DESC:FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition/formulation for use in controlling neuropathic pain. More particularly, the invention relates to a composi-tion/formulation comprising a synergistic combination of Palmitoylethanolamide (PEA) and one or more natural ingredients.

BACKGROUND OF THE INVENTION
Humans and animals suffering from chronic and severe pain require good clinical man-agement. Multiple pharmacological agents are generally employed to treat diverse pathological pain states. Specifically, these pharmacological agents include opiates, nonsteroidal anti-inflammatory drugs, anticonvulsants, antidepressants, ketamine and others (Guindon et al., 2007). However, adverse side effects from these pharmacological agents constrain therapeutic dosing ultimately limiting therapeutic efficacy.
Improvements have been made in understanding pathophysiological mechanisms un-derlying chronic pain states. In addition, efforts have been made in developing different anal-gesic mechanisms for chronic pain that are not only effective, but also nontoxic and devoid of unwanted central side effects. Further improvements in chronic pain management are still re-quired.
Neuropathic pain (NP) is one such chronic pain which needs good clinical management. Neuropathic pain is defined as a pain that comes from problems with signals from the nerves. Neuropathic pain is different from the common type of pain caused by an injury, burn, pressure, etc. Indeed, neuropathic pain results from damage to or dysfunction of the peripheral or central nervous system, rather than stimulation of pain receptors. Diagnosis is suggested by out of proportion pain to tissue injury, dysesthesia (e.g., burning, tingling), and signs of nerve injury detected during neurologic examination. While different therapies have been suggested for treating and managing Neuropathic pain, one therapy in particular suggests employing Palmitoylethanolamide (PEA). PEA is an endogenous, fatty acid amide food component first discovered in the late 1950s when it was shown that the anti-allergic and anti-inflammatory activity exerted by egg yolk, peanut oil or soybean lecithin was due to a specific lipid fraction corresponding to PEA (Esposito and Cuzzocrea, 2013). PEA, was used many decades ago in some countries, but due to a lack of insight in its mechanism of action, interest weaned. Since the 1990s, interest surged again due to the discovery of its effects in many different animal paradigms for pain and chronic inflammation (J Pain Res. 2012; 5: 437–442). PEA is synthe-sized and metabolized by different animal cell types and is also present in herbs or plants. It exerts a multitude of physiological functions related to metabolic and cellular homeostasis. It is a key element in the regulation of pathways linked to the inflammation process particularly in the down-regulation of the mastocytes degranulation process, and processes underlying itching and pain.
Cannabinoid-based medicines have therapeutic potential for the treatment of pain. Augmentation of levels of endocannabinoids with inhibitors of fatty acid amide hydrolase (FAAH) is analgesic. FAAH is a membrane-bound serine hydrolase that belongs to the amidase signature family of hydrolases. FAAH enzyme breaks down fatty acid amides such as anandamide (N-arachidonoylethanolamide), N-oleoylethanolamide (N-OEA), PEA and oleamide. FAAH belongs to a large and diverse class of enzymes referred to as the amidase signature (AS) family.
FAAH Inhibitors are a class of molecules that inactivate the FAAH Enzymes by pre-venting the hydrolysis of anandamide, oleoylethanolamide and PEA. It thereby increases en-dogenous levels. Known chemically synthesized FAAH inhibitors are BIA 10-2474, URB524, URB-597, URB694, URB937, etc. These inhibitors are disclosed in the article published by Colombano et al. titled, “O-(Triazolyl) methyl carbamates as a novel and potent class of fatty acid amide hydrolase (FAAH) inhibitors” and in the article published by Otrubova et al. titled, “The discovery and development of inhibitors of fatty acid amide hydrolase (FAAH).”

Related Prior Arts
US 5990170 discloses a method of synthesis of PEA.
US 5506224 refers to a method for treating diseases involving mast cell degranulation, as a consequence of a neurogenic and/or immunogenic hyper-stimulation, comprising the ad-ministration of an effective amount of a series of compounds included in a general formula, comprising also the PEA.
EP1082292 discloses a composition comprising anandamide and PEA.
WO 2001/010434 describes a pharmaceutical composition comprising PEA in mi-cronized form having particle size less than 10 µm for use in the veterinary field.
WO 2001/024645 discloses a nutritional or therapeutic composition for oral administra-tion, which comprises a naturally occurring precursor that is metabolized to a compound having anandamide activity for use as a medicament, in which such precursor is a long chain poly-unsaturated fatty acid (LCPUFA) (e.g. arachidonic acid ARA or docosahexaenoic acid DHA) or a derivative thereof having a given general formula. According to an embodiment reported in such application, the composition also comprises an inhibitor of an anandamide inactivating enzyme (amidase), which is said to include PEA. However, no biological effects or further technical results of such hypothetical combination comprising PEA have been shown in such document.
WO 2002/080860 and WO 2005/046580 refers to a method of reducing food intake or reducing appetite in a mammal, said method comprising orally administering a fatty acid alka-nolamide compound, derivative, homolog, or analog. PEA is reported to be one of such fatty acid alkanolamide compounds.
WO 2011/027373 A1 discloses a pharmaceutical composition containing an ultra-micronized form of PEA, in which more than 90% by weight of PEA has particle sizes lower than 6 microns (mm).
NL2011448 discloses a pharmaceutical composition comprising PEA particles and/or pharmaceutically acceptable esters or salts thereof, in which the PEA particles are substantially free of pharmaceutical excipients.
WO 2013/121449 discloses a use of chemically synthesized FAAH / NAAH inhibitor in association with oxazoline of PEA, for a combined, separate or sequential administration.
EP2444078 describes the activity of PEA and other Aliamides in the treatment of renal diseases. Silymarin is an extract of the plant Silybum marianum, also known as milk thistle, the activity of which in the treatment of liver diseases is known.
EP2944309 and WO 2016/185468 disclose a pharmaceutical composition comprising a combination of PEA and Opioid use for the treatment of pain.
WO 2016/063217 discloses a combination of PEA and Spirulina for the treatment of in-flammatory states.
WO 2016/146453 discloses a pharmaceutical composition comprising a combination of PEA and a vitamin B.
WO 2016/183134 provides compositions comprising PEA, and an anti-inflammatory or anti-pain component.
WO 2016/193905 discloses a pharmaceutical composition comprising a combination of PEA and lycopene, and/or pharmaceutically acceptable salts and/or derivatives thereof.
EP3130336 relates to a food and/or nutraceutical composition comprising PEA. In par-ticular, it relates to a food and/or nutraceutical composition comprising PEA in association with at least one component selected from a second active ingredient and an agent that modifies its release in the organism.
There are several patent applications (WO 2012/015704, WO 2013/028570, WO 2014/017936, WO 2015/07613, WO 2015/07615, WO 2015/012708, WO 2015/016728, WO 2015/157313), which disclose chemically synthesized different types of FAAH inhibitors which elevate PEA level. However, these chemically synthesized FAAH inhibitors may have side effects upon administration in human or animals. Several studies reveal the serious side-effects (including death) of chemically synthesized FAAH inhibitors. Some of them include Eddleston Michael et al; “Implications of the BIA-102474-101 study for review of first-into-human clinical trials”, Br J Clin Pharmacol (2016) 81 582–586; Mallet et.al.; “FAAH inhibitors in the limelight, but regrettably”, International Journal of Clinical Pharmacology and Therapeutics, Vol. 54 – No. 7/2016 (498-501); and Kaur et al.” “What failed BIA 10–2474 Phase I clinical trial? Global speculations and recommendations for future Phase I trials”, J Pharmacol Pharmacotherapy. 2016 Jul-Sep; 7(3): 120–126.
Current treatment options for neuropathic pain mainly focus on neuronal system sup-pressing GABA or other inhibitory receptors. Most of the drugs used for neuropathic pain cause drowsiness, dizziness, blurred vision, somnolence, peripheral edema, psychomotor slow-ing and paresthesia and many more. These side effects decrease the Quality of Life of patient and reduce active working life. Also these drugs require dosage adjustment in different disease conditions such as renal disease or liver disease etc. Moreover using these drugs for long term causes de-sensitisation of receptors. Therefore, the requirement of increase in the dose of these drugs is required to elicit the desired response and that leads to more number of side effects. In conclusion, the current treatment paradigm has some gaps and requires some new arsenal to fight against Neuropathic Pain.
The above mentioned documents disclosing use of FAAH inhibitors are chemically synthesized, and there can be side effects due to synthetic ingredients. Hence, there is a re-quirement to develop formulations which use natural ingredients, including natural FAAH in-hibitors. Further, there is also requirement to provide a highly effective relief for neuropathic pain by PEA and its combination with other active ingredients without any side effects in hu-mans or animals accompanied with good tolerability at an effective dose and good safety pro-file. Hence, there exists a need for combinations of PEA which are highly effective in a neuro-pathic pain, accompanied by acceptable safety profile and without any adverse effects.

