Claims:We Claim
1. A stable ternary solid dispersion composition with enhanced solubility, dissolution comprising: a) about 1% wt. to about 50% wt. of one or more poorly soluble active pharmaceutical ingredient (API) which belong to Biopharmaceutics Classification System (BCS) class II and/or IV; b) about 11% wt. to about 50% wt. of at least one water-soluble polymers or skimmed milk; and c) about 20% wt. to about 99% wt. of diluent wherein the solid dispersion is capable of inhibiting crystallization of API in the solid state and/or aqueous gastrointestinal tract (GIT) medium.

2. The solid dispersion composition according to claim 1, wherein said composition is storage-stable, transit- stable and/or able to increase dissolution rate and/or maintain supersaturation of API (a) during dissolution.

3. The solid dispersion composition according to claim 1, wherein said API is selected from the group of BCS class II or IV consisting of Albendazole, Acyclovir, Azithromycin, Cefdinir, Cefuroxime axetil, Chloroquine, Clarithromycin, Clofazimine, Diloxanide, Efavirenz, Fluconazole, Griseofulvin, Indinavir, Mefenamic Acid, Itraconazole, Ketoconalzole, Lopinavir, Mebendazole, Nelfinavir, Nevirapine, Niclosamide, Praziquantel, Pyrantel, Pyrimethamine, Quinine, Ritonavir, Bicalutamide, Cyproterone, Gefitinib, Imatinib, Tamoxifen, Cyclosporine, Mycophenolate mofetil, Tacrolimus. Acetazolamide, Atorvastatin, Benidipine, Candesartan cilexetil, Carvedilol, Cilostazol, Clopidogrel, Ethylicosapentate, Ezetimibe, Fenofibrate, Irbesartan, Manidipine, Nifedipine, Nisoldipine, Simvastatin, Spironolactone, Telmisartan, Ticlopidine, Valsartan, Verapamil, Warfarin, Acetaminophen, Amisulpride, Aripiprazole, Carbamazepine, Celecoxib, Chlorpromazine, Clozapine, Diazepam, Diclofenac, Flurbiprofen, Haloperidol, Ibuprofen, Ketoprofen, Lamotrigine, Levodopa, Lorazepam, Meloxicam, Metaxalone, Methylphenidate, Metoclopramide, Nicergoline, Naproxen, Olanzapine, Oxcarbazepine, Phenyloin, Quetiapine, Risperidone, Rofecoxib, Valproic acid, Isotretinoin, Dexamethasone, Danazol, Epalrestat, Gliclazide, Glimepiride, Glipizide, Glyburide (glibenclamide), levothyroxine sodium, Medroxyprogesterone, Pioglitazone, Raloxifene, Mosapride, Orlistat, Cisapride, Rebamipide, Sulfasalazine, Teprenone, Ursodeoxycholic Acid, Ebastine, Hydroxyzine, Loratadine, and Pranlukast.and combinations thereof.

4. The solid dispersion composition according to claim 1, wherein the API is present in the range of from about 15% wt. to about 55% wt and water- soluble polymer is present in the range of from about 15% wt. to about 35% wt.

5. The solid dispersion composition according to claim 1, wherein said surfactant is selected from the group consisting of skimmed milk, dodecanesulfonic acid, sodium dodecyl sulfate, sodium lauryl sulfate (SLS), (poly)-oxyethylene sorbitan long-chain fatty acid esters, Vitamin E-TPGS, bile salts, sodium deoxycholate, sodium glycocholate, polyoxyethylene polyoxypropylene glycols and combinations thereof.

6. The solid dispersion composition according to claim 1, wherein said plasticizer is optionally selected from the group consisting of Triethyl Citrate, Glycerol Monostearate, Dibutyl Sebacate, Diethyl Phthalate, Polyethylene Glycol, Triacetin, Vitamin E-TPGS, Tween 80, Sodium Lauryl Sulfate, Sodium Docusate, Poloxamer F-68, Poloxamer F-127 and combinations thereof.

7. The solid dispersion composition according to claim 1, formulated with pharmaceutically acceptable excipients selected from the group consisting of disintegrants, lubricants, glidants, carriers, anti-adherents, inert fillers, wetting agents, pH modifiers, binders, solubility modifiers, recrystallization inhibitors, diluents and combinations thereof.

8. The solid dispersion composition according to claim 1, wherein said solid dispersion is formulated into tablets, rings, patches, capsules, pellets, granules, fine granules or a powder.

9. The solid dispersion composition according to claim 1, wherein the composition is prepared by spray-drying, hot-melt extrusion, solvent-evaporation, melt- granulation, melt-congealing or spray-congealing.

