DESC:FIELD OF THE INVENTION
The present invention generally relates to pharmaceutical sciences. Specifically, the present invention is related to a topical composition comprising isolated ß-caryophyllene, benzalkonium chloride, pharmaceutically acceptable excipients, and optionally an additional active component for the management of pain, inflammation, and other pain related disorders. Also, the present invention provides a method for producing the same and uses thereof.

BACKGROUND OF THE INVENTION
Beta-Caryophyllene (ß-Caryophyllene) chemically represented as trans-(1R, 9S)-8-Methylene-4,11,11-trimethylbicyclo-7.2.0 undec-4-ene or 1R-(1R4E.9S)-4,11,11-trimethyl-8-methylene-bicyclo7.2.0 undec-4-ene) is a natural bicyclic sesquiterpene compound found in spice blends, citrus flavors, Soaps, detergents, creams and lotions, and also in a variety of food products and beverages.

In nature, it mainly occurs as trans-caryophyllene ((E)-BCP) mixed with small amounts of its isomers, (Z)-ß-caryophyllene (iso-caryophyllene) and a-humulene (a-caryophyllene), as well as its oxidation derivative—ß-caryophyllene oxide (BCPO). In scientific literature, BCP mainly stands for (E)-BCP or the natural mixture of BCP isomers. ß-caryophyllene is the first known dietary cannabinoid, a common component of food that has GRAS (Generally Recognized as Safe) status and approved by FDA as well as by the European Food Safety Authority (EFSA) with identification number FL no: 01.007 for food use.

BCP is a colorless to slightly buttery liquid with a light clove-like fragrance. It is soluble in ether and ethanol, insoluble in water. The chemical structure of ß-caryophyllene is as follows:

BCP is one of the major active components of essential oils derived from large number of spice and food plants. According to Essential Oil Database, BCP as a plant volatile compound is commonly found in basil (Ocimum spp.), cinnamon (Cinnamomum spp.), black pepper (Piper nigrum L.), cloves (Syzygium aromaticum), cannabis (Cannabis sativa L.), lavender (Lavandula angustifolia), oregano (Origanum vulgare L.), rosemary (Rosmarinus officinalis), hops (Humulus lupulus), and copaiba (Copaifera langsdorffii).

ß-caryophyllene has several biological effects including anti-inflammatory, anticarcinogenic, antimicrobial, antioxidative, and analgesic activities. ß-caryophyllene is the primary sesquiterpene contributing to the spiciness of black pepper. ß-caryophyllene belongs to a class of cannabinoids (CBs), specifically phytocannabinoids (pCBs), which were identified as plant derivatives of Cannabis sativa L.

Natural and synthetic cannabinoids activate the cannabinoid receptors CB1 and CB2, however ß-caryophyllene activates exclusively CB2 and exhibits no affinity to CB1. Klaudyna et. al. [Cancer Medicine 2016; 5(10):3007-3017] in a study reported through quantitative radioligand binding experiments that ß-caryophyllene displays insensibly higher biding affinity to CB2 and do not bind to CB1. This implies that ß-caryophyllene action is devoid of psychoactive side effects associated with CB1 activation and suggests its potential use in medicine.

This selective CB2 activation properties of ß-caryophyllene suggests that ß-caryophyllene has potential as natural analgesic through significant cannabimimetic anti-inflammatory effects.

Further, Clayton et al. [Pain 96(2002) 253-260] in a study reported that activation of CB2 receptor alone is sufficient to produce anti-inflammatory and analgesic effect. Activation of CB1 receptor is likely to produce unwanted CNS side effects as these receptors have a wide distribution in the brain and are associated with psychoactivity, dependence and sedation. There is no such reported side effect associated with CB2 agonists. CB2 receptors are expressed exclusively in peripheral tissues and are not associated with any side effects. CB2 agonists therefore have the potential to provide safe and effective treatment of chronic inflammatory disorders.

Pain is a subjective sensation, evoked by various internal and external stimuli. It is an unpleasant feeling, which arises from sensitization of nociceptors—peripheral neurons responding to pain stimuli. Pain is classified as acute or chronic, according to its duration. Short-lived pain, generally associated with tissue damage or painful stimuli (e.g. the pain associated with a slight burn, a cut etc.), is defined "acute pain", and has an adaptive value as it warns us of the presence and location of a lesion and allows us to correct the behavior which causes it or contributes to it.

On the other hand, pain which persists beyond the time necessary for resolution of an acute condition is defined as "chronic pain". Pain is a serious social burden; it affects quality of life and leads to economic loss for patients as well as health services. It has been estimated that 20% of adults suffer from pain globally and around 10% of population worldwide suffers from long lasting pain [Goldberg and McGee BMC Public Health 2011, 11:770].