SUMMARY OF THE INVENTION
The present application provides a pharmaceutical composition/formulation comprising a synergistic combination of Palmitoylethanolamide (PEA) and one or more naturally occurring Fatty Acid Amide Hydrolase (FAAH) Inhibitor. In a preferred aspect, the present invention provides a composition or formulation comprising a synergistic combination of Pal-mitoylethanolamide and at least two naturally occurring FAAH inhibitors.
In another aspect, the present invention provides a pharmaceutical composi-tion/formulation comprising a synergistic combination of Palmitoylethanolamide (PEA) and one or more naturally occurring FAAH Inhibitors along with a pharmaceutically acceptable excipient.
In a further aspect, the pharmaceutical composition/formulation of the present invention additionally comprises vitamins, coenzymes or a combination thereof.
In one aspect, the natural FAAH Inhibitors in the present invention are selected from Myricetin, Isorhamnetin, Kaempferol, Pristimerin, Biochanin A, Genistein, Daidzein or a com-bination thereof.
In yet a further aspect, in the composition/formulation of the present invention, vitamins are selected from methylcobalamin, cyanocobalamin, benfotiamine or a combination thereof. The co-enzymes in the present invention are selected from ubidecarenone, thiamine pyrophosphate, Flavin adenine dinucleotide or a combination thereof.
In even another aspect, the pharmaceutical composition/formulation of the present in-vention comprises a synergistic combination of PEA, Daidzein, Genistein and a pharmaceuti-cally acceptable excipient.
In another aspect of the present application, a process for the preparation of a composi-tion/formulation is described. The process comprises (a) weighing and sieving the ingredients through a suitable sieve, (b) mixing the ingredients, (c) preparing a dough by adding a binder solution to the mixed ingredients and sieving to obtain granules, (d) drying the granules till the level of dryness (LOD) is reduced to less than 1.5 % w/w to obtain semi dried granules, and (e) sieving the semi dried granules through a suitable sieve to obtain the composition/formulation. The process further comprises adding lubricants or glidants to the semi dried granules and fill-ing the granules in Hydroxypropylmethyl cellulose (HPMC) capsule shells and sealing.
In a preferred aspect, the application provides a process for preparing the composi-tion/formulation of the present invention. The process comprises sifting previously weighed PEA, Natural FAAH Inhibitor(s), diluent(s), and disintegrating agent(s) separately through a sieve, mixing the contents to obtain a mixture, preparing a binder solution, and optionally add-ing second natural FAAH Inhibitor(s) in to the binder solution, adding the binder solution to the mixture obtained above and obtaining granules, drying the obtained granules to obtain semi dried granules and sifting the semi dried granules through a sieve, sifting previously weighed Lubricant(s) or glidant(s) separately through a sieve and mixing with the sifted semi dried granules to obtain a blend of the composition/formulation. The blend is further filled and sealed with HPMC capsule shells.

