BRPI0708386A2 - Preparation method for modern stable composition including aceclofenac and 2,5-di-o-methyl-1,4: 3,6-dianhydro-d-glucitol as a solvent and method of use - Google Patents

Abstract

Preparation Method for modern Stable composition that includes Aceclofenac and 2,5-Di-O-methyl-1,4: 3,6-Dianhydro-D-Glucitol as Solvent and Method of use "endo a stable composition that includes Aceclofenac and 2,5-di-O-methyl-1,4: 3,6-dianhydro-D-glucitol or higher alkyl derivative of 2,5-di-O-aryl-1,4: 3,6-dianhydro- D-glucitol as a solvent with or without other excipients Aceclofenac is present in an amount of 1mg to 250mg / ml of 2,5-di-O-aryl-1,4: 3,6-dianhydro-D-glucitol in the composition.

Description

Patent Descriptive Report "Preparation Method for Modern Stable Composition Including Aceclofenac and 2,5-Di-0-Methyl-1,4: 3,6-Dianhydro-D-Glueitol as a Solvent and Method of Use"

Field of Invention

The present invention relates to modern compositions including combinations having anti-inflammatory activity and preparations thereof, using combination modern liquid form and the method of its use for the local parenteral oral delivery for use in mammals. More particularly the present invention resides in providing a stable composition including Acclofenac and 2,5-di-O-methyl-1,4: 3,6-dianhydro-D-glucitol as a solvent.

There are various drugs available in the market like nonstcroidal antiinflammatory drugs. These drugs include combinations such as aspirin, pyrazolones such as phenylbutazonam fenenamates as mefanamic acid and similar combinations, riimcsulide, diclofenac, aceclofenac, piroxicam, meloxicam, diflunisal, acetic acid derivative such as indomethacin, etodolacde sulindac, kprofen acid, kprofen derivative, kprofen flurbiprofen, carboprofen, ketoprofen, naproxen and oxicams. The mechanism of action of such drugs involves reducing the inflammatory process by inhibiting COX-me and COX-II pathways. These drugs are used for the common pain caused due to inflammatory joint diseases like rheumatic arthritis or osteoarthritis.

The formulation of the above drugs is mainly available in oral dosage forms or few parenteral drugs. The known parenteral formulations are dediclofenac, meloxicam and nimesulide, are made very poorly formulating injectables of other drugs like Aceclofenac, mefanamic acid derivatives, ketorolac, ketoprofen. By whether these drugs are having a poor solubility or even if solubilised, difficulties are encountered. and administration at a dose that is too low to show beneficial effect. The analgesic activity of such drugs is very good but achieving clinical analgesic parenteral formulations is always beneficial.

There are several prior art formulations for carboxymethyl acid 2 - {(2,6dichlorophenyl) amino] benzenacetic ester are reported. However this patent informs modifications to reach the limitations of solubility and poor bioavailability. US Patent 2004097434 teaches joining de Aceclofenac with various macrolides for the treatment of inflammatory disease and conditions but does not teach use of parenteral formulation.

Withdrawal of various COX-II in inventive market was caused by side effects on cardiovascular system and one by one all COX-II are under cloud and consequently attention is taken to safer acetic acid derivative. Diclofenac is available in injectablc form with Diclofenacin dose which concentration of 75 mg dissolved in 3ml.

Consequently, the patient is given 3ml injection into the muscles for pain relief. The high volume amount of liquid. 3ml for therapy are painful for patients and also cause difficulties for doctors or nurse. The concentrated solution of such an injection is not available in a small volume. This injection is indicated for Rheumatoid arthritis pain in a chronically ill patient who requires repeated injections and also for post operative pain.

Diclofenac is reported to cause epigastric pain, nausea, vomiting, headache, seizures, drowzeness, tinnitus, coma, disorientation, metabolic acidosis, acute hepatic failure, acute renal failure, dyspepsia, depression, syncope, blurred vision, melaena, pruritus ani, thrombocytopenia. Further on, Diclofenac is contraindicated in liver disease if taken orally. It is also reported for causing sodium and water retention with an increased degastrointestinal risk that bleeds in liver disease. (Ref. Internet for Diclofenac Sodium (parentcral), Web based Drug Database (1.07 Linux) - script / Safe Fern.

Aceclofenac is another molecule in the same category and is available in tablet and cream form. However, no parenteral form is known or commercially available or even available, the source of such is not known. One such reference is available on Medline search in Spanish and refers to which injections cause necrolysis. (Arzemeittal forsch 1991, 41 (12) 1265-76 Pharmacology). Other reference shows delyophilized composition of Aceclofenac and separate composition of debenzyl alcohol, polyethylene glycol and water to be reconstituted and therefore no reference is available for ready to use injection.

The effect of necrolysis on tableted formulation of Acclofenac is not observed but absorption of Aceclofenac is always a matter of concern when taken by oral numbers and consequently it is available to improve oral profiling and kinetic absoprtion. Such patents include ElJA 20040235803Al - Dispersible formulation of an anti-inflammatory agent; USA 20040180961 AlCompositions and preparation methods for bioavailableAceclofenac oral dosage forms; USA 20040185100A1 -Stabilized pharmaceutical composition including an extended release non-steroidal anti-inflammatory agent and an immediate release prostaglandin;

US20040072798A1 - Compositions including cnon-releasing drug cyclodextrins.