In the treatment of pain, in particular chronic pain, various substances are used, generally of a synthetic nature such as non-steroid anti-inflammatory drugs, opioids, etc., which induce analgesia, i.e., reduction in the sensation of pain. The treatments may be necessary for long periods, sometimes even for life. This leads to overuse of synthetic or semisynthetic pain killers such as opioids or nonsteroidal anti-inflammatory drugs (NSAIDs). Prolonged consumption of these medicines may cause serious side effects leading to health complications as well as drug tolerance for analgesic effect and addiction.

To decrease use of synthetic drugs, natural products with strong analgesic activities and low side effects are sought. Because of these cannabinoid receptors have been extensively studied as mediators of analgesia and thus potential targets for treatment of acute and neuropathic pain and inflammation. Activation of those receptors by endo- and exogenous ligands may inhibit pain responses, therefore CBs are considered as substances with high analgesic activities. Highly studied natural product i.e., cannabinoids from cannabis majorly contains tetrahydrocannabinol (THC), which is approved for the supportive care of several medical conditions in Austria, Belgium, Canada, and several states of the United States. THC mediates through cannabinoid receptors CB1 and CB2. Therefore, long term usage can lead to psychoactivity, dependence and sedation.

In view of the above findings, it is evident that ß-caryophyllene has potential as an efficient natural analgesic without any side effects like psychoactivity, dependence and sedation. ß-caryophyllene based analgesic compositions have been reported.

US20080280996 provides a composition comprising caryophyllenes including ß-caryophyllene for the treatment of inflammatory conditions and inflammatory pain.

AU2020412501 provides a composition comprising terpenes including ß-caryophyllene for the treatment of pain and anxiety.

However, topical composition comprising ß-caryophyllene has limitation with respect to absorption of ß-caryophyllene on the skin due to its low solubility in biological fluids. This restricts use of this highly safe natural analgesic in topical analgesic formulations.

Therefore, an unmet need exists for a topical composition based on ß-caryophyllene which is stable and has enhanced absorption on the skin for enhanced bioavailability of ß-caryophyllene to generate sufficient and quick analgesic effect.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides a topical pharmaceutical composition for the management of pain, inflammation, and pain related disorders. The said composition comprises 10% w/w to 60% w/w of an isolated ß-caryophyllene, 0.01% w/w to 35% w/w of benzalkonium chloride, 30% w/w to 70% w/w of at least one excipient, and optionally 0.5% w/w to 30% w/w of an additional active component.

The said composition is in a topical dosage form which can be applied on the skin to obtain relief from pain and inflammation within 2 minutes and the analgesic effect imparted by the said topical composition sustains for about 8 hours. The topical composition provided herein has enhanced absorption on the skin.

The present invention also provides simple processes for the preparation of said topical pharmaceutical composition.

The topical pharmaceutical composition provided herein is natural, safe, economic, and easy to prepare on industrial scale.

The topical analgesic composition provide herein has an analgesic effect equivalent to standard diclofenac-based analgesic topical compositions and has no side-effects like psycho-activity, dependence, and sedation.
BRIEF DESCRIPTION OF DRAWINGS
The accompanying drawings illustrate some of the embodiments of the present invention and, together with the descriptions, serve to explain the invention. These drawings have been provided by way of illustration and not by way of limitation. The components in the drawings are not necessarily drawn to scale, emphasis instead being placed upon clearly illustrating the principles of the aspects of the embodiments.
Figure 1 illustrates response latency of the composition disclosed herein (20% w/w of ß-caryophyllene, TruMove Gel) in comparison with a standard diclofenac-based analgesic gel (1% w/w of Diclofenac sodium).
Figure 2 illustrates % protection against acute pain imparted by the composition disclosed herein (20% w/w of ß-caryophyllene, TruMove Gel) in comparison with a standard diclofenac-based analgesic gel (1% w/w of Diclofenac sodium).
Figure 3 illustrates WOMAC and McGill pain scores from baseline to Post study in both the groups: the composition disclosed herein (20% w/w of ß-caryophyllene, TruMove Gel) in comparison with a standard diclofenac-based analgesic gel (1% w/w of Diclofenac sodium)
DETAILED DESCRIPTION OF THE INVENTION
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully interpreted and comprehended. However, any skilled person or artisan will appreciate the extent to which such embodiments could be generalized in practice.

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "the step" includes reference to one or more steps and equivalents thereof known to those skilled in the art, and so forth.

The publications discussed herein are provided solely for their availability to the applicant before the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by the prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred method, and materials are now described.

The term “TruMove” or “TruMove gel” used herein refers to a series of test products based on the topical pharmaceutical composition provided herein.

In one aspect of the present invention, there is provided a topical pharmaceutical composition for the management of pain, inflammation, and pain related disorders comprising:
- a therapeutically effective amount of isolated ß-caryophyllene;
- a pharmaceutically acceptable amount of benzalkonium chloride;
- a pharmaceutically acceptable excipient; and optionally an additional active component.