DETAILED DESCRIPTION OF THE INVENTION
While the invention has been described and illustrated with reference to certain particu-lar embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a con-sequence of variations in responsiveness of the mammal being treated for any of the indications with the compounds of the invention indicated above. The specific pharmacological responses observed may vary according to and depending upon the particular active compounds selected along with the present pharmaceutical carriers. Further, the responses may vary depending upon the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.
An objective of the present invention is to provide a composition/formulation compris-ing a synergistic combination of PEA and one or more natural ingredients.
In an embodiment, the present application provides a composition/formulation compris-ing a synergistic combination of PEA with at least one of a naturally occurring FAAH Inhibi-tor. In one aspect, the composition/formulation of the present invention may optionally com-prise vitamins and coenzymes. The composition/formulation of the present invention is able to provide a safe composition/formulation of PEA with one or more natural ingredients with en-hanced or synergistic effects compared to PEA alone in the treatment of neuropathic pain.
Another object of the present invention is to provide a composition/formulation com-prising a synergistic combination of PEA along with at least one of a naturally occurring FAAH Inhibitor to avoid side effects associated with synthetic FAAH inhibitors.
Another object of the present invention is to provide a composition/formulation com-prising a synergistic combination of PEA along with at least one of a naturally occurring FAAH Inhibitor, and other active ingredients selected from vitamins, coenzymes or a combination thereof.
In one preferred embodiment, a composition/formulation comprising PEA in micronized or non-micronized form is described. The composition/formulation includes at least one of a naturally occurring FAAH Inhibitor. The composition/formulation optionally includes vitamins or co-enzymes.
In a preferred aspect, the present invention provides a pharmaceutical composi-tion/formulation for treatment of neuropathic pain, wherein said composition/formulation comprises a synergistic combination of PEA with at least one of a naturally occurring FAAH inhibitor and a pharmaceutically acceptable excipient. The said composition/formulation op-tionally comprises vitamins or co-enzymes.
In a preferred aspect, the ratio of PEA:Natural FAAH Inhibitors is in a range of 99:1 to 50:50. In a more preferred aspect, the ratio of PEA: FAAH Inhibitor is 84:15.
The pharmaceutical composition/formulation of the present invention comprises PEA in micronized or non-micronized form. The amount of PEA in the pharmaceutical composi-tion/formulation of the present invention ranges from 35% by wt. to 80% by wt. of the compo-sition/formulation. In an embodiment the amount of PEA ranges from 45 to 80% by weight. In another embodiment, the amount of PEA ranges from 50 to 80% by weight. In yet another em-bodiment, the amount of PEA ranges from 60 to 80% by weight. In yet another embodiment, the amount of PEA ranges from 65 to 80% by weight. In yet even another embodiment, the amount of PEA ranges from 70 to 80% by weight. In yet a further embodiment the amount of PEA ranges from 75 to 80% by weight.
In a preferred embodiment, the pharmaceutical composition/formulation of the present invention comprises PEA in micronized or non-micronized form, wherein the amount of PEA in the pharmaceutical composition/formulation ranges from 150 mg to 2400 mg per unit dose.
The pharmaceutical composition/formulation of the present invention comprises at least one natural FAAH Inhibitor selected from Myricetin, Isorhamnetin, Kaempferol, Pristimerin, Biochanin A, Genistein, Daidzein. The amount of natural FAAH Inhibitor in the pharmaceuti-cal composition/formulation of the present invention ranges from 0.5% by wt. to 40% by wt. of the composition/formulation. In an embodiment, the amount of natural FAAH Inhibitor ranges from about 1 to 40% by weight. In an embodiment, the amount of natural FAAH Inhibitor ranges from about 10 to 40% by weight. In an embodiment, the amount of natural FAAH In-hibitor ranges from about 20 to 40% by weight. In a further embodiment, the amount of natural FAAH Inhibitor ranges from about 30 to 40% by weight.
In a preferred embodiment, the pharmaceutical composition/formulation of the inven-tion comprises at least one natural FAAH Inhibitors selected from Myricetin, Isorhamnetin, Kaempferol, Pristimerin, Biochanin A, Genistein, Daidzein, wherein the amount of natural FAAH Inhibitor in the pharmaceutical composition/formulation ranges from 2 mg to 2722 mg per unit dose.
The pharmaceutical composition/formulation of the invention optionally comprises vit-amins, co-enzymes or a combination thereof.
The vitamins are selected from methylcobalamin, cyanocobalamin, benfotiamine or a combination thereof. The amount of vitamins in the pharmaceutical composition/formulation of the present invention ranges from 0.01% by wt. to 30% by wt. of the composition/formulation. The amount of vitamins in the pharmaceutical composition/formulation of the present invention ranges from 0.1 mg to 200 mg per unit dose.
The co-enzymes are selected from ubidecarenone, thiamine pyrophosphate, flavin ade-nine dinucleotide or a combination thereof. The amount of co-enzymes in the pharmaceutical composition/formulation of the present invention ranges from 10 % by wt. to 40 % by wt. of the composition/formulation. The amount of co-enzymes in the pharmaceutical composi-tion/formulation of the present invention ranges from 50 mg to 200 mg per unit dose.
The pharmaceutical composition/formulation of the present invention can be formulated as tablets, capsules, granules, powder, sachets, suspension, solution, modified release for-mulations, topical formulations, etc.
The formulations of the present invention comprise suitable excipients such as diluents, disintegrants, binders, solubilizing agent, lubricants, glidants, solvents etc.
The diluents are selected from microcrystalline cellulose, lactose (anhydrous / monohy-drate / spray dried), starch, cellulose powder, silicified microcrystalline, ammonium alginate, calcium carbonate, calcium lactate, dibasic calcium phosphate (anhydrous/ dibasic dehydrate/ tribasic), calcium silicate, calcium sulfate, cellulose acetate, compressible sugar, confectioner’s sugar, corn starch, pregelatinized starch, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, fumaric acid, glyceryl palmitostearate, isomalt, kaolin, lactitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, medium-chain triglycerides, polydextrose, polymethacrylates, simethicone, sodium alginate, sodium chloride, sorbitol, sterilizable maize, sucrose, sugar spheres, sulfobutylether ß-cyclodextrin, talc, tragacanth, trehalose, xylitol or the like. The amount of diluent in the pharmaceutical composition/formulation of the present in-vention ranges from 5% by wt. to 50% by wt. of the composition/formulation.