10. The solid dispersion composition according to claim 1, wherein the composition can be in form of solid dosage form of medicament selected from tablet or capsule or tablet in capsule or combinations thereof.

, Description:TITLE: IMPROVED COMPOSITION OF MEFENAMIC ACID UTILISING SKIMMED MILK AS CARRIER

FIELD OF THE INVENTION
The present invention relates to stable pharmaceutical composition of Mefanamic acid having improved solubility and dissolution profile by introducing solid dispersion technique using skimmed milk as a carrier. The term solid dispersion is used herein to mean a drug-containing pharmaceutical bulk substance comprising the drug dissolved or dispersed in a polymer.

Background of the Invention
Mefenamic acid being a fenamate, is a COX selective non steroidal anti inflammatory drug having primarily anti-inflammatory property with mild anti pyretic and analgesic activity. It is used in the symptomatic relief of rheumatoid arthritis, osteoarthritis, musculoskeletal disorders, dysmenorrheal, and postoperative pain. Prolong use of this may result in gastric irritation, tachycardia, haematemesis, tinnitus, constipation, and pruritis. It is a BCS class II drug comprising poor solubility.
It has been estimated that more than 60% of Active Pharmaceutical Ingredients (API) in development have poor bioavailability due to low aqueous solubility (Manufacturing chemist, March 2010, 24-25). This percentage is likely to increase in the future with the increased use of combinatorial chemistry in drug discovery targeting lipophilic receptors. Poor bioavailability results in increased development times, decreased efficacy, increased inter- and intra- patient variability and side effects, and high dose that reduce patient compliance and increase cost. Thus, the ability to improve drug solubility and/ or dissolution rate and, hence, bioavailability through formulation technology is critical to improve a drug product's efficacy and safety, and reduce its cost. In recent years, one of the major focuses for the pharmaceutical formulators is to identify strategies that would improve the bioavailability of active pharmaceutical ingredients (APIs) by enhancing their dissolution rate and/or solubility. In particular, poorly soluble API's can be changed to amorphous or microcrystalline forms through formulation approaches, which provide a fast dissolution rate and/or higher apparent solubility in the gastric and intestinal fluids.
Amongst the many available solubility enhancement techniques like micronization, complexation, co solvency, hydrotrphy, co crystallization, solid dispersions, liquid solid compact, self nano emulsifying drug delivery systems and other nanotechnology approaches, solubility improvement by formulating solid dispersions is emerging as a promising technique. Solid dispersion is a dispersion of active ingredients in an inert carrier or matrix at solid state prepared by the melting (fusion), solvent or melting- solvent method (Pharm. Sci., 1971; 60: 1281-1302). It provides a drug release profile that is largely determined by the carrier properties. The advantages of employing solid dispersion method are to reduce particle size, to improve wettability, to improve porosity of drug, to decrease the crystalline structure of drug in to amorphous form, to improve dissolvability in water of a poorly water-soluble drug in a pharmaceutical, to mask the taste of the drug substance, to prepare rapid disintegration oral tablets, to obtain a homogenous distribution of small amount of drugs at solid state, to stabilize unstable drugs, to dispense liquid or gaseous compounds, to formulate a faster release priming dose in a sustained release dosage form, to formulate sustained release dosage or prolonged release regimens of soluble drugs using poorly soluble or insoluble carriers.
At the early stage of solid dispersions development, small molecule crystalline carriers were used, wherein the solid dispersions of API were integrated in the crystal lattice of the carrier. A well known example of small molecule crystalline carrier is urea (Chem. Pharm. Bull. 12, 134-144, 1964). The solid dispersion is a eutectic mixture that can increase the dissolution rate. However due to the crystalline nature of the poorly soluble APIs in the system; solubility enhancement cannot be expected, hence the bioavailability enhancement by such systems could be limited.
Later on, binary solid dispersions were developed with amorphous or crystalline polymeric carriers, in which API compounds were dispersed in amorphous form (Int. J. Pharm. 303, 132-142, 2005). Exemplary polymer carriers employed to prepare a binary solid dispersion include polyvinylpyrrolidone (Int. J. Pharm. 302, 103-112, 2005), polyethyleneglycols (/. Pharm. Sci. 59, 937-942, 1970), polymethacrylates (Int. J. Pharm. 319, 44-54, 2006), hydroxypropylmethylcellulose (/. Pharm. Sci. 95, 2692-2705, 2006), ethylcellulose (Int. J. Pharm. 327, 45-50, 2006), hydroxypropylcelluloses (/. Contr. Release 108, 386-395, 2005), cyclodextrins (Eur. J. Pharm. Sci. 26, 184-193, 2005), skimmed milk, silica gel, gelatin and egg albumin etc.
Natural excipients show lack of toxicity, easy availability and economic considerations in pharmaceutical industry as compared to their synthetic counterparts. Naturally derived excipients have shown promising results in the modification of drug release from the formulations. In the present invention skimmed milk is being used as naturally originated carrier.
Our inventors of present invention surprisingly found that solid dispersions of Mefenamic Acid were prepared with skimmed milk using rotary vacuum evaporation technique with enhanced aqueous solubility and dissolution rate due to presence of lactose in skimmed milk which provide polar effect and also due to reduced crystallinity of the drug thus imposing better bioavailability.
In order to eliminate or reduce gastro intestinal disorders of non-steroidal drugs, amino acids are suggested either as additives per oral application or in the form of amino acid salts.
In the present work, an effort was made not only to improve the solubility but also to minimize the ulcerogenic side effect associated with the prolong administration of Mefenamic Acid by making use of inherent advantageous properties of skimmed milk in preventing ulcers due to its amino acid content.

