorporate more amount of drug in the hydrophilic matrix. A viscosity modifier is capable of gelling the solubilizer vehicle like polyethylene glycol. The viscosity modifier must be present in an amount equal to or greater than the amount necessary to substantially gel the vehicle. Viscosity enhancing agent like vinyl derivatives especially polyvinyl pyrrolidone is preferred. Another viscosity modifying agent is acrylic polymer such as Carbopol 934-P or alternatively fumed silica that serves both as a gelling agent and as a glidant for the fill material during the manufacturing process. Though vinyl derivatives are preferred, other viscosity modifiers may be used that are capable of gelling the vehicle. Pharmaceutically) acceptable excipients
Other excipients such as cosolvent, glidant, antiadherant may be used so as to aid the preparation of soft gelatin capsules containing supersaturated drug matrix. Process of Preparation
The pharmaceutical compositions of the present invention may be prepared by any known or otherwise effective technique suitable for providing a pharmaceutical composition that provides a therapeutic benefit, especially a therapeutic benefit in the prevention and treatment of symptoms associated with moderate to severe pain. A typical preparation of the pharmaceutical compositions of the present invention involves heating a solution of solvents such as PEG 400/PEG600 or combination and

propylene glycol to 70°C, and povidone and one more pharmaceutically active agent were dissolved in it then forming a hot wet mass by adding pharmaceutical active ingredient and continue the heating up to 150°C to become hot wet matrix thereafter decreasing the temperature to feasible for encapsulation.
The resultant matrix is then encapsulated within a soft gelatin mass using encapsulation machine at appropriate temperature condition. Method of Use
The pharmaceutical compositions of the present invention are encapsulated within soft gelatin capsules for the administration of supersaturated drug matrix. The amount of pharmaceutical active ingredients that are administered will depend upon factors such as the type of pharmaceutical active such as acetaminophen and the desired treatment response, however, typically from about 500 mgs to about 1000 mgs of supersaturated drug matrix is administered per soft gelatin capsule. It has been found that the pharmaceutical compositions of the present invention can be administered using soft gelatin capsules such that increased concentration of pharmaceutical active can be administered using one dosage regimen as compared to typical dosage regimens of two or more capsules.
A preferred method of using the pharmaceutical compositions of the present invention involves the administration of soft gelatin capsules to treat and prevent symptoms associated with the moderate to severe pains. Typically, one soft gelatin capsule comprising from about 500 mgs to about 1000 mgs of pharmaceutical active

like acetaminophen is administered one to four times per day to effectively prevent
and treat moderate to severe pain-like symptoms.
EXAMPLES
The following examples further describe and demonstrate embodiments within the
scope of the present invention. The examples are given solely for the purpose of
illustration and are not to be construed as limitations of the present invention, as
many variations thereof are possible without departing from the spirit and scope of
the invention. All exemplified concentrations are weight-weight percents, unless
otherwise specified.
Example 1: Preparation of supersaturated drug matrix

Ingredients Qty in mg
Acetaminophen 650
Polyethylene glycol 400 160
Propylene glycol 20
Polyvinyl pyrrolidone K30 17
Colloidal silicon dioxide 3
Total 850
Procedure:
Polyethylene glycol and propylene glycol mixture was heated to 70°C, to which povidone and one more pharmaceutically acceptable excipient like colloidal silicon dioxide agent was added and mixed well. To this hot wet mass pharmaceutical active ingredient such as acetaminophen was added and the heating was continued up to 150°C thereafter decreasing it to the temperature feasible for encapsulation. The resultant matrix is then encapsulated within a soft gelatin mass using encapsulation machine at appropriate temperature condition.