It is evident from the publication WO 03/004060 that Aceclofenac has a low solubility and thus dissolution in gastric fluid and digestive fluid absorption is leading to delayed lower availability and consequently several attempts have been made to achieve better absorption.

WO 90/06746 also describes fat soluble drug emulsion with emulsifier, water soluble carbohydrate and distilled water.WO 03/004060 and JP H08-157362A Further states about its emulsifier and emulsifier circumstability. Thus from the above available literature it can be seen that There is no adequately available dosage form of Aceclofenac injections and consequently there is a consistent need for it in acute pain conditions.

Present inventors have prepared clear injection and other formulations which are safe, stable, effective now for non-toxic Aceclofenac by use of a selective solvent.

The composition of such inventive process does not utilize ingredients that are unsafe for parenteral preparation and for other preparations.

Summary of Invention

According to one aspect of the present invention there is provided a stable composition including Aceclofenac and 2,5-di-O-methyl-1,4: 3,6-dianhydro-D-glucitol or higher alkyl derivatives of 2,5- di-O-aryl-1,4: 3,6-dianhydro-D-glucitol as a solvent. According to another aspect of the present invention there is provided a stable composition including Aceclofenac and 2,5-di-O-methyl-1. , 4: 3,6-dianhydro-D - glucitol or higher alkyl derivative of 2,5-di-O-aryl - 1,4: 3,6-dianhydro-D - glucitol as a solvent comferacrylum and other drugs as shown in the examples and suggestive description.

Description of Invention

The inventive injection composition is specifically prepared at the concentration of Img-250 mg / ml with various solvents like 2,5-di-0-methyl-1,4,4,6-dianhydro-D-glucitol, water and other combinations in a composition by parenteral, oral, nasal, dermal or because opthalmic use for delivering over pain elimination routes. Tallinn composition will include the use of excipients like 2,5-di-0-methyl-1,4,4,6-dianhydro-D-glucitol or higher alkyl derivative of 2,5-di-O-aryl- 1,4: 3,6-dianhydro-D-glucitol selected from short chain decarbon atom and alone or in combination of variousexcipients such as Benzyl alcohol, oil arachis, oleate deethyl, dimethylacetamide and lutrol 868, CA VILHAM 20monooleate, polysorbate 80, HAIR 20 monolaurat dcglyccrol, octoxynol 9 laurether 23.

This composition has proven to be having a better pharmacokinetic profile when compared against internationally available formulation.

These excipients may be used for the preparation of insoluble drugs of selected type of acetic acid derivative. Other NSAID drugs, oncological drugs, antihypertensivcness, steroidal, aneseletic, anthelmentics, antidepressants, antidiabetics and antiepiliptics drugs are selected. These parenteral preparations may preferably contain antioxidants. The oxidants that these can be used for preparation include parenterally acceptable antioxidants like Vit. Their derivatives BIiT, BlIA, ascorbylpalmetatc. Oral delivery may include such a solution to be filled into capsules and be administered orally for pain relief. Nasal and pulmonary delivery system may include dissolving Aceclofenac mixed with ecofriendly acceptable inhalating agent to deliver to appropriate dosage. Other inhalating gases include derivative such as Hydrofluroalkane (IIFA).

Local delivery of Aceclofenac in such a system includes Aceclofenac solution within 2,5-di-0-methyl-1,4,4,6-dianhydro-D-glucitol with water and other combinations such as soothner's Tissue Relaxant selected from comonicotinate combinations. of methyl, tolperisone, eperisone etc. and reliever of dor as methyl salicylate and coolant like menthol. Application of eye drops may include drug like Aceclofcnacdentro 2,5-di-O-methyl-1,4, 3,6-dianhydro-D - glucitol with about 30 preservatives like NipaginM and Nipasol or similar condoms.

The composition may be mixed with known combinations such as Feracrylum having haemostatic and antiseptic property in a composition of 1% to 5% Feracrylum and 0.5% to 2.5% 35 of Aceclofenac. The detailed description of the derivatives is described in detail with examples.

The composition may also contain small amount of anesthetic agent which could be added in sufficient amount to sensitive patients. The selected combination is from the local anesthesia range such as benzyl alcohol, lignocaine and special combinations such as Centbucridine Hydrochloride. Centbucridine is 5 times more potent than lignocaine when applied locally.

Later this combination of composition provides use of Feracrylum. This combination is a high pesomolecular combination that works with a haemostatie antiseptic in the various conditions of capillary bleeding and deferred cure that may be classified as a device and thus it is advisable that the device may be useful for external application. A range including 0.5% to 2.5% Aceclofenac, 1% to 5% Fcracrylum, 0.1% to 0.2% Centbucridine UCl or 0.5% to 4% Lignocaine or any other appropriate anesthetic agent. .

This composition can be used as a wound healing agent in a painful patient suffering condition to bleed and drain cells. Further this composition may be combined with antibiotics such as framycetin, clarithromycin and ecombinations used for comeretronidazole, secnidazoles and tinidazoles anerobic infections.

Further this formulation may also contain anticholenegic as a relaxant as dicycloamine under conditions for the treatment of renal colic.

