WO2023126979A1

WO2023126979A1 - Topical composition comprising duloxetine or its salt and capsaicin

Info

Publication number: WO2023126979A1
Application number: PCT/IN2022/051146
Authority: WO
Inventors: Vipin Sharma; Praveen Kumar MANDAPALLI; Mogallapalli LV SETTI; Anup Avijit Choudhury
Original assignee: Dr.Reddy's Laboratories Limited
Priority date: 2021-12-31
Filing date: 2022-12-30
Publication date: 2023-07-06
Also published as: CN118715009A

Abstract

The present specification relates to pharmaceutical composition comprising duloxetine, or pharmaceutically acceptable salts thereof, and capsaicin. The present specification more particulary relates to topical pharmaceutical composition comprising duloxetine, or pharmaceutically acceptable salts thereof, and capsaicin, for the treatment and/or management of neuropathic pain. Methods of preparing such compositions are also provided.

Description

TOPICAL COMPOSITION COMPRISING DULOXETINE OR ITS SALT

AND CAPSAICIN

CROSS REFERENCE

This application claims priority from Indian Patent Application No. 202141062105 filed on December 31 , 2021.

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

Neuropathic pain is a result of direct injury or disease to the nervous system, specifically the somatosensory system. This type of pain includes diabetic neuropathic pain which constitutes 30% of neuropathic pains, post-herpatic neuralgia & trigeminal neuralgia.

Current treatment regimen for neuropathic pain includes oral drugs such as gabapentin, pregabalin, topiramate, carbamazepine, lamotrigine, amitriptyline, nortriptyline venlafaxine or duloxetine, topical preparations of capsaicin or lidocaine. However, the oral drugs cause serious side effects on prolonged usage and the current topical preparations are associated with burning, stinging, or irritation effects.

There exists a need for compositions for the treatment of neuropathic pain that have less side effects & less burning, stinging, or irritation effects.

Duloxetine or its pharmaceutically acceptable salt, duloxetine hydrochloride, is a selective serotonin and norepinephrine reuptake inhibitor (SNRI). It is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and is approved as CYMBALTA® delayed-release oral capsules by USFDA for the treatment of Major depressive disorder (MDD), Generalized anxiety disorder (GAD), Diabetic peripheral neuropathic pain (DPNP), Fibromyalgia (FM) and Chronic musculoskeletal pain. The structural formula of duloxetine hydrochloride is:

Clinically prescribed oral duloxetine hydrochloride has limited therapeutic efficacy in terms of intolerable side effects such as hepatic impairment, renal insufficiency, weight gain, anorexia, fatigue, dry mouth etc and poor nerve repair. Moreover, oral administration demonstrates poor bioavailability (~50 %) due to first pass metabolism. Consequently, an alternative delivery, particularly topical delivery systems would be more preferable, as it delivers efficacious amount of the drug directly into the bloodstream across the skin, and thus avaoids the systemic side-effects.

Capsaicin is a synthetic equivalent of the naturally occurring compound found in chili peppers. Capsaicin is an agonist for the transient receptor potential vanilloid 1 receptor (TRPV1), which is an ion channel-receptor complex expressed on nociceptive nerve fibers in the skin and is approved as Qutenza® topical system in the United States & as Axsain® 0.075% w/w Cream in the United Kingdom for the treatment of neuropathic pain associated with postherpetic neuralgia (PHN) and neuropathic pain associated with diabetic peripheral neuropathy (DPN) of the feet. The structural formula of capsaicin is:

Capsaicin is associated with burning/ stinging sensation as a known side effect in majority of patients (50%-66%) that leads to early discontinuation or under-dosing resulting in suboptimal efficacy.

There is an unmet need for a topical preparation which eliminates or substantially ameliorates initial stinging pain caused by capsaicin observed in the administration with anti-inflammatory properties thereby making the preparation tolerable in long-term administration.