The disintegrating agent is selected from croscarmellose sodium, crospovidone, car-boxymethyl cellulose (sodium / calcium), sodium starch glycolate, alginic acid, calcium alginate, cellulose powdered, chitosan, colloidal silicon dioxide, corn starch, docusate sodium, glycine, guar gum, hydroxypropyl cellulose low-substituted, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, povidone, sodium alginate, pregelatinized starch or the like. The amount of disintegrating agent in the pharmaceutical composition/formulation of the present invention ranges from 0.5% by wt. to 10% by wt. of the composition/formulation.
The binder is selected from hypromellose, starch, acacia, agar, alginic acid, calcium carbonate, calcium lactate, carbomers, carboxymethylcellulose sodium, carrageenan, cellulose acetate phthalate, ceratonia, chitosan, copovidone, corn starch, pregelatinized starch, cotton-seed oil, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum, hy-drogenated vegetable oil type I, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hy-droxypropyl cellulose, inulin, lactose, liquid glucose, low-substituted Hypromellose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, microcrystalline cellulose, pectin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, povidone, sodium alginate, stearic acid, sucrose, sunflower oil, tricaprylin, vitamin E polyethylene glycol succinate, zein or the like. The amount of binder in the pharmaceutical composition/formulation of the present invention ranges from 0.1% by wt. to 10% by wt. of the compo-sition/formulation.
The solubilizing agent is selected from polysorbate 80, sodium lauryl sulfate, anionic emulsifying wax, nonionic emulsifying wax, glyceryl monooleate, phospholipids, polyoxyeth-ylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxylglycerides, sorbitan esters, triethyl citrate, vitamin E polyethylene glycol succinate, microcrystalline cellulose, carboxymethylcellulose sodium, di-ethanolamine, ethylene glycol palmitostearate, glycerin monostearate, hypromellose, hypro-mellose acetate succinate, lecithin, polyethylene alkyl ethers, aluminum oxide, poly(methylvinyl ether/maleic anhydride), calcium carbonate, crospovidone, cyclodextrins, fructose, hydroxpropyl betadex, oleyl alcohol, povidone, benzalkonium chloride, benzethonium chloride, benzyl alcohol, benzyl benzoate, cetylpyridinium chloride, inulin, meglumine, poloxamer, pyrrolidone, sodium bicarbonate, starch, stearic acid, sulfobutylether b-cyclodextrin, tricaprylin, triolein, docusate sodium, glycine, alcohol, self-emulsifying glyceryl monooleate, cationic benzethonium chloride, cetrimide, xanthan gum, lauric acid, myristyl alcohol, butylparaben, ethylparaben, methylparaben, propylparaben, sorbic acid or the like. The amount of Solubilizing Agent in the pharmaceutical composition/formulation of the present invention ranges from 0.25% by wt. to 15% by wt. of the composition/formulation.
The lubricant is selected from magnesium stearate, zinc stearate, calcium stearate, glyc-erin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydro-genated vegetable oil type I, light mineral oil, magnesium lauryl sulfate, medium-chain triglyc-erides, mineral oil, myristic acid, palmitic acid, poloxamer, polyethylene glycol, sodium ben-zoate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, potas-sium benzoate or the like. The amount of Lubricant in the pharmaceutical composi-tion/formulation of the present invention ranges from 1% by wt. to 10% by wt. of the composi-tion/formulation.
The glidant is selected from Colloidal silicon dioxide, talc, calcium phosphate tribasic, cellulose powdered, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, mag-nesium trisilicate, silicon dioxide or the like. The amount of Glidant in the pharmaceutical composition/formulation of the present invention ranges from 1% by wt. to 10% by wt. of the composition/formulation.
The solvent is selected from water, alcohol, isopropyl alcohol, propylene glycol, almond oil, benzyl alcohol, benzyl benzoate, butylene glycol, carbon dioxide, castor oil, corn oil (maize), cottonseed oil, dibutyl phthalate, diethyl phthalate, dimethyl ether, albumin, dimethyl phthalate, dimethyl sulfoxide, dimethylacetamide, ethyl acetate, ethyl lactate, ethyl oleate, glycerin, glycofurol, isopropyl myristate, isopropyl palmitate, light mineral oil, medium-chain triglycerides, methyl lactate, mineral oil, monoethanolamine, octyldodecanol, olive oil, peanut oil, polyethylene glycol, polyoxyl 35 castor oil, propylene carbonate, pyrrolidone, safflower oil, sesame oil, soybean oil, sunflower oil, triacetin, tricaprylin, triethanolamine, triethyl citrate, triolein, water-miscible solvents or the like. The amount of solvent in the pharmaceutical com-position/formulation of the present invention is used in a quantity sufficient.
In a preferred embodiment, the pharmaceutical composition/formulation is formulated for oral administration. Specifically, the solid pharmaceutical compositions, for example, can be in the form of tablets, capsules, pills, hard capsules filled with liquids or solids, soft capsules, sachets, powders, granules, suspensions, solutions or modified release formulations.
Developing pharmaceutical compositions or formulations wherein one or more ingredi-ents are obtained from natural sources poses challenges for the formulator. Such challenges include providing a suitable size dosage form containing the effective amount of the active in-gredients. Challenges also include providing stable formulations while retaining desirable pharmacokinetic properties. As currently understood, synthetic FAAH Inhibitors are not ap-proved for therapeutic use in any country by any drug regulatory authority. The present inven-tion provides stable and therapeutically effective compositions and formulations comprising PEA and one or more natural ingredients.
Some of the exemplary compositions /formulations of the present invention are de-scribed below:
Composition/Formulation 1:
S. No. Ingredient Amount (% w/w)
1. PEA 35 to 80
2. One Natural FAAH Inhibitor 0.5 to 40
Composition/Formulation 2:
S. No. Ingredient Amount (% w/w)
1. PEA 35 to 80
2. Two Natural FAAH Inhibitors 0.5 to 40
Composition/Formulation 3:
S. No. Ingredient Amount (% w/w)
1. PEA 35 to 80
2. Natural FAAH Inhibitor(s) 0.5 to 40
3. Vitamin 0.01 to 30
Composition/Formulation 4:
S. No. Ingredient Amount (% w/w)
1. PEA 35 to 80
2. Natural FAAH Inhibitor(s) 0.5 to 40
3. Co-enzyme 10 to 40
Composition/Formulation 5:
S. No. Ingredient Amount (% w/w)
1. PEA 35 to 80
2. Natural FAAH Inhibitor(s) 0.5 to 40
3. Vitamin 0.01 to 30
4 Co-enzyme 10 to 40
Composition/Formulation 6:
S. No. Ingredient Amount (% w/w)
1. PEA 35 to 80
2. Two Natural FAAH Inhibitors 0.5 to 40
3. Vitamin 0.01 to 30
4 Co-enzyme 10 to 40