It is one of the present invention the clear composition of Aceclofenacé hydrophobic / hydrophilic in nature and is compatible with body fluids during administration and therefore will not cause parenteral, local, oral application. The application and invention of this patent are also tested for its safety and efficacy in animal models.

The formulation of such liquid solution can be useful for filling Hard filled capsules, Soft gelatin capsules, for the preparation of cream, lotion, surgical dressing, eye drops, rectal suppositories, dental solution, gel and spray. Following are non limiting Illustrative example of composition. Use of the same type of drug and another drug dissolved within 2,5-di-O-methyl-1,4: 3,6-dianhydro-D-glucitol and composed for formulation with other excipients is anticipated before one who is skilled in the art of formulation and the same is obvious pharmaceutical births.

Example 1: 28.23 mmol of Aceclofenac is taken into the bottom flask, 50 ml of 2,5-di-O-methyl-1,4: 3,6-dianhydro-D-glucitol and added and stirred. Nitrogen is stained and allowed the combination to dissolve completely at 30 ° C to 35 ° C. Compose the volume up to 100 ml in 2,5-di-O-methyl-1,4,4,6-dianhydro-D - glucitol and filter by 66 synthetic filter.Aseptically filled filter using nitrogen in vials or ampoules.Example 2 : 28.23 mmol Aceclofenac is taken with 1 mgCentbucridine and 50 ml 2,5-di-O-methyl-1,4: 3,6-dianhydro-D-glucitol is added and mixed with stirring. The solution is stained under Nitrogen and allowed the combination to dissolve completely at 30 ° C to 35 ° C. The volume is composed 100 mldentro 2,5-di-O-methyl-1,4,4,6-dianhydro-D-glucitol and filteredeptically by filter. The solution is filled with vials and ampoules and can even be used for the depray preparation as determined in example 20. Example 3: 28.23 mmole Aceclofenac is mixed with 5.78 mmole Dicycloamine dissolved in 50 ml 2,5-di-O- methyl-1,4: 3,6-dianhydro-D-glucitol and thoroughly mixed with stirring. Nitrogen is stained and allowed the combination to completely dissolve at 30 ° C to 35 ° C. The volume is made up 100 ml with water and filtered through a filter. And filled and sealed vials or ampoules under hermatic conditions. Example 4: 42.33 mmol of Aceclofenac is taken with 1 mg of Centbucridine and 50 ml of 2,5-di-O-methyl-1, 4: 3,6-dianhydro-D -glucitol is added and mixed with stirring. Stained solution with Nitrogen and allowed the combination to dissolve completely at 30 ° C to 35 ° C. Compound the volume to 100 µm inside 2,5-di-O-methyl-1,4,4,6-dianhydro-D-glucitol and filter through the synthetic filter. Filled the solution in bottles or ampoules.

Example 5: 42.33 mmol of Aceclofenac is taken with 1 mgCentbucridine and 60 ml of 2,5-di-O-methyl-1,4: 3,6-dianhydro-D-glucitol is added and mixed with stirring. Stained solution with Nitrogen and allowed the combination to dissolve completely at 30 ° C to 35 ° C. Made up to volume up to 100ml with distilled water and filtered aseptieally by Synthetic Fiber 66filter. Filled the solution in vials or ampoules.Example 6: 28.23 mmol Aceclofenac is dissolved in 10ml of 2,5-di-O-methyl-1,4: 3,6-dianhydro-D-glucitol and 10ml dimethyl deacctamide is added and mixed with stirring. Add 4 ml of benzyl alcohol and add 10 ml of 300 CAVIL and dilute with water to make 100 ml. and filtered aseptieally by Fibrasynthetic 66 filter. Filled the solution in vials or ampoules.Example 7: 28.23 mmol Aceclofenac is dissolved in 1 ml 2,5-di-O-methyl-1,4: 3,6-dianhydro-D-glucitol and add 2 ml benzyl alcohol To dissolve and add 10 ml of dimethylacetamide, add 80 ml of water and make up the volume with CAVILI IA 300 c filter aseptieally by filter. Fill the solution in vials or ampoules.

Example 8: 28.23 mmol Aceclofenac is dissolved in 1 ml 2,5-di-O-methyl-1,4,4,6-dianhydro-D-glucitol and 2 ml debenzyl alcohol is added to dissolve and 10 ml acetamide of dimethyl is added with a stir. 20 ml of propylene glycol is somadoc made up 100 ml with distilled water and filtered aseptieally by Synthetic Fiber 66 filter. Filled the solution in vials or ampoules.

Example 9: 42.33 mmol Aceclofenac is dissolved in 10 ml of 2,5-di-O-methyl-1,4,4,6-dianhydro-D-glucitol and 10 ml of dimethylacetamide is added and mixed with stirring. Add 4ml of benzyl alcohol and add 10ml of 300KL and dilute with water to make 100ml. and aseptieally filter by Synthetic Fiber66 filter. Fill the solution in vials or ampoules.

Example 10: 42.33 mmole Aceclofenac is dissolved in 1 ml 2,5-di-0-methyl-1,4: 3,6-dianhydro-D-glucitol and added 2 ml benzyl alcohol to dissolve and add 10 ml dedimethylaccamide, Add 80 ml of water and make up the volume with 300 c filter ascptically by Synthetic Fiber 66 filter.