Further, there is no drug product/composition comprising duloxetine and capsaicin combination which is available or reported. Moreover, there is no such combination composition which is suitable for topical administration. Knowing the stability challenges associated with duloxetine, it is difficult to formulate both the drugs in a single composition. Thus, there also exists a need to develop stable topical composition of duloxetine and capsaicin.

SUMMARY OF THE INVENTION

The present specification provides novel pharmaceutical compositions comprising duloxetine, or, pharmaceutically acceptable salts thereof, and capsaicin, which is stable, non-irritant, easily penetrable and with aesthetic properties such as less stickiness/ greasiness, odor, texture etc, and with improved patient compliance and suitable to be administered topically for the treatment and/or management of pain associated with diabetic neuropathy, post herpatic neuralgia & other neuropathic pain; and that reduces burning sensation associated with topical capsaicin. The inventors have surprisingly and unexpectedly discovered that duloxetine in combination with capsaicin, in a topical dosage form, provide a synergistic therapeutic effect in treating neuropathic pain.

Accordingly, present specification discloses stable topical pharmaceutical compositions comprising a synergistic combination of duloxetine, or pharmaceutically acceptable salts thereof, and capsaicin for treatment and/or management of pain associated with diabetic neuropathy, post herpatic neuralgia & other neuropathic pain. Methods of preparing such compositions are also provided.

In one aspect, the present specification relates to a pharmaceutical compositions comprising: a) duloxetine, or a pharmaceutically acceptable salt, b) capsaicin, and

In one aspect, the present specification relates to fixed dose compositions comprising: c) duloxetine, or a pharmaceutically acceptable salt, d) capsaicin, and e) one or more pharmaceutically acceptable excipient.

In one aspect, the present specification relates to topical compositions comprising: a) duloxetine, or a pharmaceutically acceptable salt, b) capsaicin, and c) one or more pharmaceutically acceptable excipient.

In one aspect, the present specification relates to stable topical compositions comprising: a) duloxetine, or a pharmaceutically acceptable salt, b) capsaicin, and c) one or more pharmaceutically acceptable excipient.

In yet another aspect, the present specification relates to topical compositions comprising duloxetine, or pharmaceutically acceptable salts thereof, and capsaicin which are stable, nonirritant, easily penetrable, without burning sensation and with aesthetic properties such as less stickiness/ greasiness, odor, texture etc, and with improved patient compliance and and that reduces burning sensation associated with topical capsaicin.

In yet another aspect, the present specification relates to topical compositions comprising duloxetine, or pharmaceutically acceptable salts thereof, and capsaicin that reduces burning sensation associated with topical capsaicin.

In yet another aspect, the present specification relates to use of topical compositions comprising duloxetine, or pharmaceutically acceptable salts thereof, and capsaicin for the treatment and/or management of pain associated with diabetic neuropathy, post herpatic neuralgia & other neuropathic pain.

BRIEF DESCRIPTION OF FIGURES:

Figure 1: Paw licking test- Marketed capsaicin (Axsain®)

Figure 2: Paw licking test- Marketed capsaicin (Axsain®) & oral duloxetine

Figure 3: Paw licking test- example la

DESCRIPTION OF THE INVENTION

The present specification relates to pharmaceutical compositions comprising duloxetine, or pharmaceutically acceptable salts thereof, and capsaicin. The present specification more particulary relates to topical pharmaceutical composition comprising duloxetine, or pharmaceutically acceptable salts thereof, and capsaicin, for the treatment and/or management of pain. Methods of preparing such compositions are also provided.

In one aspect, the present specification relates to a fixed dose compositions comprising: f) duloxetine, or a pharmaceutically acceptable salt, g) capsaicin, and h) one or more pharmaceutically acceptable excipient.

As used herein, the term “topical" is used in its conventional sense to mean delivery of a topical drug or pharmacologically active agent to the skin or mucosa, as in, for example, the treatment of various skin disorders. Topical administration, in contrast to transdermal administration, primarily provides a local rather than a systemic effect.