Preparation of soft gelatin capsule shell for encapsulation of supersaturated drug matrix

Soft gelatin capsules shell 650mg lOOOmg
S.No. Ingredients Qty/ Capsule (mg) Qty/ Capsule (mg)
1 Gelatin 240 254.4
2 Glycerin 75 79.5
3 Liquid Sorbitol (70%) (Non-Crystalline) 40 42.4
4 Ponceau 4R supra 0.1 0.106
5 Quinolline Yellow supra 0.05 0.053
6 Titanium Dioxide 1.25 1.325
7 Purified water 143.6 152.216
Total 500 530
Procedure:
Glycerin and liquid sorbitol solution along with water were added in gelatin melting tank and heated up to 70°C. Gelatin was then added into gelatin melting tank with continuous mixing and heated to form gel mass. The colors and opacifying agent (Titanium dioxide) were milled by using colloidal mill and added to gelatin melting tank followed to which the contents were mixed. Vacuum was applied to gelatin mass to make it free from air bubbles and gelatin mass was unloaded into gelatin holding tank. Example 2: Preparation of Acetaminophen soft gelatin capsules

Ingredients Qty in mg
Acetaminophen 650
Polyethylene glycol 400 360
Propylene glycol 20
Polyvinyl pyrrolidone K30 17
Colloidal silicon dioxide 3
Total 1050

Procedure:
Acetaminophen capsules were prepared in the same way as described for Example 1. Stability Study for Acetaminophen Soft Gelatin Capsules 650mg (62% active) The formulation was appropriately packed and stored at 25 C ± 2 C and RH 60% ± 5% for 6 months and evaluated for disintegration time, dissolution and assay.

Testing parameter Specifications Initial 3 Month 6 Month
Disintegration time (min) Not more than 60 minutes 17 18 20
claim) 70.0% of the label claim dissolves in 60 minutes 945 95-3 92.1
Related substances (%, w /w)
4-Aminophenol Not more than 0.20 Below detection limit Below
detection
limit Below detection limit
4-Chloroacetanilide Not more than 0.20 Below detection limit Below
detection limit Below detection limit
Unknown individual impurity Not more than 0.50 0.11 0.13 0.16
Total unknown impurities Not more than 1.00 0.23 0.28 0.34
Assay (% Label claim) 90.0 to 110.0% of the label claim 100.2 99.5 99.1
The above data indicates that the product is stable for 6 Months at 25°C ± 2°C and RH 60% ± 5%. These soft gelatin capsules exhibit desired dissolution profile and physical and chemical stability over extended time period.

Example 3: Preparation of Acetaminophen soft gelatin capsules

Ingredients Qty in mg
Acetaminophen 650
Polyethylene glycol 400 260
Propylene glycol 20
Polyvinyl pyrrolidone K30 17
Bentonite 3
Total 950
Example 4: Preparation of Acetaminophen soft gelatin capsules

Ingredients Qty in mg
Acetaminophen 650
Polyethylene glycol 400 460
Propylene glycol 20
Polyvinyl pyrrolidone K30 17
Colloidal silicon dioxide 3
Total 1150
Example 5: Acetaminophen soft gelatin capsules 1000mg

S. No. Ingredients Qty/ Capsule (mg)
1 Acetaminophen 1000
2 Macrogol - 400 446.154
3 Propylene glycol 84.615
4 Povidone K30 15.385
5 Colloidal Silicon Dioxide 7.692
6 Purified water 61.538
Total 1615.384
Same procedure as used for example 1 was used to get supersaturated soft gelatin capsules.

The formulation was orange to reddish coloured, opaque, oblong shaped soft gelatin
capsules containing white to pale reddish colored viscous paste.
Stability Study for Acetaminophen Soft Gelatin Capsules 1000mg (62%active)
The formulation was packed accordingly and stored at 25°C ± 2°C and RH 60% ± 5% for 6 months and evaluated for disintegration time, dissolution and assay.

Testing parameters Specifications Initial 3 Month •6 Month
Disintegration time (min) Not more than 60 minutes 16 16 17
Dissolution (% Label claim) Not less than 70.0% of the label claim dissolves in 60 minutes 96.5 95.1 93.7
Related substances (%, w w)
4-Aminophenol Not more than 0.20 Below detection limit Below detection limit Below
detection limit
4-Chloroacetanilide Not more than 0.20 Below
detection limit Below detection limit Below
detection limit
Unknown individual impurity Not more than 0.50 0.13 0.16 0.15
Total unknown impurities Not more than 1.00 0.21 0.28 0.33
Assay (% Label claim) 90.0 to 110.0% of the label claim 99.8 99.5 99.4
The above data indicates that Acetaminophen Soft Gelatin Capsules lOOOmg are stable for 6 Months at 25°C ± 2°C and RH 60% ± 5%. These soft gelatin capsules exhibit desired dissolution profile and physical and chemical stability over extended time period.