Filled the solution in vials or ampoules.

Example 11: 42.33 mmole Aceclofenac is dissolved in 1 ml 2,5-di-O-methyl-1,4,4,6-dianhydro-D-glucitol and 2 ml benzyl alcohol is added to dissolve and 10 ml dimethylacetamide is added. added with a stir. 20 ml of propylene glycol is added and made up 100 ml with distilled water and ascptically filtered by Synthetic fiber 66 filter. Filled the solution in vials or ampoules.

Example 12: Example 1 Aceclofenacequivalent solution to 150 mg of Aceclofenac solution is filled with hard filled capsules or soft gelatin capsules within 2,5-di-O-methyl-1,4: 3,6-dianhydro-D-glucitol and other excipients.

Example 13: Taking 100 ml of round bottom vial, add 25 mg to 150 mg of Aceclofenac dissolving in 1 ml of 2,5-di-O-methyl-1,4: 3,6-dianhydro-D-glucitol added 0.9% of sodium bisulphite, 0.2 gm sodium bisulphite, set pll a7 with 0.1 N NaOH or 0.1 N HCl and make up the volume up toOOml with 0.9% sodium chloride and aseptically filtered by Fibrasynthetic 66 filter and filled the solution into flasks. Eye drop for opthalmic use.

Example 14: Carried 100 ml round bottom flask with 25 to 150 mg Aceclofenac dissolved in Iml of 2,5-di-O-methyl-1,4: 3,6-dianhydro-D-glucitol and added 0.9% chloride of sodium, added 0.5% benzyl alcohol to make it 100 ml with sodium chloride, adjusting the pFI to 7 with 0.1 N NaOFIou 0.1 FICl and made up the volume with sodium chloride easeptically filtered by Synthetic Fiber 66 filter. Filled the solution in vials or ampoules.

Example 15: 28.23 wart of the preparation is taken in a flask to which 10 ml solution of 2,5-di-0-methyl-1,4: 3,6-dianhydro-D-glucitol is added. Dissolve the 10 ml demethyl icylate salt material is added and 10 ml of 400 CAVIL, 10 gm of menthol, 4.7 gm of Camphor, 0.2 g BHT, Ig Phenoxyethanol and make the volume with ethyl alcohol and fill the clear solution for application with a roller for painful conditions.

Example 16: Bring 100 ml round bottom flask with 25 to 150mg of Accclofenac dissolved in Iml of 2,5-di-0-methyl-1,4,4,6-dianhydro-D-glucitol and add 1% Feracrylum in one 1% 934 carbomer matrix, 12% propylene glycol containing 0.2% antioxidant as BHT and adjusting pH with triethanolamine to 5 to 5.5. This is filled into a tube as a geltransparent as an antiseptic and pain relieving gel. Example 17: Bring 100 ml round bottom vial with 25 to 15015 mg of Aceclofenac dissolved in Iml of 2,5-di-0-methyl- 1,4: 3,6-dianhydro-D-glucitol and sum 1% Feracrylum and 0.1% Ccntbucridine in a matrix of 1% 934 carbomer, 12% deglycol of propylene containing 0.2% antioxidant as BFFf and adjusting pFl with triethanolamine to 5 to 5.5. This is filled in a tube like a transparent gel for antiseptic, anesthetic and pain relieving gel.

Example 18: 100 ml round bottom flask with 25 to 150 mg of Aceclofenac dissolved in Iml of 2,5-di-O-methyl-1,4, 3,6-dianhydro-D-glucitol and added 1% Feracrylum and 1 % Mctronidazole in a 1% 934 carbomer, 12% deglycol propylene matrix containing 0.2% antioxidant as BHT and adjusting pFI with triethanolamine to 5 to 5.5. This is filled in a tube as a clear gel for antiseptic and reliever green for wounds caused by anerobic infection.Example 19: Brought a vial containing Aceclofenac Ig, dissolve in 1 to 10 ml of 2,5-di- 0-Methyl-1,4: 3,6-dianhydro-D-glucitol, 40 g CAV 400 and 50 g CAV 4000, warm and stir well to weight 100 g, allow to cool and set. Spread inside on a sterile cotton gauze, cut 10 χ 10 cm pieces covered with a plastic film, accumulated in a container and radiates with gamma rays. This is used for wound care.

Example 20: A vial containing Aceclofenac Ig, 3 g Feracrylum is brought to it and a mixture of 40 g CAVILIA 400 and 50 g CAV 4000 is added, and then dissolved and dispersed. Make to 100 g with water, cool and spread a surgical cotton gauze, cut in 10x 10 cm pieces covered with a plastic film, accumulated in a container and irradiate with gamma rays. This is used for deferred care.

Example 21: Aceclofenac is taken from 1 mg to 250mg and attempted to dissolve in 1 ml ie. approximately 1 gm of the 2,5-di-O-methyl-1,4: 3,6-dianhydro-D-glucitOl solvent. The combination dissolves to provide a clear liquid.

Comparative study carried out with Aceclofenac in the same range up to 250 mg and when trying to dissolve in Benzyl alcohol, Propylene Glycol, the obtained solution is not clear. Only 37.5 mg of Aceclofenac is dissolved in solvents such as Propylene Glycol Mixture, Benzyl Alcohol and water in alkaline condition leading to a clear solution.