SUMMARY OF THE INVENTION
The present application provides a stable solid dispersion composition with enhanced bioavailability comprising: (a) about 0.1% wt. to about 20% wt. of one or more poorly soluble active pharmaceutical ingredient (API) which is in this case Mefenamic Acid; (b) 80 % to 99% Skimmed Milk, wherein the solid dispersion is capable of inhibiting crystallization of API in solid state and/or bio-relevant aqueous medium.
The present application also provides a method for preparing the solid dispersion composition by solvent, or melting (fusion) or solvent-melting methods including spray- drying, hot-melt extrusion, solvent-evaporation, and melt-granulation, melt-congealing or spray-congealing.
In accordance with one aspect of the present application, there is provided a process for preparing a solid dispersion composition comprising the steps of: (a) preparing a homogenous aqueous and/or organic solution of (i) Skimmed milk which itself contains water soluble (Lactose) as well as water insoluble polymers within it along with the naturally originated surface active agent (Casein), (ii) at least one active pharmaceutical ingredient (API) which belongs to BCS class II ( Mefenamic Acid) to yield a suspension or dispersion; and (b) rotary vacuum evaporation of the resultant of step (a) to yield a dry powder form of a solid dispersion composition and (c) drying over calcium chloride containing desiccators, triturating, sieving and storing in an air tight container of step (b) until further use.
In yet another aspect of the present application, the desired solid dispersion composition further comprises a pharmaceutically acceptable excipient selected from the group consisting of surfactants, plasticizers, disintegrants, lubricants, glidants, carriers, anti- adherents, inert fillers, wetting agents, pH modifiers, binders, anti- oxidants, solubility modifiers, and recrystallization inhibitors, alone or in combination.
In yet another aspect of the present application, the desired solid dispersion composition further comprises a pharmaceutically acceptable excipient selected from the group consisting of surfactants, plasticizers, disintegrants, lubricants, glidants, carriers, anti- adherents, inert fillers, wetting agents, pH modifiers, binders, anti- oxidants, solubility modifiers, and recrystallization inhibitors, alone or in combination can be filled into a capsule or tablet or tablets filled into capsule or directly filled into capsule as such.
In yet another aspect of the present application, the desired solid dispersion composition further comprises with an excipient which is comparably economical and less expensive to other excipients and also can be filled into capsule or tablet as such.

Brief Description of the Drawings
Figure 1 of 1 describes the dissolution profile of Solid Dispersion and Pure Drug