General Process for preparation of the formulations of the present invention
1. Weigh accurately all the ingredients in separate containers.
2. Sift previously weighed PEA, Natural FAAH Inhibitor(s), a diluent (s) and disinte-grating agent(s) separately through sieve #40.
3. Mix content of step 2 in rapid mixer granulator (RMG) with impeller of slow speed.
4. Binder solution Preparation: In separate container, weigh a binding agent(s) and Solubilizing agent(s) and dissolve it into solvent(s) and add second natural FAAH Inhibitor(s) (if any) in to same solution.
5. Add binder solution to step 3 in RMG at slow speed of impeller.
6. Sift and dry the obtained granulated wet mass in a Fluid bed dryer at 50 °C+ 5 °C till the level of dryness (LOD) of the blend is reduced to less than 1.5 % w/w.
7. Sift semi dried granules through sieve # 20 and sieve # 30.
8. Sift previously weighed Lubricant(s) or Glidant(s) separately through sieve # 40 and mix with Step-7.
9. Fill and seal the blend with HPMC capsule shells.
10. Transfer the filled capsules into the hopper of polishing and visual inspection ma-chine to remove the debris of powder sticking with the capsule shells.

Examples
It is understood that the foregoing examples are merely illustrative of the present invention. Certain modifications of the articles and/or methods employed may be made and still achieve the objectives of the invention. Such modifications are contemplated within the scope of the claimed invention.
Example 1
S. No Ingredients Std. Qty. mg/unit % w/w
Intragranular Ingredients
1 Micronized PEA 300 66.67
2 Natural FAAH Inhibitor (Daidzein) 50 11.11
3 MCC pH 101 45.5 10.11
4 Croscarmellose Sodium 15 3.33
Binder Solution
5 PVP K-30 5 1.11
6 Polysorbate 80 10 2.22
7 IPA QS
8 Water QS
Extragranular Ingredients
9 Magnesium Stearate 10 2.22
10 Talc 4 0.89
11 Zinc Stearate 6 1.33
12 Colloidal silicon dioxide 4.5 1.00
Average Wt. 450 100.00

Example 2
S. No Ingredients Std. Qty. mg/unit % w/w
Intragranular Ingredients
1 Micronized PEA 300 60.00
2 Natural FAAH Inhibitor (Myricetin) 100 20.00
3 Lactose Monohydrate 45.5 9.10
4 Crospovidone 15 3.00
Binder Solution
5 Hypromellose 5 1.00
6 Polysorbate 80 10 2.00
7 IPA QS
8 Water QS
Extragranular Ingredients
9 Magnesium Stearate 10 2.00
10 Talc 4 0.80
11 Zinc Stearate 6 1.20
12 Colloidal silicon dioxide 4.5 0.90
Average Wt. 500 100.00

Example 3
S. No Ingredients Std. Qty. mg/unit % w/w
Intragranular Ingredients
1 Micronized PEA 300 66.67
2 Natural FAAH Inhibitor (Isorhamnetin) 50 11.11
3 MCC pH 102 45.5 10.11
4 Croscarmellose Sodium 15 3.33
Binder Solution
5 PVP K-30 5 1.11
6 Sodium Lauryl Sulfate 10 2.22
7 IPA QS
8 Water QS
Extragranular Ingredients
9 Magnesium Stearate 10 2.22
10 Talc 4 0.89
11 Zinc Stearate 6 1.33
12 Colloidal silicon dioxide 4.5 1.00
Average Wt. 450 100.00
Example 4
S. No Ingredients Std. Qty. mg/unit % w/w
Intragranular Ingredients
1 Micronized PEA 300 60.00
2 Natural FAAH Inhibitor (Kaempferol) 100 20.00
3 Mannitol 45.5 9.10
4 Sodium starch glycolate 15 3.00
Binder Solution
5 PVP K-30 5 1.00
6 Polysorbate 80 10 2.00
7 IPA QS
8 Water QS
Extragranular Ingredients
9 Magnesium Stearate 10 2.00
10 Talc 4 0.80
11 Zinc Stearate 6 1.20
12 Colloidal silicon dioxide 4.5 0.90
Average Wt. 500 100.00

Example 5
S. No Ingredients Std. Qty. mg/unit % w/w
Intragranular Ingredients
1 Micronized PEA 300 46.15
2 Natural FAAH Inhibitor (Pristimerin) 250 38.46
3 MCC pH 102 45.5 7.00
4 Croscarmellose Sodium 15 2.31
Binder Solution
5 Hypromellose 5 0.77
6 Polysorbate 80 10 1.54
7 IPA QS
8 Water QS
Extragranular Ingredients
9 Magnesium Stearate 10 1.54
10 Talc 4 0.62
11 Zinc Stearate 6 0.92
12 Colloidal silicon dioxide 4.5 0.69
Average Wt. 650 100.00

Example 6
S. No Ingredients Std. Qty. mg/unit % w/w
Intragranular Ingredients
1 Micronized PEA 300 60.00
2 Natural FAAH Inhibitor (Biochanin) 100 20.00
3 Lactose Monohydrate 45.5 9.10
4 Crospovidone 15 3.00
Binder Solution
5 PVP K-30 5 1.00
6 Sodium lauryl sulfate 10 2.00
7 IPA QS
8 Water QS
Extragranular Ingredients
9 Magnesium Stearate 10 2.00
10 Talc 4 0.80
11 Zinc Stearate 6 1.20
12 Colloidal silicon dioxide 4.5 0.90
Average Wt. 500 100.00

Example 7
S. No Ingredients Std. Qty. mg/unit % w/w
Intragranular Ingredients
1 Micronized PEA 300 75.0
2 Natural FAAH Inhibitor (Genistein) 4 1.0
3 MCC pH 101 41.5 10.38
4 Croscarmellose Sodium 15 3.75
Binder Solution
5 PVP K-30 5 1.25
6 Polysorbate 80 10 2.50
7 IPA QS
8 Water QS
Extragranular Ingredients
9 Magnesium Stearate 10 2.50
10 Talc 4 1.0
11 Zinc Stearate 6 1.50
12 Colloidal silicon dioxide 4.5 1.13
Average Wt. 400 100.00

Example 8
S. No Ingredients Std. Qty. mg/unit % w/w
Intragranular Ingredients
1 Micronized PEA 300 66.67
2 Natural FAAH Inhibitor (Daidzein) 50 11.11
3 MCC pH 101 41.5 9.22
4 Croscarmellose Sodium 15 3.33
Binder Solution
5 PVP K-30 5 1.11
6 Polysorbate 80 10 2.22
7 Natural FAAH Inhibitor (Genistein) 4 0.89
8 IPA QS
9 Water QS
Extragranular Ingredients
10 Magnesium Stearate 10 2.22
11 Talc 4 0.89
12 Zinc Stearate 6 1.33
13 Colloidal silicon dioxide 4.5 1.00
Average Wt. 450 100.00

Example 9
S. No Ingredients Std. Qty. mg/unit % w/w
Intragranular Ingredients
1 Micronized PEA 300 54.55
2 Natural FAAH Inhibitor (Myricetin) 100 18.18
3 Natural FAAH Inhibitor (Isorhamnetin) 50 9.09
4 Dicalcium Phosphate 45.5 8.27
5 Sodium starch glycolate 15 2.73
Binder Solution
6 Hypromellose 5 0.91
7 Polysorbate 80 10 1.82
8 IPA QS
9 Water QS
Extragranular Ingredients
10 Magnesium Stearate 10 1.82
11 Talc 4 0.73
12 Zinc Stearate 6 1.09
13 Colloidal silicon dioxide 4.5 0.82
Average Wt. 550 100.00

Example 10
S. No Ingredients Std. Qty. mg/unit % w/w
Intragranular Ingredients
1 Micronized PEA 300 54.55
2 Natural FAAH Inhibitor (Kaempferol) 100 18.18
3 Natural FAAH Inhibitor (Pristimerin) 50 9.09
4 Dicalcium Phosphate 45.5 8.27
5 Croscarmellose Sodium 15 2.73
Binder Solution
6 PVP K-30 5 0.91
7 Polysorbate 80 10 1.82
8 IPA QS
9 Water QS
Extragranular Ingredients
10 Magnesium Stearate 10 1.82
11 Talc 4 0.73
12 Zinc Stearate 6 1.09
13 Colloidal silicon dioxide 4.5 0.82
Average Wt. 550 100.00