Thus it is apparent that the present invention the drug for the solvent relationship is 200 mg: There is complete dissolution considering that the experimental condition of commercially available formulation shows drug dissolution in the range of 37.5 mg to 1 ml. The present inventive composition provides a clear solution which is ready to use considering that the commercially available solution is lyophilized and can only be after reconstitution. So it has to be reconstituted and not ready to use distinct present invention

Example 22: 2.4799 g of Aceclofenac taken and dissolved in 2 ml of 2,5-di-O-methyl-1,4: 3,6-dianhydro-D-glucitol and mixed with IIydrofluroalkane (IIFA) to make 17.2 g of spray bottles for the inhabitant as well as nasal delivery for pain relief.

Capsule formulations are studied for comparative drug dissolution.Solution study:

Example drug dissolution capsules were tested to evaluate the in-vitro standard release drug of the matrix. The result indicates that Aceclofenac 100 mg capsules prepared in 2,5-di-0-methyl-1, 4: 3,6 Dianhydro-D-glucitol according to the present invention has a better dissolution pattern and the release drug is much faster when compared to the commercialized preparation of Aceclofenac 100 mg tablets. The in-vitro dissolution studies were carried out with following parameters.

<table> table see original document page 13 </column> </row> <table>

Analysis for drug dissolution was carried out by IlPLC method after 15 mins, 30 mins. , 90 mins & 120 mins with following parameters.

Column used: C18 Microbondapak (5 microns), 4.6 χ 150 mmReport Length: 282 mmFlow Rate: 1 ml / min

Mobile methanol phase: 0.02 M KFI2P04 (65:35), Injection Vol .: 20 1

Result: The result of the in-vitro dissolution study indicates a dissolution pattern better clearly when it performed a simulated gastric fluid condition.

A) Test: Aceclofenac 100 mg capsules (prepared as an example)

B) Reference: Aceclofenac 100 mg tablets (marketed) <table> table see original document page 13 </column> </row> <table> Efficacy Studies:

Efficacy studies on Gel and Turtledoves Em was taken out to use Animal model inducing inflammation due to Arachidonic Acid induced ear edema in rats, in which the result of the formulation prepared using Aceclofenac and 2,5-di-O-methyl-1,4 matrix : 3,6-dianhydro-D-glucitol exhibits excellent efficacy as against commercially prepared Diclofenac gel preparation.

Similar efficacy was also observed when the animals were treated with Aceclofenac Roll Em.

The study protocol is as follows:

Ε ARACHIDONIC ACID COMBINATION MADE INDEED EAR EDEMA IN RATS

Arachidonic acid-induced ear edema is an experimental model of inflammation for the evaluation of topical and systemic anti-inflammatory potential of Aceclofcnac as an NSAID.

Materials and methods

Arachidonic acid (Calbiochem, Sigma), acetone, 7mm diameter Ear punch, micropipettes.

Animals

Healthy male or female BAEB / C mice weighing between 25-30g are used.

Animal grouping

Each group consists of eight animals as described in Table -1.

Dosing drug

Oral administration

Test combination is suspended at 0.5% C.M.C. the control group receives 0.5% C.M.C vehicle; 10 ml / kg). The drug has been administered 30 minutes before arachidonic acid application.

Topical application

The drug or compound of which antiinflammatory potential to be evaluated is dissolved in acetone or if it is then in the form of deformulation which required concentration is adjusted to 10 1 of acetone or applied as a 10 volume formulation of 1, 30 minutes prior to application of arachidonic acid right ear. The left ear receives either melts (semdroga) or acetone only. Proper care is taken to note that no subsequent drug application coat or film is formed on the ear which may result in a false positive.

Arachidonic Acid Application

2-5% Arachidonic Acid (AA) solution is prepared emacetone. 20 1 of AA solution is uniformly applied to the right by micropipette. Left ear receives vehicle as mentioned earlier and serves as ego control. One hour later the animals are sacrificed and the diameter of mm is pierced by ear and weighed. The difference between right and left ear weight is calculated.

Table 1

<table> table see original document page 15 </column> </row> <table>

Data analysis

Antiinflammatory effect is determined by calculating the inhibition of percent increase in ear weight subsequent to AA application. Statistical significance is determined by applying student T test.

Table 2

Arachidonic Acid Result Induced Ear Edema in Mice: Evaluation of Aceclofenac Anti-inflammatory Potency Topical, Roll in and Capsules and Comparison thereof with Gelde Diclofenac and Aceclofenac Tablets

<table> table see original document page 15 </column> </row> <table> <table> table see original document page 16 </column> </row> <table>

The above result indicates that 1% Aceclofcnac c Rolls Hm gel has better anti-inflammatory activity than the available 1% Dielofenac Gel. Thus the effectiveness of the present formulation is easily imagined,

The test stability of these formulations was carried out using the stability indicating HPLC method (Cl8 column (50 χ4.6 mm), 20 injection of 1, FR Iml for 3 months at previous RTOs results indicate that the selected formulations were studied for Dissolution (In-vitro availability).