The term “ß-caryophyllene" or “beta-caryophyllene” or “BCP” or “beta caryophyllene” used herein refers to a compound represented by the following formula:

and chemically defined as trans-(1R, 9S)-8-Methylene-4,11,11-trimethylbicyclo-7.2.0 undec-4-ene or 1R-(1R4E.9S)-4,11,11-trimethyl-8-methylene-bicyclo7.2.0 undec-4-ene).

The term “isolated ß-caryophyllene” used herein refers to ß-caryophyllene available commercially as mixture of oils, ß-caryophyllene extracted from natural plants by conventional methods, or ß-caryophyllene prepared by synthetic routes.

The topical pharmaceutical composition provided herein comprises a therapeutically effective amount of isolated ß-caryophyllene.

In an embodiment of the present invention, the topical pharmaceutical composition provided herein comprises about 10% w/w to 60% w/w of isolated ß-caryophyllene.

In an embodiment of the present invention, the isolated ß-caryophyllene present in the topical pharmaceutical composition is in form of oil comprising about 70% w/w to 100% w/w of ß-caryophyllene.

In an embodiment of the present invention, the isolated ß-caryophyllene present in the topical pharmaceutical composition is in form of oil extracted from a group of plants comprising basil (Ocimum spp.), cinnamon (Cinnamomum spp.), black pepper (Piper nigrum L.), cloves (Syzygium aromaticum), cannabis (Cannabis sativa L.), lavender (Lavandula angustifolia), oregano (Origanum vulgare L.), rosemary (Rosmarinus officinalis), hops (Humulus lupulus), and copaiba (Copaifera langsdorffii).

In an embodiment of the present invention, the isolated ß-caryophyllene is extracted from cloves.

In an embodiment of the present invention, the isolated ß-caryophyllene is extracted from clove leaves.

The term "therapeutically effective amount" as used herein refers to the amount of the active ingredient in a composition which halts or reduces the progress of the condition being treated or which otherwise completely or partly cures or acts palliatively on the condition.

The therapeutically effective amount of isolated ß-caryophyllene in the topical pharmaceutical composition disclosed herein is in a range of about 10mg to 30mg.

In an embodiment of the present invention, the therapeutically effective amount of isolated ß-caryophyllene is in a range of about 0.2g to 1g.

The term “about” used herein refers to the referenced numeric indication plus or minus 10% of that referenced numeric indication.

The term “Benzalkonium Chloride” or “BAC” used herein refers to a compound represented by the following formula:

wherein n is equal to 8, 10, 12, 14, 16 and 18.

The topical pharmaceutical composition provided herein comprises a pharmaceutically acceptable amount of benzalkonium chloride.

In an embodiment of the present invention, the topical pharmaceutical composition provided herein comprises benzalkonium chloride in a concentration range of 0.01% w/w to 35% w/w of the composition.

The topical pharmaceutical formulation disclosed herein has enhanced skin absorption due to incorporation of benzalkonium chloride. The enhanced absorption of the composition disclosed herein is increasing the bioavailability of ß-caryophyllene and enabling sufficient analgesic effect in highly safe manner through activation of only CB2 receptor.

The topical pharmaceutical composition provided herein comprises a pharmaceutically acceptable excipient.

The term “pharmaceutically acceptable excipient” used herein refers to a compound or ingredient that is compatible with the other ingredients in a pharmaceutical composition and not injurious to an intended subject when administered in normal or therapeutically effective amounts. As used herein, an “intended subject” includes animals and/or humans. The terms “patient” and “subject” may be used interchangeably.

In an embodiment of the present invention, the topical pharmaceutical composition provided herein comprises an excipient in a concentration range of 30% w/w to 70% w/w of the composition.

In an embodiment of the present invention, the topical pharmaceutical composition provided herein comprises an excipient selected from a group of commonly used excipients in topical pharmaceutical compositions comprising rheology modifier, antioxidant, chelating agent, emulsifier, penetration enhancer, preservative, emollient, stabilizing agent, solvent, and a combination thereof.

In an embodiment of the present invention, the topical pharmaceutical composition provided herein comprises a pharmaceutically acceptable rheology modifier selected from a group of commonly used rheology modifiers comprising trihydroxystearin, dextrin fatty acid esters such as dextrin palmitate, cholesterol and derivatives such as lanosterol, silicone gellants such as organopolysiloxane elastomers, oil soluble cellulose derivatives such as methylcellulose, ethyl cellulose, and polymers or mixed copolymers, such as ethylene/methacrylic acid copolymer, ethylene/acrylic acid copolymer, organo-clays, such as bentone, polyamides(amine- terminated, ester-terminated, acid-terminated, silicone-modified and tertiary amine terminated), N-acyl amino acids, and esters or amides thereof, 12-hydroxystearic acid and esters or amides thereof, alkylamides of di- and tricarboxylic acids, or polyethylene, and a combination thereof.