Detailed Description of the Invention
While this specification concludes with claims particularly pointing out and distinctly claiming that which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
The singular forms "a," "an," and "the" include plural forms unless the context clearly dictates otherwise specified or clearly implied to the contrary by the context in which the reference is made. The term "comprising" and "comprises of includes the more restrictive claims such as "consisting essentially of and "consisting of.
The term "about" can indicate a difference of 10 percent of the value specified. Numerical ranges as used herein are meant to include every number and subset of numbers enclosed within that range, whether particularly disclosed or not. Further, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range.
All percentages, parts, proportions and ratios as used herein, are by weight of the total composition, unless otherwise specified. All such weights as they pertain to listed ingredients are based on the active level and, therefore; do not include solvents or byproducts that may be included in commercially available materials, unless otherwise specified.
All references to singular characteristics or limitations of the present invention shall include the corresponding plural characteristic or limitation, and vice-versa, unless otherwise specified or clearly implied to the contrary by the context in which the reference is made.
As used herein, the words "preferred" or "preferably" and variants refer to embodiments of the invention that afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the invention.
References herein to "one embodiment" or "one aspect" or "one version" or "one objective" of the invention include one or more such embodiment, aspect, version or objective, unless the context clearly dictates otherwise.
All publications, articles, papers, patents, patent publications, and other references cited herein are hereby incorporated herein in their entirety for all purposes to the extent consistent with the disclosure herein.
The term "poorly soluble" refers to slightly soluble or very slightly soluble compounds and it requires from about 100 or more parts of solvent for one part of solute and wherein the poorly soluble means the solubilization of API compounds becomes the rate limiting step for absorption of such API compounds.
According to the present application, the term "solid dispersion" means a solid state which comprises at least two constituents, wherein one constituent is homogenously dispersed significantly evenly throughout the other constituent or constituents. It includes solid or glassy solutions, i.e., the dispersion of the constituents is in such a way that the composition is chemically and physically homogenous in nature. The "solid dispersion" of the present application advantageously comprises a co-precipitate or co-melt of an active pharmaceutical ingredient (API) and skimmed milk as carrier, wherein the API is dispersed significantly uniformly all over the carrier system. The API may be present in an amorphous state or in fine crystalline dispersed form. Also, the API may be available as a mixture of amorphous and crystalline forms. The term "Pharmaceutically acceptable excipients" refers to an inert additive included to solid formulations in the form such as powders, granules, capsules, pellets and tablets to increase the bulk of the desired formulation comprising the present solid dispersion.
What is described herein is a stable solid dispersion composition with enhanced bioavailability comprising: (a) about 0.1% wt. to about 20% wt. of one or more poorly soluble active pharmaceutical ingredients (APIs) which belongs to Biopharmaceutics Classification System (BCS) class II ; (b) about 80% wt. to about 99% wt. of liquid naturally originated carrier system; wherein the solid dispersion is capable of inhibiting crystallization and or crystal growth of API in solid state and/or aqueous gastrointestinal tract (GIT) medium.
The APIs that belong to BCS Class II are poorly soluble, but are absorbed from the solution by the lining of the stomach and/or intestine. The non- limiting BCS Class II drugs are selected from the group consisting of Albendazole, Acyclovir, Azithromycin, Cefdinir, Cefuroxime axetil, Chloroquine, Clarithromycin, Clofazimine, Diloxanide, Efavirenz, Fluconazole, Griseofulvin, Indinavir, Mefenamic Acid, Itraconazole, Ketoconalzole, Lopinavir, Mebendazole, Nelfinavir, Nevirapine, Niclosamide, Praziquantel, Pyrantel, Pyrimethamine, Quinine, Ritonavir, Bicalutamide, Cyproterone, Gefitinib, Imatinib, Tamoxifen, Cyclosporine, Mycophenolate mofetil, Tacrolimus. Acetazolamide, Atorvastatin, Benidipine, Candesartan cilexetil, Carvedilol, Cilostazol, Clopidogrel, Ethylicosapentate, Ezetimibe, Fenofibrate, Irbesartan, Manidipine, Nifedipine, Nisoldipine, Simvastatin, Spironolactone, Telmisartan, Ticlopidine, Valsartan, Verapamil, Warfarin, Acetaminophen, Amisulpride, Aripiprazole, Carbamazepine, Celecoxib, Chlorpromazine, Clozapine, Diazepam, Diclofenac, Flurbiprofen, Haloperidol, Ibuprofen, Ketoprofen, Lamotrigine, Levodopa, Lorazepam, Meloxicam, Metaxalone, Methylphenidate, Metoclopramide, Nicergoline, Naproxen, Olanzapine, Oxcarbazepine, Phenyloin, Quetiapine, Risperidone, Rofecoxib, Valproic acid, Isotretinoin, Dexamethasone, Danazol, Epalrestat, Gliclazide, Glimepiride, Glipizide, Glyburide (glibenclamide), levothyroxine sodium, Medroxyprogesterone, Pioglitazone, Raloxifene, Mosapride, Orlistat, Cisapride, Rebamipide, Sulfasalazine, Teprenone, Ursodeoxycholic Acid, Ebastine, Hydroxyzine, Loratadine, and Pranlukast.