Example 11
S. No Ingredients Std. Qty. mg/unit % w/w
Intragranular Ingredients
1 Micronized PEA 300 60.0
2 Natural FAAH Inhibitor (Biochanin) 100 20.0
3 Natural FAAH Inhibitor (Genistein) 4 0.80
4 Mannitol 41.5 8.30
5 Sodium starch glycolate 15 3.0
Binder Solution
6 PVP K-30 5 1.0
7 Sodium lauryl sulfate 10 2.0
8 IPA QS
9 Water QS
Extragranular Ingredients
10 Magnesium Stearate 10 2.0
11 Talc 4 0.80
12 Zinc Stearate 6 1.20
13 Colloidal silicon dioxide 4.5 0.90
Average Wt. 500 100.00

Example 12
S. No Ingredients Std. Qty. mg/unit % w/w
Intragranular Ingredients
1 Micronized PEA 300 66.67
2 Natural FAAH Inhibitor (Daidzein) 50 11.11
3 Mannitol 41.4 9.20
4 Croscarmellose Sodium 15 3.33
Binder Solution
5 PVP K-30 5 1.11
6 Polysorbate 80 10 2.22
7 Natural FAAH Inhibitor (Genistein) 4 0.89
8 Vitamin (Methylcobalamin) 0.1 0.02
9 IPA QS
10 Water QS
Extragranular Ingredients
11 Magnesium Stearate 10 2.22
12 Talc 4 0.89
13 Zinc Stearate 6 1.33
14 Colloidal silicon dioxide 4.5 1.00
Average Wt. 450 100.00

Example 13
S. No Ingredients Std. Qty. mg/unit % w/w
Intragranular Ingredients
1 Micronized PEA 300 66.67
2 Natural FAAH Inhibitor (Daidzein) 50 11.11
3 MCC pH 101 37.5 8.33
4 Croscarmellose Sodium 15 3.33
Binder Solution
5 Hypromellose 5 1.11
6 Polysorbate 80 10 2.22
7 Natural FAAH Inhibitor (Genistein) 4 0.89
8 Vitamin (Cyanocobalamin) 4 0.89
9 IPA QS
10 Water QS
Extragranular Ingredients
11 Magnesium Stearate 10 2.22
12 Talc 4 0.89
13 Zinc Stearate 6 1.33
14 Colloidal silicon dioxide 4.5 1.00
Average Wt. 450 100.00

Example 14
S. No Ingredients Std. Qty. mg/unit % w/w
Intragranular Ingredients
1 Micronized PEA 300 60.00
2 Natural FAAH Inhibitor (Daidzein) 50 10.00
3 Coenzyme (Ubidecarenone) 50 10.00
4 Lactose Monohydrate 41.5 8.30
5 Sodium starch glycolate 15 3.00
Binder Solution
6 PVP K-30 5 1.00
7 Polysorbate 80 10 2.00
8 Natural FAAH Inhibitor (Genistein) 4 0.80
9 IPA QS
10 Water QS
Extragranular Ingredients
11 Magnesium Stearate 10 2.00
12 Talc 4 0.80
13 Zinc Stearate 6 1.20
14 Colloidal silicon dioxide 4.5 0.90
Average Wt. 500 100.00

Example 15
S. No Ingredients Std. Qty. mg/unit % w/w
Intragranular Ingredients
1 Micronized PEA 300 60.00
2 Natural FAAH Inhibitor (Daidzein) 50 10.00
3 Coenzyme (Thiamine Pyrophosphate) 50 10.00
4 MCC pH 101 41.5 8.30
5 Croscarmellose Sodium 15 3.00
Binder Solution
6 PVP K-30 5 1.00
7 Polysorbate 80 10 2.00
8 Natural FAAH Inhibitor (Genistein) 4 0.80
9 IPA QS
10 Water QS
Extragranular Ingredients
11 Magnesium Stearate 10 2.00
12 Talc 4 0.80
13 Zinc Stearate 6 1.20
14 Colloidal silicon dioxide 4.5 0.90
Average Wt. 500 100.00

Example 16
S. No Ingredients Std. Qty. mg/unit % w/w
Intragranular Ingredients
1 Micronized PEA 600 80
2 Natural FAAH Inhibitor (Daidzein) 50 6.67
3 MCC pH 101 46.5 6.20
4 Croscarmellose Sodium 10 1.33
Binder Solution
5 Natural FAAH Inhibitor (Genistein) 4 0.53
6 PVP K-30 5 0.67
7 Polysorbate 80 10 1.33
8 IPA QS
9 Water QS
Extragranular Ingredients
10 Magnesium Stearate 10 1.33
11 Talc 4 0.53
12 Zinc Stearate 6 0.80
13 Colloidal silicon dioxide 4.5 0.60
Average Wt. 750 100.00

Example 17
S. No Ingredients Std. Qty. mg/unit % w/w
Intragranular Ingredients
1 Micronized PEA 150 35.71
2 Natural FAAH Inhibitor (Daidzein) 75 17.86
3 MCC pH 101 70.5 16.79
4 Croscarmellose Sodium 10 2.38
Binder Solution
5 Natural FAAH Inhibitor (Genistein) 75 17.86
6 PVP K-30 5 1.19
7 Polysorbate 80 10 2.38
8 IPA QS
9 Water QS
Extragranular Ingredients
11 Magnesium Stearate 10 2.38
12 Talc 4 0.95
13 Zinc Stearate 6 1.43
14 Colloidal silicon dioxide 4.5 1.07
Average Wt. 420 100

Stability Study

Example 18 - Stability and dissolution study of formulation of Example 1
Stability Condition: ACCELERATED STABILITY TESTING: 40°C, 75% RH
S. No Duration of Study Initial 1 Month 3 Months 6 Months
TEST Specification
1.0 Description White to off white colored granular powder filled in hard HPMC base capsule having red caps and red body. Complies Complies Complies Complies
2.0 Average weight of capsules 550 ± 7.5 % 551.2 mg 559.3 mg 551.4 mg 552.6 mg
3.0 Net fill content 450 ± 7.5 % 447.3 mg 448.1 mg 450.9 mg 451.7 mg
4.0 Disintegration time Not More Than 30 minutes 2 - 4 minutes 4 - 5 minutes 4 - 5 minutes 4 - 5 minutes
5.0 Assay
5.1 Assay of PEA Between 90.0 % and 110.0 % of LC 99.1 % 100.7 % 101.3 % 99.5 %
5.2 Assay of Daidzein Between 90.0 % and 110.0 % of LC 101.5 % 101.3 % 100.1 % 98.6 %
6.0 Dissolution (60 minutes)
6.1 Dissolution of PEA Not Less than 70 % in 60 minutes 92.1 % 95.1 % 93.3 % 91.3 %
6.2 Dissolution of
Daidzein Not Less than 70 % in 60 minutes 89.6 % 90.6 % 89.1 % 92.2 %