The term "composition" is intended to encompass a combination including one or more active ingredients and pharmaceutically acceptable excipients.The excipients that are useful in preparing pharmaceutical compositions are generally safe, non- toxic, and are acceptable for veterinary use as well as human pharmaceutical or cosmetic use. The term includes both one and more than one such excipients. The topical composition of the present specifications may be in the form of lotions, liquids, creams, gel, ointments, liniments, spray etc. that are suitable for topical administration.

The term "about" is used to provide flexibility to a numerical range endpoint by providing that a given value may be "a little above" or "a little below" the endpoint. As used herein, the term "about" means a slight variation of the value specified, preferably within 10 percent of the value specified. Nevertheless, the term "about" can mean a higher tolerance of variation depending on for instance the experimental technique used. Said variations of a specified value are understood by the skilled person and are within the context of the present application. The topical compositions of the present specification comprising duloxetine, or a pharmaceutically acceptable salt, capsaicin and pharmaceutically acceptable excipients.

The term “duloxetine” as used in the context of the present specification relates to the free base form, acid form, salt form, polymorphic crystalline or amorphous form, solvates, ethers, esters, etc. Preferably duloxetine is present in the pharmaceutically acceptable salt form, e.g. duloxetine hydrochloride. 20, 30, or 60 mg of duloxetine is equivalent to 22.4, 33.7, or 67.3 mg of duloxetine hydrochloride, respectively. The amount of duloxetine, or pharmaceutically acceptable salt thereof, employed in the composition is in the range of about 0.01 % to about 8% (w/w), about 0.1 % to about 2 % (w/w) of total composition, e.g. 0.25 % (w/w), 0.5% (w/w) or 0.75% (w/w).

The term “capsaicin” as used in the context of the present specification relates to the free base form, acid form, salt form, polymorphic crystalline or amorphous form, solvates, ethers, esters, etc. Preferably capsaicin is present in base form. The amount of capsaicin or pharmaceutically acceptable salt thereof employed in the composition is in the range of about 0.025 % to about 2.5% (w/w), 0.05 % to 0.5% (w/w) of total composition, e.g. 0.05% (w/w), 0.075 % (w/w) or 0.1% (w/w).

Useful pharmaceutical acceptable excipients of the present specification include, but are not limited to vehicles, permeation enhancer, emulsifying agents, emollients, humectants, alkalizing agents, preservatives, antioxidants, fragrance imparting agents, film formers, chelating agents, and buffering agents and the like, including any combinations of two or more thereof.

The topical compositions of the present specification may comprise a vehicle or diluent or base. Suitable vehicles include hexylene glycol, polyethylene glycol such as that of macrogol 300, macrogol 3350, water or mixtures thereof. The amount of vehicles employed in the composition is in the range of about 1% to about 80% (w/w) of total composition i.e. about 50% (w/w), about 60% (w/w), about 70% (w/w), e.g. 50% (w/w), 60% (w/w), 70% (w/w).

The topical compositions of the present specification include one or more permeation enhancers. Examples of permeation enhancers that are useful for preparing compositions of the present specification include, but are not limited to, diols and esters, including propylene glycol; polyols and esters, including polyethylene glycol, polyethylene glycol monolaurate, and butanediol; alcohols including isopropyl alcohol; sulfoxides, including dimethylsulfoxide and decylmethylsulfoxide; ethers, including diethylene glycol monoethyl ether (e.g., Transcutol® P) and diethylene glycol monomethyl ether; fatty acids, including lauric acid, oleic acid, and valeric acid; fatty acid esters, including isopropyl myristate, isopropyl palmitate, methyl propionate, and ethyl oleate; nitrogenous compounds including urea, dimethyl acetamide, dimethylformamide 2- pyrrolidone, ethanolamine, methyl-2-pyrrolidone, diethanolamine, and triethanolamine; terpenes; alkanones; organic acids, including salicylic acid, citric acid, and succinic acid; and any mixtures thereof. A permeation enhancer can be used in concentration of about 0.001-15%, or about 0.05- 12%, or about 3-10%, of the total weight of the composition.