TABLE 3

<table> table see original document page 16 </column> </row> <table> <table> table see original document page 17 </column> </row> <table>

TABLE 5

Aceclofenac Gel Stability Study Data

<table> table see original document page 17 </column> </row> <table>

TABLE 6

<table> table see original document page 17 </column> </row> <table>

TABLE 7

Data on Aceclofenac Spray Stability Study

<table> table see original document page 17 </column> </row> <table>

TABLE 8

Aceclofenac Eye Drops Stability Study Data <table> table see original document page 18 </column> </row> <table>

The above results of the invented formulation for Aceclofenac are stable in the stated example formulations where Aceclofenac is dissolved 2,5-di-O-methyl-1,4: 3,6-dianhydro-D-glucitol.

Feraerylum 3% Healing Activity + Aceclofenac 1% Gel Prepared according to Present Invention

The word "wound" primarily refers to fracture in the skin including damage to lying tissues or organs beneath the broken area of the skin. A wound is caused by an external agent such as mechanical trauma, burns or chemical damage.

Wounds can be classified in different ways:

According to the healing mode, a wound can be called as acute or chronic.

A wound is acute when the healing process is progressing without any problem that achieves a continuous restoration of anatomical structure and function.

A wound is chronic when the healing process is not continuous or complete and remains unhealed for a long period of time.

As the wound is the disruption of an area of the body and its function, the body attempts to normalize it by healing.

Healing is a natural, continuous restoration of damaged structure and function. But many of the tissues cannot be regenerated. When tissue regeneration is not possible, a white fibrous tissue is formed known as scar tissue. This scar tissue formation process is often called repair.

The Characteristics of an Ideal Wound Dressing:

Reduces serious leaking, Keeps most environment wound-wound interface, Provides thermal insulation, Low or non-adherent, Requires infrequent changing, Provide mechanical protection, Particulate contaminant-free, Safe to use (Non-toxic, non-sensitising, Non- allergicizing), Comfortable, Good Absorbing Characteristics, Impervious to microorganisms, Acceptable to patient, Cost effective.

MARITIME AND MlVI ODOS

Feracrylum 3% with 1% Aceclofenac in a gel formulation.

Wistar albino rats (150-180gm) were used for the present investigation. The animals were kept at a well ventilated, temperature controlled fourth animal for 7 days prior to the experimental period. Animals were fed commercial diet and ad-libitum water during the experiment.

Wound Healing Activity

The present investigation was carried out on two different deferred rat models such as excision and incision wound to evaluate wound healing activity.

Fxcision Wound

The mice were shaved on the back. An excision wound was inflicted by cutting about 500mm2 full densities of depilated skin by anesthetizing with anesthetic ether. The wound was left naked to open environment. The animals were divided into three groups of six animals each. The group I was considered as the control and received Aceclofenac 1% gel base, group II was served as the reference standard & received 0.2% w / w nitrofurazone anointing, group 3 respectively 3% Feracrylum animals with 1% Gel of Acclofenac. Gels were once topically applied in one day, from the day of operation, culture full epithelization happens. The parameters studied were closure of excision wound percentage and epithelization time. Measurements were located on mm2 graph paper on O, 4th, 8th, 12th & 16th day and thereafter every other day until complete. The percentage of wound closure. The epithelization period was calculated as the number of days required for scarring without any residual wound.

Incision Wound In the incision wound model, two paravertebral 6 cm direct incisions were made by the entire skin densities on either side of the spine with the aid of anaesthetized sharp blade. Care was taken to see that the incisions were at least 1 cm lateral to the spine. In complete laemostasis the wounds were closed by means of suspended sutures placed at equidistant points approximately 1 cm apart, using 4-zero descending line & a curved needle. The animals were divided into three groups of six animals each. The grouping of experimental animals was similar to the Accclofcnac cxcision.Gcl wound model (1% Controls), Nitrofurazone Ointment (0.2% w / w - Reference Standard) and 3% Feracrylum with 1% Gcl dc Aceclofenac once daily. applied for 7 days. Suture removal was completed at 8th boiling post and tensile strength of the healed wound was measured at 10th post injuring day by Lee's constant continuous water flow technique.

Statistical analysis

Data are expressed as bad + SEM and subjected to students "t" test and significance level was fixed at P <0.001.FABEL 1: !! made of our product i.e. Gel dc

3% Feracrylum + 1% Aceclofenac on Excision Wounds

<table> table see original document page 20 </column> </row> <table> Values are ms + S.E. of 6 animals in each group. Parenthesis numbers indicate percentage of wound contraction. * P <0.001 Vs respective control by students "t." Test

Results c Discussion

The 3% Feracrylum + effect was hidden 1% Aceclofenac Gel in excision and incision wound models simultaneously with the control (1% Aceclofenac Gel). As measured by control-induced wound healing progress (1% Aceclofenac gel), reference standard (Nitrofurazonc Ointment 0.2% w / w), 3% Feracrylum with 1% Aceclofenac Gel is shown in the excision wound method in Table 1. It is noted that the wound contraction ability of 3% Feracrylum with 1% Aceclofenac Gel was significantly greater than that of control. The 3% Feracrylum with 1% Aceclofenac Gel treated group showed much greater contraction deferred from the 8th day than they treated with 1% Gcl Aceclofenac treated group. The wound closure time of the Nitrofurazone Urge (0.2% w / w) treated group was found to be 16 + 2d. The wound closure time for the 1% Aceclofenac Gel Treated Group (18 + 1 d) was less than the 3% Fcracrylum with 1% Aceclofenac Gel Treated Group (20 + 1d) and the Control Group.