Example 19 - Stability and dissolution study of formulation of Example 7
Stability Condition: ACCELERATED STABILITY TESTING: 40°C, 75% RH
S. No Duration of Study Initial 1 Month 3 Months 6 Months
TEST Specification
1.0 Description White to off white colored granular powder filled in hard HPMC base capsule having red caps and red body. Complies Complies Complies Complies
2.0 Average weight of capsules 500 ± 7.5 % 503.5 mg 505.8 mg 504.9 mg 500.9 mg
3.0 Net fill content 400 ± 7.5 % 401.9 mg 403.8 mg 404.5 mg 400.5 mg
4.0 Disintegration time Not More Than 30 minutes 1 – 2
minutes 2 - 3 minutes 2 – 3
minutes 2 – 3
minutes
5.0 Assay
5.1 Assay of PEA Between 90.0 % and 110.0 % of LC 99.2 % 99.6 % 100.3 % 100.9 %
5.3 Assay of Genistein Between 90.0 % and 110.0 % of LC 95.9% 98.9% 98.3 % 99.9 %
6.0 Dissolution (60 minutes)
6.1 Dissolution of PEA Not Less than 70 % in 60 minutes 95.9 % 96.3 % 92.3 % 94.3 %
6.3 Dissolution of Genistein Not Less than 70 % in 60 minutes 88.1 % 89.9 % 92.3 % 87.6 %

Example 20 - Stability and dissolution study of formulation of Example 8
Stability Condition: ACCELERATED STABILITY TESTING: 40°C, 75% RH
S. No Duration of Study Initial 1 Months 3 Months 6 Months
TEST Specification
1.0 Description White to off white colored granular powder filled in hard HPMC base capsule having red caps and red body. Complies Complies Complies Complies
2.0 Average weight of capsules 550 ± 7.5 % 555.8 mg 559.6 mg 555.3 mg 552.1 mg
3.0 Net fill content 450 ± 7.5 % 458.0 mg 452.4 mg 459.4 mg 455.8 mg
4.0 Disintegration time Not More Than 30 minutes 3 – 4
minutes 3 - 4 minutes 3 – 4
minutes 4 - 6 minutes
5.0 Assay
5.1 Assay of PEA Between 90.0 % and 110.0 % of LC 106.9 % 107.3 % 106.2 % 108.2%
5.2 Assay of Daidzein Between 90.0 % and 110.0 % of LC 100.8 % 100.4 % 98.9 % 99.0 %
5.3 Assay of Genistein Between 90.0 % and 110.0 % of LC 95.6 % 96.8 % 94.6 % 96.9 %
6.0 Dissolution (60 minutes)
6.1 Dissolution of PEA Not Less than 70 % in 60 minutes 99.0 % 91.8 % 100.7 % 100.2 %
6.2 Dissolution of Dai-dzein Not Less than 70 % in 60 minutes 88.8 % 85.4 % 94.0 % 94.8 %
6.3 Dissolution of Genistein Not Less than 70 % in 60 minutes 80.1 % 88.5 % 89.6 % 95.9 %

Example 21 – Animal Study – Screening effect of synergistic combination or composi-tion/formulation comprising PEA and other natural ingredients against Oxaliplatin induced peripheral neuropathy in rat.

TEST SYSTEM AND ANIMAL HUSBANDRY
Species: Rat (Rattus norvegicus);
Strain: Wistar; Sex: Male / Female
No. of animals: 54 Animals (n=6 per group)
Animal House conditions:
Lighting: 12 / 12 hour light-dark cycle
Temperature: 25 ± 2 °C
Relative Humidity: 30 to 70%
Temperature and relative humidity were recorded Thrice daily.

During Experiments, Standard certified rat pellet feed (Manufactured• by Keval Sales Cor-poration, Vadodara) and drinking water treated by reverse osmosis) were provided ad libitum to all animals.
EXPERIMENTAL PROCEDURE: In study fifty-four (54) rats, were divided into total nine (09) groups.Group 1 served as the normal control, Group 2 served as the disease control, Group 3, Group 4 and Group 5 served as component (A, B and C), Group 6, Group 7 and Group 8 served as formulation of test drug, while Group 9 served as the Reference standard group. For these studies, the following combinations were used.

Table 1: represents various treatments to respective groups.
Table 1
S. No. Group No. of Animals Test Drug
1 G1 6 Normal Control
2 G2 6 Disease Control
3 G3 6 PEA (60 mg/kg, P.O.)
4 G4 6 DAIDZEIN (10 mg/kg, P.O.)
5 G5 6 GENISTEIN (0.8 mg/kg, P.O.)
6 G6 6 PEA (60 mg/kg, P.O.) + DAIDZEIN (10 mg/kg, P.O.) (Example 1)
7 G7 6 PEA (60 mg/kg, P.O.) + GENISTEIN (0.8 mg/kg, P.O.) (Example 7)
8 G8 6 PEA (60 mg/kg, P.O.) + DAIDZEIN (10 mg/kg, P.O.) + GENISTEIN (0.8 mg/kg, P.O.) (Example 8)
9 G9 6 Pregabalin (20 mg/kg, P.O.)

Group-1 received vehicle (0.25% w/v Sodium CMC) orally (p.o.) for three consecutive days (Day 1, 2 & 3). Group-2 to Group-8 received test drugs, while Group 9 received Pregabalin orally (p.o.) on Day-1, Day-2 and Day-3. All treatment groups (Group 2 to 9) were adminis-tered with oxaliplatin (12 mg/kg, i.p.) on Day-3 prior to 2 hrs of test drug administration. Af-ter 24 hrs of oxaliplatin administration, treated groups as well as the normal control group were assessed using the Cold hyperalgesia method.