In an embodiment of the present invention, the topical pharmaceutical composition provided herein comprises a pharmaceutically acceptable emulsifier selected from a group of commonly used emulsifiers comprising non-ionic surface active agent e.g., polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, sucrose fatty acid ester, glycerin fatty acid ester, sorbitan fatty acid ester, anionic surface active agent e.g., alkyl phosphoric acid ester, alkyl sulfate ester, soap, polyoxyethylene alkyl phosphate acid ester, polyoxyethylene alkyl sulfate, and a combination thereof.

In an embodiment of the present invention, the topical pharmaceutical composition provided herein comprises a pharmaceutically acceptable antioxidant selected from a group of commonly used antioxidants comprising amino acids and derivatives thereof, imidazoles, peptides such as carnosine and derivatives, carotenoids, carotenes (such as a-carotene, ß-carotene, and lycopene), a-hydroxy acids (such as citric acid, lactic acid, or malic acid), tocopherols and derivatives (such as Vitamin E), vitamin A, co-enzyme Q10, bioflavonoids, glutathione, plant extracts (such as rosemary extract, olive leaf extracts), and green tea extracts, lignans, and aurones, and a combination thereof.

In an embodiment of the present invention, the topical pharmaceutical composition provided herein comprises a pharmaceutically acceptable chelating agent selected from a group of commonly used chelating agents selected from aminocarboxylic acids or salts thereof, polyphosphoric acids or salts thereof, diphosphonic acids, salts of diphosphonic acids, tertiary amines, aminophosphonic acids, iminodiacetic acid derivatives, azines, hydroxyquinolines, amino acid esters, ethylene diamine tetra acetic acid, salt of ethylene diamine tetraacetic acid, sodium pyrophosphate, sodium tripolyphosphate, 8-hydroxyquinoline, DL-(Methylene)dinitrolo tetra acetic acids, trans-decahydronaphthylene-trans-2, 3-bis-iminodiacetic, aminophenyl methylene diphosphonic acid, ethylene-bis-N~Nl-(2,6-carboxyl) piperdine, adenosine triphosphate, L-cysteine methyl ester, 8-hydroxyquinoline, and a combination thereof.

In an embodiment of the present invention, the topical pharmaceutical composition provided herein comprises a pharmaceutically acceptable stabilizing agent selected from a group of commonly used stabilizing agents comprising sorbitan oleate, sorbitan stearate, sorbitan sesquioleate, cetomacrogol, glycerol monostearate, sodium alginate, sodium carboxymethyl cellulose (CMC), guar gum, locust bean gum, carrageenan, gelatin, pectin, and a combination thereof.

In an embodiment of the present invention, the topical pharmaceutical composition provided herein comprises a pharmaceutically acceptable preservative selected from a group of commonly used preservatives comprising benzalkonium chloride, diazolidinyl urea; iodopropnyl butylcarbamate; vitamin E (alpha- tocopherol) and its derivatives including vitamin E acetate (alpha-tocopherol acetate); vitamin C (ascorbic acid); butylated hydroxytoluene (BHT); butylated hydroxyanisole (BHA); esters of p-hydroxy benzoic acid such as methylparaben (p-hydroxybenzoic acid methyl ester), ethylparaben (p- hydroxybenzoic acid ethyl ester), propylparaben (p-hydroxybenzoic acid n- propyl ester), and butylparaben (p-hydroxybenzoic acid n-butyl ester), and a combination thereof.

In an embodiment of the present invention, the topical pharmaceutical composition provided herein comprises a pharmaceutically acceptable emollient selected from a group of commonly used emollients comprising oils, waxes, natural oils derived from plants, silicone oil, polyunsaturated fatty acid, lanoline, dicaprylic ether, isopropyl palmitate, dicaprylyl carbonate, C12-C15 alkyl benzoate, isopropyl isononate, sucrose palmitate, sucrose oleate, isostearyl lactate, glyceryl behenate, triglycerol-4 isostearate, lauryl pirrolidone carboxylic acid, pantenyl triacetate, and a combination thereof.

In an embodiment of the present invention, the topical pharmaceutical composition provided herein comprises a pharmaceutically acceptable solvent selected from a group of commonly used solvents comprising ketones such as acetone, diacetone alcohol, dihydroxyacetone, ethyl butyl valerolactone, methyl ethyl ketone etc., aliphatic or aromatic alcohols such as methanol, ethanol, propanol, benzyl alcohol, butyl alcohol, t-butyl alcohol, butylene glycol, diethylene glycol, abietyl alcohol, propylene carbonate, hexyl alcohol, isopropanol etc., glycol ethers such as butoxyethanol, butoxypropanol, 3-methyl-3-methoxy-butanol, methoxypropanol etc., esters such as butyl acetate, ethyl acetate, 1-methoxy-2-propanol acetate etc., benzoates, siloxanes, cyclic silicones, and a combination thereof.