The above disclosed non-limiting BCS Class II drugs can be a free acid, free base or neutral molecules, or in the form of an appropriate pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a pharmaceutically acceptable co-crystal, a pharmaceutically acceptable enantiomer, a pharmaceutically acceptable derivative, a pharmaceutically acceptable polymorph, pharmaceutically acceptable ester, pharmaceutically acceptable amide or a pharmaceutically acceptable prodrug thereof.
One of the embodiments of the present invention relates to naturally originated carriers that are selected from Locust bean gum, Karaya gum, Guar gum, Xanthan gum, Hupu gum, Aegle marmalos gum, a, ß & ? Cyclodextrin, Hydroxypropyl ß-Cyclodextrin, meta hydrated ß-Cyclodextrin, Lactose, corn starch, Sorbitol, Mannitol, Chitosan, Maltose, Gelatin, Egg albumin, Skimmed milk, Silica gel, Urea etc.
One of the embodiments of present invention describes the composition of the present invention to have
a. 0.1% wt. to 20% wt. of Active Pharmaceutical Ingredient (API), more preferably 0.1% wt. to 10% wt. of API, most preferably 0.3% wt. to 5% wt. of API and
b. 80% wt. to 99% wt. of naturally originated carrier, more preferably 90% wt. to 99% wt. of naturally originated carrier, most preferably 95% wt. to 99% wt. of naturally originated carrier.
The ratio of Active Pharmaceutical Ingredient and the naturally originated carrier may be from about 0.1- 3: 5-15. The preferred ratio is from about 0.5-1.5: 5-12and the most preferred ratio is 1:9.
The suitable plasticizers employed in the present application include by way of example and without limitation, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, acetylated monoglycerides, glycerol, polyethylene glycol, triacetin, propylene glycol, dibutyl phthalate, diethyl phthalate, isopropyl phthalate, dimethyl phthalate, dibutylsebacate, dimethyl sebacate, castor oil, glycerol monostearate, fractionated coconut oil, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester-type plasticizers, glycol esters, poly(propylene glycol), multi-block polymers, single-block polymers, low molecular weight poly(ethylene glycol), citrate ester-type plasticizers, triacetin, propylene glycol, glycerin, ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, Methylene glycol, tetraethylene glycol and other poly(ethylene glycol) compounds, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutylsebacate, acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate, polyethylene glycols such as PEG 200, PEG 300, PEG 400 and PEG 600, and/or allyl glycolate.
According to one embodiment of the present application, at least one disintegrating agent can be added to the solid dispersion composition to facilitate the breakup or disintegration of a formulation when contacted with gastrointestinal (GIT) fluid. The suitable disintegrant can be selected from the group including, but not limited to, calcium carbonate, methylcellulose, cross-linked carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium, agar, guar, locust bean, karaya, pectin, tragacanth, bentonite, cation-exchange resin, polyvinylpyrrolidone, crosslinked polyvinyl pyrrolidone, alginic acid, alginates, sodium alginate, microcrystalline cellulose, polacrillin potassium, starch, pregelatinized starch, carboxymethyl starch, corn starch, potato starch, sodium starch glycolate, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate alone or in combination.
Lubricants and Glidants can be employed in the present application to prevent, reduce or inhibit adhesion or friction of ingredients of the composition. They facilitate the compression and ejection of compressed compositions from a desired die. They are compatible with the ingredients of the pharmaceutical composition, and they do not significantly reduce the solubility, hardness, chemical stability, physical stability, or the biological activity of the pharmaceutical composition. The pharmaceutically acceptable lubricants and glidants for the present application are selected from the group including but not limited to stearic acid, metallic stearates, zinc stearate, magnesium stearate, magnesium trisilicate, calcium hydroxide, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium stearate, glyceryl monostearate, waxes, glycerides, glyceryl behenate, glyceryl palmitostearate, silicone oil, hydrogenated vegetable oil, hydrogenated castor oil, light mineral oil, mineral oil, polyethylene glycol, methoxypolyethylene glycol, sodium acetate, sodium oleate, sodium chloride, leucine, sodium benzoate, alkyl sulfates, sodium lauryl sulfate, sodium stearyl fumarate, talc, colloidal silica, corn starch, powdered cellulose, and/or boric acid.
According to one embodiment of the present application, suitable binders can be selected from the group including, but not limited to, starches, modified starches, pregelatinized starch, partially pregelatinized starch, agar, gelatin, dextrin, alginic acid, sodium alginate, agar, calcium carrageenan, tragacanth gum, xanthan gum, gum acacia, sugars, lactose, liquid glucose, guar gum, hyaluronic acid, pectin, wax binders, sodium chondroitin sulfate, polyvinylpyrrolidone, povidone, polyvinyl alcohol, carboxyvinyl polymer, polyacrylic acid-series polymer, polylactic acid, polyethylene glycol, cellulose ethers, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, and/or polyethylene oxides.