Cold Hyperalgesia method (Tail Immersion Test): In the Tail-immersion test, water was maintained at low (0 to 4?C) temperature. The tail of the rat was immersed in cold water and the duration (time in seconds) of tail immersion was recorded, until the tail was withdrawn from water. The cut-off time of 20 seconds was used. The decrease in tail contact time with cold water was indicative pain whereas prolonged contact time was noted as anti-allodynic effect.
Table 2: Effect of administration of ‘Test Composition/formulation’ on Oxaliplatin induced peripheral neuropathy in rats
(Cold Hyperalgesia Method)

Groups 1 2 3 4 5 6 7 8 9
Animal Mark Normal Control Disease Control PEA
(60 mg/kg) Daidzein
(10 mg/kg) Genistein (0.8 mg/kg) PEA (60 mg/kg) + Dai-dzein
(10 mg/kg) PEA (60 mg/kg) + Genistein (0.8 mg/kg) PEA (60 mg/kg) +
Dai-dzein (10 mg/kg) + Genistein (0.8 mg/kg) Pregabalin (20 mg /kg)
1 20.00 16.00 11.32 8.55 7.68 17.13 16.93 18.87 17.20
2 20.00 14.81 11.55 8.00 7.15 17.13 16.93 18.87 20.00
3 20.00 6.19 10.85 8.98 7.23 17.13 16.93 18.87 20.00
4 20.00 5.66 10.97 7.95 7.68 17.13 16.93 18.87 19.95
5 20.00 4.05 11.44 8.12 7.68 17.13 16.93 18.87 18.37
6 20.00 3.78 10.75 8.05 7.68 17.13 16.93 18.87 20.00
AVG
(seconds) 20.00 8.42 11.15 8.28 7.52 17.13 16.93 18.87 19.25
% 55.73 41.38 37.58 85.65 84.65 94.35 96.27

Table 3: Effect of administration of ‘Test Composition/formulation’ on Oxaliplatin induced peripheral neuropathy in rat

Groups 1 2 3 4 5 6 7 8 9
Group Name
(Human Effective Dose / Day) Normal Control Disease Control PEA (600 mg) Dai-dzein (100 mg) Genistein (8 mg) PEA (600 mg) +
Dai-dzein (100 mg) PEA (600 mg)
+ Genistein (8 mg) PEA (600 mg)+
Daidzein (100 mg)+
Genistein (8 mg) Pregabalin (200 mg)
Day 0 20.00 20.00 20.00 20.00 20.00 20.00 20.00 20.00 20.00
Day 4 20.00 8.42 11.15 8.28 7.52 17.13 16.93 18.87 19.25
% 55.73 41.38 37.58 85.65 84.65 94.35 96.27

RESULT & DISCUSSION: In this study, Oxaliplatin (12 mg/kg) was administered via in-traperitoneal injection in rats. After intraperitoneal injection of Oxaliplatin, there was a sig-nificant reduction in tail withdrawal latency in the disease control group. In all treatment groups, either alone or in combination, tail withdrawal latency periods were significantly in-creased compared to the disease control group. This indicates that treatments were effective against peripheral neuralgia induced by oxaliplatin injection. The effect of treatment groups 6-8 was comparable with that of the standard drug pregabalin as shown in Table 2-3.

CONCLUSION: Based on the above experiments, when rats were treated only with PEA, Daidzein, or Genistein (i.e., Groups 3-5), in comparison to PEA+Daidzein, PEA+Genistein, and PEA+Daidzein+Genistein (i.e., Groups 6-8), the latter was found to be more effective in treating Oxaliplatin induced neuropathic pain in rats at defined dose levels

While the invention has been described and illustrated with reference to certain particular em-bodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in responsiveness of the mammal being treated for any of the indications with the compounds of the invention indicated above. The specific pharmacological responses observed may vary according to and depending upon the particular active compounds selected or wheth-er there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the res tills arc con-templated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.
,CLAIMS:We Claim:
1. A pharmaceutical composition comprising: Palmitoylethanolamide (PEA) and one or more naturally occurring Fatty Acid Amide Hydrolase (FAAH) Inhibitor.

2. The pharmaceutical composition as claimed in claim 1, wherein the amount of PEA ranges from 35 to 80% by wt. of the composition.

3. The pharmaceutical composition as claimed in claim 1, wherein the amount of naturally occurring FAAH inhibitor ranges from 0.5 to 40% by wt. of the composition.

4. The pharmaceutical composition as claimed in claim 1, wherein the naturally occurring FAAH Inhibitor is selected from Myricetin, Isorhamnetin, Kaempferol, Pri-stimerin, Biochanin A, Genistein, Daidzein or a combination thereof.

5. The pharmaceutical composition as claimed in claim 4, wherein the naturally occurring FAAH inhibitor is selected from Daidzein, Genistein or combination thereof.

6. The pharmaceutical composition as claimed in any of the preceding claims, fur-ther comprising vitamins, coenzymes or a combination thereof.

7. The pharmaceutical composition as claimed in claim 6, wherein the vitamins are selected from methylcobalamin, cyanocobalamin, benfotiamine or a combination there-of; and co-enzymes are selected from ubidecarenone, thiamine pyrophosphate, Flavin adenine dinucleotide or a combination thereof.

8. The pharmaceutical composition as claimed in claim 6, wherein the amount of vitamins ranges from 0.01 to 30% by wt. of the composition.

9. The pharmaceutical composition as claimed in claim 6, wherein the amount of co-enzymes ranges from 10 to 40% by wt. of the composition.

10. The pharmaceutical composition as claimed in any of the preceding claims, fur-ther comprising pharmaceutically acceptable excipients.

11. The pharmaceutical composition as claimed in claim 10, wherein the pharma-ceutically acceptable excipient is selected from a diluent, disintegrant, binder, solubiliz-ing agent, lubricant, glidant, or solvent.

12. The pharmaceutical composition as claimed in claim 11, wherein the amount of diluent ranges from 5% to 50% by wt. of the composition, disintegrant ranges from 0.5% to 10 % by wt. of the composition, binder ranges from 0.1% to 10% by wt. of the composition, solubilizing agent ranges from 0.25% to 15% by wt. of the composition, lubricant ranges from 1.0% to 10% by wt. of the composition, glidant ranges from 1.0% to 10% by wt. of the composition, or amount of solvent is quantity sufficient.

13. The pharmaceutical composition as claimed in claim 1, wherein the composition is in the form of a tablet, capsule, sachet, pill, hard capsule filled with liquid or solid, soft capsule, powder, granule, suspension solution or modified release formulation.

14. A process for preparing a pharmaceutical composition as claimed in claim 1 comprising:
a. weighing accurately all the ingredients in separate containers,
b. sifting previously weighed PEA, Natural FAAH Inhibitor(s), diluent(s), and a disintegrating agent(s) separately,
c. mixing content of step b,
d. preparing binder solution in separate container and add it to step c and sieve the dough to obtain granules,
e. drying the obtained granulates until the level of dryness (LOD) is reduced to less than 1.5 % w/w,
f. sifting semi dried granules through suitable sieve,
g. sifting previously weighed lubricant(s) or glidant(s) separately through suitable sieve and add to step f.