The topical compositions of the present specification include one or more emulsifying agents. Examples of emulsifying agents that are useful for preparing compositions of the present specification include, but are not limited to, sodium lauryl sulfate, sodium laureth sulfate (or sodium lauryl ether sulfate), polysorbate 60, polysorbate 80, emulsifying wax, fatty acids having 12-18 carbon atoms, such as undecylenic acid, lauric acid, myristic acid, palmitic acid, stearic acid, cetostearyl alcohol, isostearic acid, aracel, oleic acid, decyloleate, hydroxyoleic acid, linoleic acid, and their derivatives, glyceryl stearate, polyglycol esters of fatty acids (Cl 2-20), propylene glycol monostearate, sorbitanmonolaurate, sorbitanmonopalmitate, sorbitanmonostearate, sorbitantristearate, sorbitanmonooleate or sorbitantrioleate or mixtures thereof.In some embodiments, the emulsifying agent includes mixture of glyceryl stearate and polyethylene glycol - 100 stearate (ARLACEL 165). Useful emulsifying agents further include cetyl alcohol, acacia, carbomers, carrageenan, cetostearyl alcohol, ceresin wax, and any combinations thereof.

The topical compositions of the present specification may comprise an emollient. Suitable emollients include, for example, stearyl alcohol, formaldehyde glycerine, glyceryl monooleate, glyceryl monoricinoleate, glyceryl monostearate, cetyl alcohol, ispropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di-n-butyl sebacate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin alcohol, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, medium-chain triglycerides, butyl myristate, isostearic acid, palmitic acid, isopropyl linoieate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and mixture thereof. In some embodiments the emollient includes mixture of polysorbate 80, cetyl acetate, stearyl acetate, oleyl acetate acetylated lanolin alcohol (Crodalan AWS).

The topical compositions of the present specification may comprise a humectant. Examples of humectants that are useful in the context of the present specification include, but are not limited to, glycerin, propylene glycol, cyclomethicones, dimethicones, sorbitol, xylitol, urea, sugars and starches, sugar and starch derivatives (e.g., alkoxylated glucose), D-panthenol, hyaluronic acid, lactamide monoethanolamine, acetamide monoethanolamine, 2 -pyrrolidone-5 -carboxylic acid, urea, and any mixtures thereof.

The topical compositions of the present specification may comprise a thickener. Suitable thickeners include carboxylic acid polymers like carbomers (e.g. Carbopol.RTM. 954), polyacrylamides, acrylates/vinyl neodecanoate crosspolymer (e.g. Aculyn 38), medium-chain triglycerides, natural gums (e.g. guar, xanthan), cellulose derivatives (e.g. carboxy methylcellulose, methyl cellulose), PEG 6000, polyvinyl alcohol and mixtures thereof. The thickener could be pH dependent or pH independent.

The topical compositions of the present specification include one or more alkalizing agents. Suitable examples of alkalizing agents that may be used in the present application include, but are not limited to, primary, secondary and tertiary aliphatic amines, ethanolamines such as triethanolamine (TEA), diethanolamine (DEA), monoethanolamine (MEA), and the hydroxide of alkaline metals, such as sodium hydroxide, potassium hydroxide and the like. Preferred alkalizing agents include triethanolamine (trolamine). The alkalizing agent helps to stabilize the antifungal agent and pramoxine in a single composition. The use of such alkalizing agents also aids to maintain the pH of the composition which is suitable to apply topically. The pH of the compositions can range from about 4 to about 10, but preferably is in the range of about 5 to about 8, most preferably is in the range of about 4.5 to about 6.5.