The desired pH of the composition can be achieved by employing any suitable pH modifying agents. The non-limiting pH modifiers include weak carboxylic acids, citric acid, acetic add, lactic acid, tartaric acid, aspartic acid, succinic acid, phosphoric acid, salicylic acid, sulfamic acid, benzoic acid or their salts, phosphates, pyrophosphate and its salts, metaphosphate and its salts, carbonic acid and its salts, hydroxylammonium, adidic acid and its salts, maleic acid and its salts, ascorbic acid and its salts, sodium acetate, potassium acetate, calcium oxide, magnesium oxide, trisodium phosphate, sodium hydroxide, ammonium hydroxide, pottasium hydroxide, calcium hydroxide, aluminum hydroxide, amines, triethanol amine, diethanol amine, monoethanol amine.
Diluents or Filling agents increase the bulk of the composition to ease compression or produce sufficient bulk for homogenous blend for the composition. The appropriate diluents for the present application may be selected from the following non- limiting examples including lactose, anhydrous lactose, spray-dried lactose, mannitol, sorbitol, compressible sugar, starch, sucrose, dextrose, trehalose, maltose, xylitol, lactitol, amylase, calcium sulfate, calcium sulfate dehydrate, calcium lactate trihydrate, monobasic calcium sulfate monohydrate, calcium carbonate, tribasic calcium phosphate, diabasic calcium phosphate, maltodextrin, starch, modified starch, starch hydrolyzates, pregelatinized starch, microcrystalline starches, microcrystalline cellulose, powdered cellulose, cellulose and cellulose derivatives, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, glycine, kaolin, sodium chloride, inositol, bentonite.
The suitable anti-oxidants include Ascorbic acid derivatives such as ascorbic acid, erythorbic acid, Na ascorbate, Thiol derivatives such as thioglycerol, cysteine, acetylcysteine, cystine, dithioerythreitol, dithiothreitol, glutathione, Tocopherols, Butylated hydroxyanisole (BHA), Butylated hydroxytoluene (BHT), Sulfurous acid salts such as sodium sulfate, sodium bisulfite, acetone sodium bisulfite, sodiummetabisulfite, sodium sulfite, sodium formaldehyde sulfoxylate, and sodium thiosulfate, Nordihydroguaiaretic acid.
One important embodiment of the application is a process for preparing a solid dispersion composition comprising the steps of: (a) preparing a homogenous aqueous and/or organic solution of (i) at least one active pharmaceutical ingredient (API) which belongs to BCS class II or class IV and (ii) a naturally originated carrier; and (b) rotary vacuum evaporation of the resultant of step (a) to yield a dry powder form of solid dispersion composition and (c) drying over calcium chloride containing desiccators, triturating, sieving and storing in an air tight container of step (b) until further use.
One important embodiment of the application is a process for preparing a solid dispersion composition comprising the steps of: (a) preparing a homogenous aqueous and/or organic solution of (i) at least one active pharmaceutical ingredient (API) which belongs to BCS class II or class IV and (ii) a naturally originated carrier; and (b) rotary vacuum evaporation of the resultant of step (a) to yield a dry powder form of solid dispersion composition and (c) drying over calcium chloride containing desiccators, triturating, sieving and storing in an air tight container of step (b) the resulted powder is further mixed with a suitable pharmaceutical acceptable excipient and compressed either to a tablet or directly filled into a capsule, or tablets filled into a capsule.
According to one embodiment of the present application, the poorly soluble API was mixed with the naturally originated liquid carrier at a temperature to make a suspension of those components. The resultant suspension was then dried using rotary vacuum evaporator at a moderate speed and at a fixed rpm. The mass obtained was then dried over a calcium chloride containing desiccators at room temperature, triturated, sieved through and stored in an air tight container until further use.
According to one embodiment of the present application, alternative methods for preparing solid dispersions would include, but are not limited to, fusion/melt technology, hot- melt coating, prilling, melt-congealing, melt-granulation, spray-congealing, solvent- evaporation, spray-drying, co-precipitation, supercritical fluid method, and electrostatic spinning method.
According to one particularly preferred embodiment of this application, Mefenamic Acid (API) and Skimmed milk (naturally originated carrier) are mixed, heated, dried under rotary vacuum evaporator to form a solid dispersion along with, optionally, one or more pharmaceutical acceptable excipients, which may comprise suitable processing aids, bulking agents, plasticizer, surfactants, plasticizers, disintegrants, lubricants, glidants, anti-oxidants, anti-adherents, inert fillers, wetting agents, pH modifiers, binders, solubility modifiers, and/or recrystallization inhibitors.
The solid dispersion of the present application can be advantageously formulated with or without pharmaceutically acceptable additives. The preferred dosage formulations of the present application would include, but are not limited to, powder, granules, fine granules, tablets, rings, capsules, pellets, suppositories, ointments, plasters, cataplasms, aerosols, powders and the like.
Further, certain aspects of the present invention are illustrated in more detail by way of the below given examples. The examples are given herein for illustration of the invention and are not intended to be limiting thereof.