In an embodiment of the present invention, the topical pharmaceutical composition provided herein comprises a pharmaceutically acceptable fragrance or flavouring agent selected from a group of commonly used fragrances or flavouring agents selected from a group comprising natural oils, synthetic oils, alcohols, aldehydes, ketones, esters, lactones, hydrocarbons, and a combination thereof.

In an embodiment of the present invention, the topical pharmaceutical composition provided herein comprises a pharmaceutically acceptable penetration enhancer selected from a group comprising pyrrolidone, alcohol especially, ester, water, ester sulfoxide (such as dimethyl sulfoxide) and their derivatives, hydrocarbon, terpene and derivatives, benzalkonium chloride, azone and its analogs, amide (including urea and its derivatives), fatty acids, surfactants, oleodendrimers, ionic liquids, and deep eutectic solvents, and a combination thereof.

The topical pharmaceutical composition provided herein comprises an optional additional active component.

The term “active component” used herein refers to a component which has some already known biological activity. The said component can be an individual biologically active compound or a mixture of biologically active compounds. The biologically active compounds may or may not have analgesic activity. The said component can be of natural origin, a natural identical of a natural compound, or a semi-synthetic derivative of a natural compound.

In an embodiment of the present invention, the topical pharmaceutical composition provided herein comprises optionally an additional active component in a concentration range of 0.5% w/w to 30% w/w of the composition.

In an embodiment of the present invention, the topical pharmaceutical composition provided herein comprises optionally an additional active component selected from a group comprising methyl salicylate, pudina crystals, terpene oil, eucalyptus oil, capsaicin, clove oil, and a combination thereof.

The topical pharmaceutical composition provided herein is in a dosage form selected from a group liquid, ointment, foam, lotion, cream, gel, paste, ointment, patch, emugel, emulsion, solution, oil, suspension, poultice, plaster, paint, liniment, collodion, and roll-on.

The topical pharmaceutical composition provided herein is applied topically on the skin once a day to four times a day to a patient or subject.

The topical pharmaceutical composition provided herein has an onset time between 2 minutes to 15 minutes.

The term "onset time" as used herein refers to the period of time between the topical application of the topical dosage form comprising the composition of the present invention and the release of the active ingredient thereof.

The topical pharmaceutical composition provided herein has analgesic effect for a duration of 7.5 hours to 8 hours from the onset time.

The topical pharmaceutical composition provided herein is used for the management of pain, inflammation, and related disorders.

As used herein, the term “pain” or “inflammation" refers to a subjective sensation, evoked by various internal and external stimuli. It is an unpleasant feeling, which arises from sensitization of nociceptors, the peripheral neurons responding to pain stimuli. The term "pain” or “inflammation includes acute pain or inflammation as well as chronic pain or inflammation. The short-lived acute pain or inflammation is generally associated with tissue damage or painful stimuli (e.g., the pain associated with a slight burn, a cut etc.). Acute pain or inflammation has an adaptive value as it warns us of the presence and location of a lesion and allows us to correct the behavior which causes it or contributes to it. On the other hand, pain or inflammation which persists beyond the time necessary for resolution of an acute condition is defined as chronic pain or inflammation.

In an embodiment of the present invention, the topical pharmaceutical composition provided herein is useful in the management of pain in medical conditions selected from a group comprising arthralgia, backache, neuralgia, ischialgia, fibromyalgia, musculo-skeletal pain, pelvic pain, and related disorders.

In an embodiment of the present invention, the topical pharmaceutical composition provided herein is useful in the management of pain in medical conditions selected from a group comprising atopic dermatitis, contact dermatitis, allergic dermatitis, pruritic dermatitis, solar (UVB-induced) dermatitis, chemical-induced dermatitis, bacterial and viral skin inflammation, acne, psoriasis, and related disorders.

In another aspect of the present invention, a process for the preparation of topical composition provided herein is disclosed. The said process comprises steps of,
- mixing the isolated ß-caryophyllene and at least one excipient and heating the mixture with continuous stirring at a temperature in range of 50 °C to 60 °C to obtain an oil phase;
- mixing purified water, an emulsifier, and a preservative in a stainless-steel container at a temperature in range of 50 °C to 60 °C to obtain an aqueous phase;
- mixing the oil phase and the aqueous phase in a homogenizer at a speed in range of 2000 rpm to 28000 rpm for a duration of 2 minutes to 12 minutes maintaining the temperature in range of 50 °C to 60 °C to obtain an emulsified mixture;
- mixing purified water and a viscosity modifier with continuous stirring and soaking for a duration of 45 minutes to 50 minutes to obtain a gel of viscosity modifier;
- mixing the emulsified mixture and the gel of viscosity modifier for a duration of 15 minutes to 30 minutes at a pH range of 5.0 to 6.0 and adding benzalkonium chloride to obtain the composition.