The topical compositions of the present specification may comprise one or more preservatives. Suitable examples of preservatives, that may be used in the present application include, but are not limited to, aliphatic or aromatic alcohols; glycols; parahydroxybenzoic acid derivatives (e.g. parabens); Vitamin E or its derivatives, ethyl alcohol, benzyl alcohol, propylene glycol, glycerin, benzoic acid/sodium benzoate, sorbic acid, methylparaben, propylparaben, benzalkonium chloride, bronopol, chlorhexidine, chlorocresol and its derivatives, mixture of methylisothiazolinone and phenoxyethanol (NEOLONE™ PE), phenoxyethanol, ethylic alcohol, phenethylic alcohol, potassium sorbate, diazolidinylurea, benzylic alcohol or combinations thereof.

The topical compositions of the present specification may include one or more antioxidants. The antioxidant may be selected from DL-alpha-tocopherol, butylhydroxy toluene (BHT), butylhydroxy anisole (BHA), ascorbyl palmitate, ascorbic acid, propyl gallate, or mixtures thereof. In some embodiments, the antioxidant may be pramoxine or any pharmaceutically acceptable salts or esters or derivatives thereof.

The topical compositions of the present specification may include excipients to reduce stickiness of the composition, Suitable examples include, but are not limited to, starch and derivatives such as maize starch, potato starch; xylose, Dextroxe anhydrous, Dextrose Monohydrate , and the like and combinations thereof.

The topical compositions of the present specification may contain additional ingredients to improve the composition. Such ingredients include film formers, chelating agents, and buffering agents. Examples of such ingredients are well known in the art.

In one embodiment, the present specification is substantially free of water or alternatively when comprises water, is present in lower amounts for example less than about 30% (w/w), less than about 20% (w/w), less than about 10% (w/w), less than about 5% (w/w).

The topical compositions of the present invention may be a cream, a gel, a dispersion, an emulsion, a foam, a mist, a mouth wash, a lotion, a salve, an ointment, a spray, an aerosol, an oil, a plaster, a patch, or a suspension, preferably the pharmaceutically acceptable carrier for topical use is a ointment. Further, the compositions of the present invention may be prepared through any of the processes and techniques known in the art. The inventors have designed different formulation procedures, and varieties of excipients of oil and aqueous phases, surfactants and solubility enhancers, and emulsifiers in order to develop stable, uniform, and aesthetically acceptable compositions.

In an embodiment, the topical composition as per the present specification is an ointment composition comprising: a) duloxetine, or a pharmaceutically acceptable salt, b) capsaicin, and c) one or more pharmaceutically acceptable excipient

The topical compositions of the present specification can be manufactured using a method comprising the steps of: i. Preparation of ointment base ii. Prepration of drug phase iii. Mixing of drug phase with ointment phase under homogenization

In an embodiment, the topical composition as per the present specification is a cream composition comprising: a) Duloxetine, or a pharmaceutically acceptable salt, b) capsaicin, and c) one or more pharmaceutically acceptable excipient

The topical compositions of the present specification can be manufactured using a method comprising the steps of: i. Preparation of aqueous phase ii. Preparation of Oil phase iii. Emulsification iv. Congealing

The topical compositions of the present specification can be part of a kit or device and may be filled into tubes, jars, bottles, aerosol containers, and any other forms of packaging that facilitate application topically. The compositions are meant to be applied topically, either manually or by using a convenient applicator, for patient compliance and ease of application. The dose, number, and frequency of applications can be determined by a person skilled in the art of treating conditions, such as a physician, a dermatologist, and the like.

Laminated tubes may be used for packaging. The features and advantages of laminated tubes include ability to retain smoothness, flexibility and softness, increase in product shelf life, excellent barrier properties, excellent sealability, resistance to print bleeding, tamper evident closures with nozzle seals available, and hot foil stamping. HDPE tubes may also be used for packaging. Examples are pre-printed monolayer plastic tubes made of LDPE/LLDPE blends by extrusion processes and fitted with snap-on flip caps made up of polypropylene.