<table> table see original document page 21 </column> </row> <table>

Values are ms + SE of 6 animals in each group. * P <0.001 Vs respective control by students "t." Test Flavia a significant increase in tensile strength of old IO due to 3% Feracrylum treatment in excision wound studies , with 1% Aceclofenac Gel (602+ 15.3) as compared to control (435 + 14.5). are shownMeasures of tensile strengths in Table II. The bad tensile strength of Nitrofurazone ointment is comparable to 3% Feracrylum with 1% Aceclofenac Gel.

Based on the results of the present investigation it can be concluded that 3% Feracrylum with 1% Aceclofenac Gel has significant wound healing activity in both wound healing models. The 3% Feracrylum + 1% Acetic healing wound seems to be due to the molecule. Fcracrylum that speeds up the healing process and confers rupture strength to the healed wound.

During observation in the formulation for syncrgistic effect of Fracrylum and Aceclofenac, it was interpreted from in-vivo experience that 3% Feracrylum with 1% Aceclofenac Gel had a better effect on wound healing activity when compared to 1% Aceclofenac gel in the rodent model.

ATlVIDADIi ANrFIINI7 1% TYPE DLACLCLOFLNAC SOLUTION

Antiinflammatory Activity:

Method used to study this activity is rat paw edema. Albino rats of either sex (150-200 gm) were divided into two groups with five animals in each group. Mice were deprived of food for 12 hours prior to expiration. The first group received the new formulation Aceclofenac 1% solution according to the present invention and the second group received 1% Diclofenac solution. These solutions were injected into the plantar region of the rat's left hind paw substitute. Immediately the paw volume was eplethismometer using measured (Initial paw volume). After 3h, paw volume is measured again. Differentiate subsequent re-reading and initial reading was used for% reduction calculation.

Pharmacological Shielding Results

<table> table see original document page 22 </column> </row> <table> Conclusion:

From the above results, it can be concluded that the i.ecombination test. 1% Aceclofenac solution is having more anti-inflammatory activity than 1% Diclofenac solution.

BIOAVAILABILITY ACECI INJECTION STUDY OFENAC 150 mg / ml

The design of the study was a single dose, randomized, three-way, three-way crossover study, with a 07-day breakout period between the three dosing sessions.

The result of Pharmacokinetic studies is shown below:

BIOAVAILABILITY STUDY ACECLOFENAC

Pharmacokinctic Parameters with Test and Reference Preparations

<table> table see original document page 23 </column> </row> <table> <table> table see original document page 24 </column> </row> <table>

Thus Cmax, Traax and AUC (dry curve) in blood was better in the present invention as compared to the commercially available formulation.

The Cmax that is obtained in our invention was 9787.47 ng / ml as compared to the formulation as commercially available. Time Tmax to achieve this was 1.44 / hr and AUC was 42049.62 (ng.hr/ml).

Combining Accclofenac with 2,5-di-O-methyl-1,4,4,6-dianhydro-D-glucitol in the demonstrousynergistic 150 mg / ml concentration range effect when tested in vivo on humans for its Pharmacokinetic characteristics. Comparative Pharmacokinetic results and synergism of 2,5-di-O-meül-1, 4: 3,6-dianhydro-D-glucitol and Aceclofenac are well shown by the fact that Cmax and Tmax achieved is better in the case of present invention when compared commercially available formulation. Thus Accclofenac as discussed, in the concentration range of 150 mg / ml showed better Pharmacokinetic profiles as against the commercially available product which is dissolved in Ben / .yl Alcohol, Propylene glycol and Water mixture.

Claims (18)