EXAMPLE: 1
A) Materials: Mefenamic acid was gifted by Robert Johnson laboratories, Hyderabad, India. Skimmed milk was purchased from local departmental store, Hyderabad, India. All other reagents and solvents utilized were of analytical grade.
B) Methods:
1. Mefenamic Acid Composition:
A Mefenamic Acid solid dispersion composition comprising (a) Mefenamic Acid and (b) Skimmed Milk is prepared for the present application.
2. Preparation of skimmed milk solid dispersions:
About 1 gm of the drug was mixed with 60 ml of skimmed milk using a magnetic stirrer at 50°C for about 30 min. The resultant suspension was then dried in a rotary vacuum evaporator (Steroglass, Germany) at 100 rpm, 50°C under vacuum for about 45 min. The mass obtained was then dried over a calcium chloride containing desiccator at room temperature for 24 hr, triturated, sieved through sieve no. 60 and stored in an air tight container until further use.
3. Drug content of solid dispersion:
Solid dispersions equivalent to 100 mg of drug was taken and dissolved separately in 100 ml of pH 7.4 phosphate buffer. The solution was filtered and was further diluted such that the absorbance falls within the range of standard curve. The absorbance of solutions was determined at 285 nm using UV- visible spectrophotometer (UV – 3200, Lab India, India). From the absorbance total drug content in the batch was calculated.
4. Solubility studies of pure drug and solid dispersion:
Excess amounts of Mefenamic acid and its solid dispersions with skimmed milk powder were added in 2 ml clicklock micro centrifuges containing 1 ml of pH 7.4 simulated gastric fluids. These centrifuges were shaken in an orbital shaker for 48 hrs at 25°C maintained at 100 rpm. They were then subjected to centrifugation at 1000 rpm for 10 min. 1 ml of the supernatant was carefully withdrawn, appropriately diluted and amount of drug dissolved was measured spectrophotometrically at 285nm.
5. In vitro drug release study:
The in vitro dissolution rate of pure drug, solid dispersion and marketed formulation was determined using type II USP dissolution apparatus (DS 800, Lab India, India) in pH 7.4 phosphate buffer at 37 ± 0.5°C and 50 rpm. Aliquots of samples were withdrawn at 5, 10, 15, 30, 45, 60, 90 and 120 min, filtered through membrane filter and amount of drug released was determined spectrophotometrically at 285 nm
In the present work, an attempt was made to improve the solubility of a poorly water soluble drug; Mefenamic acid, by formulating solid dispersions using skimmed milk as a carrier. The percentage of drug content for SD was found to be 97.62 ± 0.02. The solubility studies showed that the formulation having drug: carrier ratio of 1:3 and pure drug was 0.453 and 1.231 mg /ml respectively. The solubility of solid dispersion was 2.72 fold more than pure drug. From the data of in vitro dissolution profile of pure drug, solid dispersion, it is clear that percentage cumulative drug release from solid dispersion was remarkably higher than pure drug. At the15th minute, 55.76% of drug was released from solid dispersion, and only 8.58% from pure drug. That percentage cumulative drug release from solid dispersion and pure drug was 102.71±1.9 and 35.64±4.89 respectively. The percentage cumulative drug release from the solid dispersions was around 6.5 more than pure drug at 15th min, and it was 2.88 fold at 120 min
Solid dispersions of Mefenamic acid prepared using skimmed milk showed considerable increase in solubility and hence dissolution when compared to pure drug. The skimmed milk being natural in origin and easily available, it can be a better alternative to synthetic carriers. Also, from the literature it is evident that milk being a source of amino acids, it is recommended to use NSAIDs along with milk to prevent ulcers. Therefore, preparation of solid dispersions of Mefenamic Acid using skimmed milk is not only a good technique to improve the solubility but also to alleviate ulcers, which is a common side effect of NSAIDs.