In one of the embodiments of the present invention, the process for preparation of topical composition disclosed herein, emulsifier is Tween 80, preservative is sodium methyl paraben, viscosity modifier is Carbopol, and excipient is selected from a group comprising methyl salicylate, pudina crystals, terpene oil, eucalyptus oil, clove oil, capsaicin, glycerol monostearate, span 80, cetostearyl alcohol, and a combination thereof.

The topical pharmaceutical composition provided herein is natural, safe, economic, and easy to prepare on industrial scale.

The topical pharmaceutical composition provided herein has analgesic effect equivalent to diclofenac based topical compositions. Due to presence of natural analgesic ß-caryophyllene as major component, the topical composition provided herein is extremely safe and free from adverse reactions like application site dermatitis which is generally experienced by patients in long term usage of diclofenac based topical compositions. The safety associated with the topical composition provided herein will lead to better patient compliance.

The topical pharmaceutical composition provided herein has no side-effects like psycho-activity, dependence, sedation etc., and can be advantageously used as a safe alternative to natural cannabinoid analgesic e.g., THC which activates both CB1 and CB2 receptors to trigger undesirable psychoactivity.

It will be understood that the specification and examples are illustrative but not limitative of the present invention and that other embodiments within the spirit and scope of the present invention will suggest themselves to those skilled in the art. Other embodiments can be practiced that are also within the scope of the present invention. The following examples illustrate the invention, but by no means intended to limit the scope of the claims.
EXAMPLES
EXAMPLE 1: PREPARATION OF ANALGESIC GEL [TRUMOVE GEL]
1.1. Preparation of 20% TruMove Gel 01
Isolated ß-caryophyllene, Methyl Salicylate, Pudina crystals, Taarpeen ka Tel, Eucalyptus Oil, Clove Oil, Capsaicin, Glycerol monostearate, Span 80, and Cetostearyl Alcohol are mixed together and heated between 50 °C to 60 °C with constant stirring to obtain a clear oil phase solution. In a separate stainless-steel container, purified water, Tween 80, and sodium methyl paraben are mixed and heated between 50 °C to 60 °C to obtain aqueous phase solution. The oil phase solution and the aqueous phase solution are mixed in a high-speed homogenizer between 50 °C to 60 °C to obtain an emulsified mixture. In a separate container purified water and Carbopol is mixed with continuous stirring and soaked up to 45 minutes to obtain Carbopol gel. The emulsified mixture and Carbopol gel are mixed for a duration of 15 minutes to 30 minutes at a pH range of 5.0 to 6.0 and BAC is added to obtain 20% TruMove Gel 01 of composition provided in Table-1 below.
Table-1: Composition of analgesic gel [20 % TruMove Gel 01]
S. No. Ingredients %w/w
1. ß-caryophyllene, 20
2. Methyl Salicylate 15
3. Pudina crystals 5
4. Terpene Oil (Taarpeen ka Tel) 3
5. Eucalyptus Oil 2
6. Capsaicin 0.075
7. Clove Oil 0.5
8. Lubrizol 10 NF 0.5
9. Di sodium EDTA 0.05
10. Tween 80 1
11. Glyceryl monostearate 3
12. Sorbitan Monooleate (Span 80) 1
13. Cetostearyl alcohol 2
14. Benzyl alcohol 1
15. Sodium methyl paraben 0.2
16. Sodium Hydroxide 0.4
17. Purified water Q.s.

1.2. Preparation of 20% TruMove Gel 02
20 % TruMove Gel 02 having composition provided in Table-2 below is prepared using method detailed in Example 1.1
Table-2: Composition of analgesic gel [20% TruMove Gel 02]
S. No. Ingredients %w/w
1. ß-caryophyllene, 20
2. Lubrizol 10 NF 0.5
3. Di sodium EDTA 0.05
4. Tween 80 1
5. Glyceryl monostearate 3
6. Sorbitan Monooleate (Span 80) 1
7. Cetostearyl alcohol 2
8. Benzyl alcohol 1
9. Sodium methyl paraben 0.2
10. Sodium Hydroxide 0.4
11. Purified water Q.s.

1.3. Preparation of 20% TruMove Gel 03
20 % TruMove Gel 03 having composition provided in Table-3 below is prepared using method detailed in Example 1.1
Table-3: Composition of analgesic gel [20% TruMove Gel 03]
S. No. Ingredients %w/w
1. ß-caryophyllene, 20
2. Methyl Salicylate 15
3. Pudina crystals 5
4. Lubrizol 10 NF 0.5
5. Di sodium EDTA 0.05
6. Tween 80 1
7. Glyceryl monostearate 3
8. Sorbitan Monooleate (Span 80) 1
9. Cetostearyl alcohol 2
10. Benzyl alcohol 1
11. Sodium methyl paraben 0.2
12. Sodium Hydroxide 0.4
13. Purified water Q.s.