1. "Modern Stable Composition Preparation Method including Aceclofenac and 2,5-Di-O-Methyl-1,4: 3,6-Dianhydro-D-Glueitol as a Solvent and Method of Use" characterized in that it is a stable composition which includes Accclofenac and 2,5-di-O-methyl-1,4,4,6-dianhydro-D-glucitol or alkyl derivative plus 2,5-di-0-aryl-1,4: 3,6- dianhydro-D - co-solvent glucitol with or without other excipients. 2. "Modern Stable Composition Preparation Method Including Aceclofenac and 2,5-Di-O-Methyl-1,4: 3,6-Dianhydro-D-Glucitol as a Solvent and Method of Use" according to claim 1 characterized in that Accclofenac is present in an amount of from about Img to 250mg per ml of 2,5-di-O-methyl-1,4: 3,6-dianhydro-D-glucitol or higher alkyl derivative of 2,5- di-O-aryl-1,4: 3,6-dianhydro-D-glucitol. 3. "Modern Stable Composition Preparation Method Including Aceclofenac and 2,5-Di-0-Methyl-1,4: 3,6-Dianhydro-D-Glucitol as a Solvent and Method of Use" according to claim 1 or 2, characterized in that other excipientswhen present are selected from Benzyl alcohol, arachislubricates, ethyl oleate, dimethylacetamide and lutrol 868, CAVIUiAM 20 monooleate, polysorbate 80, CAVILl IAM 20monolaurate of glycerol, octoxynol 9 laurether 23. 4. "Modern Stable Composition Preparation Method including Accclofenac and 2,5-Di-0-Methyl-1,4: 3,6-Dianhydro-D-Glucitol as a Solvent and Method of Use" according to claim 1 3, characterized in the selected form of parenteral, oral, nasal, dermal, ophthalmic. 5. "Modern Stable Composition Preparation Method including Accclofenac and 2,5-Di-0-Methyl-1,4: 3,6-Dianhydro-D-Glucitol as a Solvent and Method of Use" according to claim 4 , characterized in which parenteral form includes selected Vitamin E antioxidants derived from themBHT, BHA, ascorbylpalmetate and the like. 6. "Modern Stable Composition Preparation Method including Aceclofencac and 2,5-Di-O-Methyl-1,4: 3,6-Dianhydro-D-Glucitol as a Solvent and Method of Use" according to claim 4 characterized in that the oral form is selected from capsule, tablet, liquid. 7. "Modern Stable Composition Preparation Method including Aceclofenac and 2,5-Di-0-methyl-1,4: 3,6-Dianhydro-D-Glucitol as a Solvent and Method of Use" according to claim 4 characterized in that nasal forms include selective lining agent Hydrofluroalkane (HFA) adapted to deliver the appropriate dosage derivatives. 8. "Preparation Method for Modern Stable Composition which includes Aceclofenac c 2,5-Di-O-Methyl-1,4: 3,6-Dianhydro-D-Glucitol as a Solvent and Method of Use" according to claim 4 , characterized in that roller dermal shapes are selected in rectal suppositories, dental solution, cspray gel. 9. "Modern Stable Composition Preparation Method which includes Aceclofenac and 2,5-Di-O-Methyl-1,4: 3,6-Dianhydro-D-Glucitol as a Solvent and Method of Use" according to claim 8 characterized in that dermal forms include water and other selected combinations of soothner, tiny relaxant, pain reliever and coolant. 10. "Preparation Method for Modern Stable Composition includes Aceclofenac and 2,5-Di-O-Methyl-1,4: 3,6-Dianhydro-D-Glucitol as a Solvent and Method of Use" according to claim 4 characterized in that the ophthalmic form is eye drops including condoms such as NipaginM and Nipasol and the like. 11. "Preparation Method for Modern Stable Composition" includes Aceclofenac and 2,5-Di-O-Methyl-1,4: 3,6-Dianhydro-D-Glucitol as a Solvent and Method of Use thereof, according to any claim of 1 to 10, characterized in terms of pharmacokinetic profile. 12. "Preparation Method for Modern Stable Composition" includes Aceclofenac and 2,5-Di-0-methyl-1,4,4,6-Dianhydro-D-Glucitol as a Solvent and Method of Use thereof characterized in that it is a stable composition which includes Aceclofenac and 2,5-di-O-methyl-1,4: 3,6-dianhydro-D-glucitol or alkyl-derived plus 2,5-di-0-aryl-1,4; dianhydro-D - co-solvent glucitol and feracrylum adapted for wound healing. 13. "Preparation Method for Modern Stable Composition includes Aceclofenac and 2,5-Di-O-Methyl-1,4: 3,6-Dianhydro-D-Glucitol as a Solvent and Method of Use" according to claim 12 , characterized in that it includes 1% to 5% of Feracrylum and 0.5 to 2.5% of Aceclofenac. 14. "Preparation Method for Modern Stable Composition includes Aceclofenac and 2,5-Di-O-Methyl-1,4: 3,6-Dianhydro-D-Glucitol as a Solvent and Method of Use" according to claim 12 or 13, characterized by having further local anesthetics including selected from benzyl alcohol, lignocaine and combinations like CentbucridineHydrochloride 15. "Preparation Method for Stable Composition modernaque includes Accclofenac and 2,5-Di-0-methyl-1,4,4,6-Dianhydro-D-Glucitol as Solvent and Method of Use" according to claim 12 to 14, characterized by including combinations used for anaerobic infections and adapted for wound healing by bleeding and leaking cells. 16. "Preparation Method for Modern Stable Composition includes Aceclofenac and 2,5-Di-O-Methyl-1,4: 3,6-Dianhydro-D-Glucitol as a Solvent and Method of Use" according to claim 15 , characterized in that framycetin antibiotics, clarithromycin are selected. 17. "Preparation Method for Modern Stable Composition includes Aceclofenac and 2,5-Di-O-Methyl-1,4: 3,6-Dianhydro-D-Glucitol as a Solvent and Method of Use" according to claim 15. , characterized in which combinations used for anaerobic infections is selected from metronidazole, secnidazoles and tinidazoles. 18. "Preparation Method for Modern Stable Composition" includes Aceclofenac and 2,5-Di-0-methyl-1,4,4,6-Dianhydro-D-Glueitol as a Solvent and Method of Use thereof characterized by 2.5 -di-O-methyl-1,4: 3,6-dianhydro-D-glueitol or higher alkyl derivative of 2,5-di-0-aryl-1,4: 3,6-dianhydro-D-glucitol as Aceclofenac solvent for formation Clear stable decomposition.