EXAMPLE: 2
A) Materials: Mefenamic acid was gifted by Robert Johnson laboratories, Hyderabad, India. Skimmed milk was purchased from local departmental store, Hyderabad, India. All other reagents and solvents utilized were of analytical grade.
B) Methods:
1. Preparation of Skimmed Milk powder:
100 mL of Skimmed Milk was dried in a Rotary vacuum evaporator (Steroglass, Germany) at 100 rpm, 35°C under vacuum for 6 h. The obtained powder was dried in an oven (100 mL skimmed milk yielded about 12.10 g powders) and passed through a sieve no (75-150 µm) and stored in air tight container till further use.
2. Preparation of Solid Dispersion:
Mefenamic Acid (1 g) was mixed in 50 mL of Skimmed Milk in a water bath at a temperature of 50°C and stirred for 30 minute using a magnetic stirrer. The resulting suspension was dried in a rotary vacuum evaporator at 100 rpm, 35°C under vacuum for 6 h forming solid dispersion of the drug in a powder form. The obtained powder was dried in an oven and passed through a sieve (75-150 µm) and stored in an airtight container till further use.
3. Preparation of Physical Mixture:
1 g of Mefenamic Acid was uniformly mixed with 6.05 g of powder Skimmed Milk using a spatula in a morter. The prepared mixture was stored in airtight container till further use.
4. Drug Content:
Solid dispersion or Physical mixture equivalent to 10 mg of Mefenamic Acid were weighed accurately and mixed with suitable quantity of methanol. The suspension was filtered through 0.22 µm nylon disc filter and drug content was analysed at 362 nm using UV spectrophotometer (UV-3200, Labindia, India). Each sample was analyzed triplicate.
5. Solubility Studies:
Pure Mefenamic Acid (20 mg), its physical mixture and solid dispersion with Skimmed Milk (141 mg equivalent to 20 mg Mefenamic Acid) under test, was placed in a glass stoppered flask containing 20 mL of distilled water. The samples were placed on a shaker, agitated at 28°C until equilibrium was achieved (48 h) and the aliquots were filtered through 0.22 µm nylon disk filter. The filtered samples were diluted suitably and assayed spectrophotometer at 362 nm.
6. Dissolution Studies:
In vitro dissolution studies of Mefenamic Acid, Physical Mixture and Solid Dispersion were carried out using USP Paddle method by dispersed powder technique. Sample equivalent to 15 mg of Mefenamic Acid was added to 900 mL of distilled water containing 0.25 w/v % sodium lauryl sulphate at 37 ± 0.5°C and stirred at 50 rpm. An aliquote of 5 mL was withdrawn at different time intervals, filtered through 0.45 µm nylon filter disc. An equal volume of fresh dissolution medium was replaced (maintained at same temperature) in order to keep the total volume constant. The filtered samples were suitably diluted, if necessary, and assayed spectrophotometrically at 362 nm.
The drug content of the prepared solid dispersion and physical mixture was found to be in the range of 99.1 and 101.4% indicating the application of the present method for the preparation of solid dispersions with high content uniformity.
Solubility of Mefenamic Acid in solid dispersion was nearly three times (36.48 µg/mL), whereas in physical mixture 2.4 times (29.72 µg/mL) higher than in the pure drug (12.41 µg/mL).
The dissolution of poorly water soluble drugs requires a dissolution medium entirely different from those used for water-soluble drugs. One of the techniques that have been useful in dissolution of insoluble drugs is the incorporation of a small amount of surfactant in the dissolution medium. The use of surfactant in the dissolution medium may be physiologically meaningful, due to the presence of natural surfactant (like bile salts) in the gastrointestinal tract. The ability of surfactants to accelerate the in-vitro dissolution of poorly water-soluble drugs has been attributed to wetting, micellar solubilization, and/or deflocculation. It is easy to understand that a biorelevant medium needs similar surface activities like bio fluids. Studies on SLS have shown to satisfy the need. Based on these facts, dissolution of pure Mefenamic Acid, physical mixture and solid dispersion were carried out in distilled water containing 0.25 w/v % SLS. The dissolution of pure drug was found to be least. Incorporation with Skimmed Milk especially in solid dispersion form significantly improved the dissolution of the drug as compared to the physical mixture and the pure drug.
It can be confidently derived that, solid dispersion with Skimmed Milk was found to be more suitable form for Mefenamic Acid in terms of solubility and dissolution when compared to physical mixture. However, the physical mixture of Mefenamic acid with Skimmed Milk also gave better results than the pure drug. Thus, it can be concluded to formulate solid dispersion of Mefenamic acid with skimmed milk with a decreased therapeutic dose and less gastrointestinal disturbance for peroral and parenteral applications.
The solid dispersions according to the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).
For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner.
The compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form e.g. in ampules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
The invention having been disclosed in connection with the foregoing embodiments, additional variations will now be apparent to persons skilled in the art. Various modifications and variations to the above described method of preparation as per examples 1or 2 and also can be made without departing from the scope of the invention.
From the foregoing it will be understood that the embodiments of the present invention described above are well suited to provide the advantages set forth, and since many possible embodiments may be made of the various features of this invention and as the process for the preparation of the compounds herein described may be varied in various parts, all without departing from the scope of the invention, it is to be understood that all matter hereinbefore set forth or shown in the accompanying schemes is to be interpreted as illustrative and that in certain instances some of the features may be used without a corresponding use of other features, all without departing from the scope of the invention.
Without being limited by theory, the preparations of the present invention may be advantageously used to deliver compounds orally or preferably sometimes along with antiseptic agents, antibacterial agents or antibiotics belonging to class II or class IV. The delivery system designed or used for the delivery of the medicament using gelatin capsule has made product stable, robust and it prevents the disadvantages of the prior art.
Further the present invention has be illustrated in the different figures. The following specific and non-limiting steps for functioning need to be construed as merely illustrative, and do not limit the present disclosure in any way whatsoever.

Dated: 12h December, 2016

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