EXAMPLE 2: STABILITY STUDIES
An analgesic gel comprising not less than 20% w/w of beta-caryophyllene is evaluated for stability at 40 °C ± 2 °C /75 ± 5 % RH and 30 °C ± 2 °C / 75 ± 5 % RH for initial, 3 months’ and 6 months’. The result of the study is provided in Table-4 below:
Table-4: Stability studies results
ß-caryophyllene gel Initial 40°C± 2°C/75%±5% 30°C± 2°C/75%±5%
Test Specification 0 Day 3 M 6M 3 M 6M
Beta Caryophyllene NLT 20.0% w/w 21.06% 20.14% 20.11% 20.19% 20.14%
Methyl Salicylate NLT 15.0% w/w 16.01% 15.47% 15.39% 15.49% 15.41%
Menthol NLT 5.0% w/w 5.83% 5.60% 5.42% 5.81% 5.63%
1,8 Cineol NLT 2.0% w/w 2.16% 2.09% 2.05% 2.12% 2.09%
Alpha pine NLT 3.0% w/w 3.09% 3.07% 3.04% 3.07% 3.06%
Cinnamic aldehyde NLT 0.5% w/w 0.57% 0.56% 0.54% 0.55% 0.53%
Eugenol NLT 0.5% w/w 0.54% 0.54% 0.52% 0.53% 0.53%

Conclusion: All the physical and chemical parameters of the gel are found satisfactory and the initial, 3M and 6M stability data at 40 °C ± 2 °C /75 ± 5 % RH, 30 °C ± 2 °C / 75 ± 5 % RH are also found to be satisfactory.
EXAMPLE 3: ANALGESIC EFFECT EVALUATION [TRUMOVE GEL VS STANDARD PAIN RELIEF GEL]
A comparative study is performed to evaluate the analgesic efficiency of the composition disclosed herein in form of a gel comprising 20% w/w of ß-caryophyllene (TruMove Gel) in comparison with a standard pain relief gel comprising 1% w/w of Diclofenac sodium.
10 healthy male Wistar rats aged between 10 weeks to 12 weeks and weighing between 220 grams to 250 grams are divided into two groups of 5 animals. TruMove gel and the standard pain relief gel were measured in 1ml BD syringe up to 2 units corresponding to 1 gm and same amount of individual gel is applied on the rats. The response in the form of jumping, withdrawal of the paws or the licking of the paws is observed and response latency recorded by a stopwatch after 0, 30, 60, 90 and 120 mins of drug administration for all groups. Table-5 below provides the results of the study.
Table-5: Results of comparative analgesic efficiency evaluation
Group Group details Baseline 0 min 15 min 30 min 60 min 120 min
1 TruMove Gel 0 0 56 59 65 66
2 Standard Pain Relief Gel 0 0 35 43 48 63

Conclusion: Heat protection activity of the TruMove gel is much better and quicker than the standard pain relief gel.
EXAMPLE 4: ANALGESIC EFFECT EVALUATION [[TRUMOVE GEL VS STANDARD PAIN RELIEF GEL]
A comparative study is performed to evaluate the analgesic efficiency of the composition disclosed herein in form of a gel comprising 20% w/w of ß-caryophyllene (TruMove Gel) in comparison with a standard pain relief gel comprising 1% w/w of Diclofenac sodium.
10 healthy male Wistar rats aged between 10 weeks to 12 weeks and weighing between 220 grams to 250 grams are divided into two groups of 5 animals. TruMove gel and standard pain relief gel were measured in 1ml BD syringe up to 2 units corresponding to 1 gm and same amount of individual gel is applied on the rats. The response in the form of jumping, withdrawal of the paws or the licking of the paws is observed and response latency recorded by a stopwatch after 0, 30, 60, 90 and 120 mins of drug administration for all groups. The study shows that there is a significant fast onset of action with Trumove gel (48 seconds) and standard pain relief gel (46 seconds) in all the Musculo skeletal pain conditions like low back ache, knee joint pain and other joint pain disorders as reflected from Table-6 below:
Table-6: Results of comparative analgesic efficiency evaluation
Parameters StandardGel Trumove Gel p-value
Mean (SD) Mean (SD)
On set of cooling/ tingling/burning (in second) 46.67 (11.59) 48.67 (10.93) 0.631

The onset of pain relief is faster (2.6 minutes) with Trumove gel when compared to standard pain relief gel (2.7 minutes) and the pain relief sustains for up to 8 hours as reflected from Table-7 and Table-8 below:
Parameters Standard Gel Trumove Gel p-value
Mean (SD) Mean (SD)
Onset of Pain relief (in minutes) 2.73 (1.28) 2.67 (1.49) 0.897