Example 6: Soft Gelatin Capsules (combination of Ibuprofen, Paracetamol, Caffeine)

S.No. Ingredients Qty/ capsule (mg)
1. Ibuprofen 400.00
2. Acetaminophen 500.00
3. Caffeine anhydrous 33.00
4. Macrogol - 600 / Poly ethylene glycol 600 450.00
5. Propylene glycol 30.00
6. Povidone K30 37.00
Total 1450.00
Procedure:
Polyethylene glycol and propylene glycol were mixed in a tank fixed with overhead stirrer and heated the solution upto 55°C to 65°C. Povidone was added into the tank slowly and dissolved with continuous heating. Caffeine anhydrous was dispersed well in above mixture & portion of Acetaminophen was added with continuous stirring at fast speed and with continuous heating to get clear viscous solution. Remaining quantity of Acetaminophen was dispersed with continuous stirring at fast speed and with continuous heating to become homogeneous white mixture. Above mixture was milled using colloidal mill to get fine white mass and collected in a medicament preparation tank and allowed the solution cool to 60°C. Ibuprofen was finally added slowly into medicament preparation tank with continuous mixing. This drug mixture was encapsulated in gelatin mass to get soft gelatin capsules of drug combination.

We claim,
1. A pharmaceutical soft gel capsule formulation for oral administration comprising:
a. therapeutically effective amount of active or pharmaceutically acceptable
salt thereof;
b. solubilizer
c. viscosity enhancing agent, and
d. at least one more pharmaceutically acceptable excipient;
wherein the formulation is devoid of any stabilizer and exhibits physical and chemical stability.
2. The pharmaceutical soft gel capsule formulation of claim 1, wherein the drug is encapsulated within soft gel capsule in the form of supersaturated matrix comprised of solubilizer, viscosity enhancing agent and at least one more pharmaceutically acceptable excipient.
3. The pharmaceutical soft gel capsule formulation of claim 2, wherein drug is present in the amounts from about 50% to 85% by weight of the composition to form the supersaturated drug matrix, most preferred amount being 55% to about 80%.
4. The pharmaceutical soft gel capsule formulation of claim 1, wherein drug present in supersaturated matrix may be selected from analgesics, antipyretics, and anti-inflammatory agents such as acetaminophen, aspirin,

sodium salicylate, salicylamide, diclofenac, diflunisat, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, ketorolac, nabumetone, naproxen, piroxicam, caffeine, ketorolac, indomethacin, meclofenamic acid and COX-2 inhibitors such as valdecoxib, celecoxib and rofecoxib, and the like or mixtures thereof.
5. The pharmaceutical soft gel capsule formulation of claim 1, wherein the solubilizer used is hydrophilic solubilizer selected from polyethylene glycol (PEG), polyethylene oxides, polyoxyethylene, preferably PEG-8, PEG-12, and the like or mixtures thereof.
6. The pharmaceutical soft gel capsule formulation of claim 1, wherein the viscosity enhancing agent used is selected from vinyl polymers such as polyvinyl pyrrolidone.
7. The pharmaceutical soft gel capsule formulation of claim 1, wherein at least one more pharmaceutically acceptable excipient may be selected from cosolvent, glidant, antitacking agent, and the like or mixtures thereof.
8. A process for preparing soft gel capsule formulation for oral administration, comprising:

(a) Heating the mixture of solubilizer and cosolvent to high temperature such as 70°C
(b) Adding the drug along with viscosity enhancer to above mixture and continuing heating up to 150°C, to prepare hot supersaturated drug matrix;

(c) Further mixing drug matrix with pharmaceutically acceptable excipient, if any, and encapsulating supersaturated drug matrix in soft gelatin capsule
9. Pharmaceutical Soft gel capsule formulation comprising supersaturated drug matrix as described in the example.