According to the invention, a topical formulation of the invention is administered at the skin, e.g. the human skin, at a dose four times daily, preferably three times daily, more preferably twice daily, more preferably daily, most preferably every other day. According to the invention, a topical formulation of the invention is administered for a period of at least one year, or longer, preferably at least one month, more preferably at least one week, most preferably at least one day, to achieve a continuous decrease of peripheral neuropathic pain or eventually a complete relief from the pain.

The topical compositions of present specification would be subjected to accelerated and long term stability studies.

The topical compositions of present specification would be subjected to in-vitro studies such as in vitro release test (IVRT) Studies, In Vitro Permeation Test (IVPT) Studies to test the release and permeation of the duloxetine and capsaicin.

The topical compositions of present specification would be subjected to in-vivo studies to test the safety and efficacy of the composition of the present specification and reduction of burning sensation associated with capsaicin.

The following examples further illustrate embodiments of the invention but should not be construed as in any way limiting its scope. Any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the invention.

EXAMPLES

Example 1: Topical ointment composition

Example la Example lb

Name of Ingredients .

(% w/w) (% w/w)

Capsaicin 0.075 0.15

Duloxetine HC1 0.5 1.25

Polyethylene Glycol 46 46

Maize Starch 1 1

Propylene glycol 25.75 23

Diethylene glycol monoethyl ether 16 18

Methylparaben 0 175 0 2

Propylparaben Q | Q |

Isopropyl alcohol 10 10

Butylated Hydroxy Toluene 0.4 0.3

Manufacturing Process: I. Preparation of ointment base a. Propylene glycol, Polyethylene Glycol were dispensed into a suitable vessel, b. Methyl paraben and propyl paraben were added under mechanical stirring at temperature of between 65 -75 °C, c. Maize starch was added under stirring under mechanical stirring, d. The mixture was cooled to a temperature of about 30°C,

II. Prepration of Drug phase e. Transcutol-P, capsaicin, duloxetine HC1, Isopropyl alcohol, Butylated Hydroxy Toluene were dispensed into a suitable vessel and the contents were mixed to make obtain a clear phase.

III. Mixing of drug phase with ointment phase under homogenization f. The drug phase was added to ointment phase and the mixture was stirred till a smooth ointment was obtained.

Example 2: Topical cream composition

Example 2a Example 2b

Name of Ingredients .

(% w/w) (% w/w)

Capsaicin 0.075 0.15

Duloxetine HC1 0.75 0.25

Isopropyl Myristate 10 10

Stearyl Alcohol 4.5 4.5

Sorbitan Monostearate 2.75 26

Polysorbate 20 (Tween 20) 2 2

Polyoxyl 20 cetostearyl ether 4 4

Cetyl Alcohol 4 5 4 5

Propyl paraben 0 1 o.l

Methyl Paraben 0.2 0.2

Titanium Dioxide 2 2

Purified water q. s. q. s. Manufacturing Process :

I. Preparation of aqueous phase a. purified water in taken in a suitable vessel and Polysorbate 20 was added to it under stirring, duloxetine HC1 is added to it and stirred until dissolved, b. heat the phase till 75°C, II. Preparation of Oil phase c. capsaicin, Isopropyl Myristate, Cetyl alcohol, stearyl alcohol, Polyoxyl 20 cetosteryl ether, sorbitan monostearate, Methylparaben and Propylparaben are taken in a suitable vessel and heated to 75 °C,

III. Emulsification d. oil phase of step c is added to to Aqueous phase of step b at 75 °C and is homogenized using Remi homogenizer at 3000 rpm for 30 min,

IV. Congealing e. The bulk of step d is cooled under stirring at 250 rpm, f. make up the weight loss with water at 36 - 38°C, to compensate for evaporation losses), g. the bove mixture is stirred at 150 rpm for 10 min.

Example 3: Topical ointment composition

Example 3a Example 3b

Name of Ingredients

(% w/w) (% w/w)

Capsaicin 0.025 2.5

Duloxetine HC1 0.011 7.984

White petrolatum 32 43.3

Mineral oil 22 6.991

Polyethylene glycol 400 25.764 23.075

Dimethyl isosorbide 20 15

2-tert-butylhydroquinone 0.2 0.15

Manufacturing Process:

I. Preparation of Ointment Base: a. White petrolatum, mineral oil, and 2-tert-butylhydroquinone mixed and melted to get clear phase.