Parameters Standard Gel Trumove Gel p-value
Mean (SD) Mean (SD)
Duration of action (in hours) 5.74 (2.50) 7.6 (6.9) 0.340

There is also statistically significant improvement in the WOMAC and McGill pain scores from baseline to Post study in both the groups. With respect to VAS score Trumove gel is showing a significant improvement when compared to standard pain relief gel.
It will thus be seen that the objects set forth above, among those made apparent from the preceding description, are efficiently attained, and since certain changes may be made in the constructions set forth without departing from the spirit and scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense. The invention has been described with reference to preferred and alternate embodiments. Modifications and alterations will become apparent to those skilled in the art upon reading and understanding the detailed discussion of the invention provided herein. This invention is intended to include all such modifications and alterations insofar as they come within the scope of the present invention. These and other modifications of the preferred embodiments as well as other embodiments of the invention will be obvious from the disclosure herein, whereby the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.
Finally, to the extent necessary to understand or complete the disclosure of the present invention, all publications, patents, and patent applications mentioned herein are expressly incorporated by reference therein to the same extent as though each were individually so incorporated.
,CLAIMS:1. A topical pharmaceutical composition for the management of pain, inflammation, and related disorders comprising:
- a therapeutically effective amount of an isolated ß-caryophyllene;
- a pharmaceutically acceptable amount of a benzalkonium chloride;
- a pharmaceutically acceptable excipient; and optionally an additional active component.

2. The composition as claimed in claim 1, wherein the isolated ß-caryophyllene is in form of an oil comprising ß-caryophyllene.

3. The composition as claimed in claim 2, wherein the oil comprises 70% w/w to 100% w/w of the ß-caryophyllene.

4. The composition as claimed in claim 1, wherein the isolated ß-caryophyllene is in a concentration range of 10% w/w to 60% w/w of the composition.

5. The composition as claimed in claim 1, wherein the benzalkonium chloride is in a concentration range of 0.01% w/w to 35% w/w of the composition.

6. The composition as claimed in claim 1, wherein the excipient is in a concentration range of 30% w/w to 70% w/w of the composition.

7. The composition as claimed in claim 1, wherein the additional active component is in a concentration range of 0.5% w/w to 30% w/w of the composition.

8. The composition as claimed in claim 1, wherein the excipient is selected from a group comprising rheology modifier, antioxidant, chelating agent, emulsifier, preservative, emollient, stabilizing agent, solvent, penetration enhancer, and
a combination thereof.

9. The composition as claimed in claim 1, wherein the additional active component is selected from a group comprising natural oil, terpene, and a combination thereof.

10. The composition as claimed in claim 1, wherein the additional active component is selected from a group comprising methyl salicylate, pudina crystals, terpene oil, eucalyptus oil, capsaicin, clove oil, and a combination thereof.

11. The composition as claimed in claim 1, wherein the composition is in a dosage form selected from a group comprising liquid, ointment, foam, lotion, cream, gel, paste, ointment, patch, emugel, emulsion, solution, oil, poultice, plaster, paint, liniment, collodion, and roll-on.

12. The composition as claimed in claim 1, wherein the composition is applied on skin once a day to four times a day to a patient.

13. The composition as claimed in claim 1, wherein the composition has an onset time from 2 minutes to 15 minutes.

14. The composition as claimed in claim 1, wherein the composition has analgesic effect of 7.5 hours to 8 hours from the onset time.

15. A process for the preparation of composition as claimed in claim 1, comprising steps of,
- mixing the isolated ß-caryophyllene and at least one excipient and heating the mixture with continuous stirring at a temperature in range of 50 °C to 60 °C to obtain an oil phase;
- mixing purified water, an emulsifier, and a preservative in a stainless-steel container at a temperature in range of 50 °C to 60 °C to obtain an aqueous phase;
- mixing the oil phase and the aqueous phase in a homogenizer at a speed in range of 2000 rpm to 2800 rpm for a duration of 2 minutes to 12 minutes maintaining the temperature in range of 50 °C to 60 °C to obtain an emulsified mixture;
- mixing purified water and a viscosity modifier with continuous stirring and soaking for a duration of 45 minutes to 50 minutes to obtain a gel of viscosity modifier;
- mixing the emulsified mixture and the gel of viscosity modifier for a duration of 15 minutes to 30 minutes at a pH range of 5.0 to 6.0 and adding benzalkonium chloride to obtain the composition.

16. The process as claimed in claim 15, wherein the emulsifier is Tween 80, the preservative is sodium methyl paraben, the viscosity modifier is Carbopol, and the excipient is selected from a group comprising methyl salicylate, pudina crystals, terpene oil, eucalyptus oil, clove oil, capsaicin, glycerol monostearate, span 80, cetostearyl alcohol, and a combination thereof.