II. Preparation of Drug Phase: b. Capsaicin and Duloxetine HC1 dissolved/dispersed in solvent mixture of Dimethyl isosorbide and PEG 400.

III. Mixing: c. Drug phase added to ointment base under homogenization and stirring. d. Mixing continued with cooling till to reach room temperature to obtain homogenous mass.

Example 4: Topical gel composition

Name of Ingredients Example 4a Example 4b Example 4c Example 4d

(% w/w) (% w/w) (% w/w) (% w/w)

Capsaicin 0.025 2.5 0.025 2.5

Duloxetine HC1 0.75 7.984 1.5 2.0

Polyethylene glycol 400 - 10

Polyethylene glycol 200 14.6 - 10 17

2-tert-butylhydroquinone 0.3 0.3 0.3 0.2

Absolute alcohol 20 17.5 45

Cyclopentadecanone - - - 4

Purified water 60 59.266 39 62.5

Sorbitol 3 - 2 5

Dimethicone - - 1 2

Pemulen TR 1 0.3 0.2

Carbomer homopolymer type B 1 1.25

Hydroxy ethyl cellulose - - 1.25 3

Manufacturing Process:

I. Preparation of Aqueous phase a. Purified water, Sorbitol, & Dimethicone mixed together. b. Polymers (Either Carbomer/HEC or both) added under vortex followed by mixing to get homogenous bulk.

II. Preparation of Alcohol Phase c. 2-tert-butylhydroquinone, Cyclopentadecanone, Capsaicin and Duloxetine HC1 dissolved in polyol and alcohol mixture. III. Mixing: d. Phase B added to Phase A followed by mixing and homogenization. Example 5: Topical spray composition

Name of Ingredients Example 5a Example 5b

(% w/w) (% w/w)

Capsaicin 0.025 2.5

Duloxetine HC1 0.05 7.5

Polyethylene glycol 400 10.75 12.8

2-tert-butylhydroquinone 0.2 0.2

Absolute alcohol 70 55

Cyclopentadecanone 4 2

Purified water 15 20

Manufacturing Process: I. Preparation of Alcohol Phase: a. 2-tert-butylhydroquinone, Cyclopentadecanone, Capsaicin and Duloxetine HC1 dissolved in polyol and alcohol mixture.

II. Preparation of Aqueous Phase: b. Purified water loaded in a vessel. III. Mixing: c. Under stirring add phase (B) to phase (A) followed by mixing.

Example 6: Topical foam composition

Name of Ingredients Example 6a Example 6b

(% w/w) (% w/w)

Capsaicin 0.025 2.5

Duloxetine HC1 0.011 8.0

Polyethylene glycol 200 12.814 8.416

2-tert-butylhydroquinone 0.15 0.1

Absolute alcohol 60 65

Cyclopentadecanone 4 2

Purified water 20 10

Sorbitol 2 2

Dimethicone 1 1

Isobutane 30% 25% Manufacturing Process:

I. Preparation of Alcohol Phase: a. 2-tert-butylhydroquinone, Cyclopentadecanone, Dimethicone, Capsaicin and Duloxetine HC1 dissolved in polyol and alcohol mixture.

II. Preparation of Aqueous Phase: b. Purified water and Sorbitol mixed.

III. Mixing: c. Phase B added to Phase A followed by mixing.

Example 7: Stability study

Stability experiments were performed on compositions prepared according to example 1(a) to assess the degree of degradation of the active ingredients in the composition over time.

Conclusion: As can be seen from the results in table above, the composition exhibits acceptable storage stability and shelf-life. Example 8: Animal study

The objective of the study is to evaluate the reduction in burning sensation with concomitant administration of duloxetine & capsaicin in comparision with marketed capsaicin formulation (Axsain®).

Design

Animals: Swiss albino mice

Application & Duration: topical application on paw for 10 days.

Evaluation for behavioural observations (paw licking): Day 1, 4, 7 & 10; up to 120 mins post dose (in interval of 10 mins)

Evaluation for mechanical hypersensitivity (Von Frey method): Day 0, 1, 4, 7 & 10; for 30 mins (120 to 150 mins post dose)

Number of animals per group: 6

*p.o- per oral

Results are depicted in figures 1 to 3.

Conclusion: Significantly less burning sensation was observed with topical preparation as per present specification compared to the marketed capsaicin (Axsain®) formulation and combination of marketed capsaicin (Axsain®) & per oral duloxetine.

Example 9: Invivo- Human study

The topical compositions of present specification would be subjected to various invivo human studies to test the Pharmacokinetic Profile, efficacy, safety & tolerability.

Claims

We Claim: A pharmaceutical composition comprising: a) duloxetine, or a pharmaceutically acceptable salt, and b) capsaicin. The pharmaceutical composition as claimed in claim 1, wherein the composition is suitable for topical administration. The pharmaceutical composition as claimed in claim 1, wherein the amount of duloxetine, or pharmaceutically acceptable salt thereof, employed in the composition is in the range of about 0.01 % to about 8% (w/w) of the total composition. The pharmaceutical composition as claimed in claim 1, wherein the amount of duloxetine, or pharmaceutically acceptable salt thereof, employed in the composition is in the range of about 0.1 % to about 2% (w/w) of the total composition. The pharmaceutical composition as claimed in claim 1 , wherein the amount of capsaisin, employed in the composition is in the range of about 0.025 % to about 2.5% (w/w) of the total composition. The pharmaceutical composition as claimed in claim 1 , wherein the amount of capsaisin, employed in the composition is in the range of about 0.05 % to about 0.5% (w/w) of the total composition. The pharmaceutical composition as claimed in claim 1, wherein the composition comprises one or more pharmaceutical acceptable excipients selected from the group consisting of vehicles, permeation enhancer, emulsifying agents, emollients, humectants, alkalizing agents, preservatives, antioxidants, fragrance imparting agents, film formers, chelating agents, buffering agents and combinations thereof. The pharmaceutical composition as claimed in claim 2, wherein composition is in the form of a cream, a gel, a dispersion, an emulsion, a suspension, a foam, a mist, a lotion, a salve, an ointment, a spray, an aerosol, an oil, a plaster, or a patch. The pharmaceutical composition as claimed in claim 1, wherein the composition is for treatment and/or management of pain associated with diabetic neuropathy, post herpatic neuralgia & other neuropathic pain. A method of treatment and/or management of pain associated with diabetic neuropathy, post herpatic neuralgia & other neuropathic pain, by administration of a pharmaceutical composition comprising: a. duloxetine, or a pharmaceutically acceptable salt, and b. capsaicin. The method as claimed in claim 10, wherein the composition is suitable for topical administration. The method as claimed in claim 10, wherein the amount of duloxetine, or pharmaceutically acceptable salt thereof, employed in the composition is in the range of about 0.01 % to about 8% (w/w) of the total composition. The method as claimed in claim 10, wherein the amount of duloxetine, or pharmaceutically acceptable salt thereof, employed in the composition is in the range of about 0.1 % to about 2% (w/w) of the total composition. The method as claimed in claim 10, wherein the amount of capsaisin, employed in the composition is in the range of about 0.025 % to about 2.5% (w/w) of the total composition. The method as claimed in claim 10, wherein the amount of capsaisin, employed in the composition is in the range of about 0.05 % to about 0.5% (w/w) of the total composition. The method as claimed in claim 10, wherein composition is in the form of a cream, a gel, a dispersion, an emulsion, a suspension, a foam, a mist, a lotion, a salve, an ointment, a spray, an aerosol, an oil, a plaster, or a patch.