DESC:FIELD OF THE INVENTION
The present invention generally relates to pharmaceutical sciences. Specifically, the present invention is related to a topical spray composition comprising isolated ß-caryophyllene, benzalkonium chloride, propellant, 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, ß-caryophyllene has extremely low solubility in biological fluids leading to low bioavailability of ß-caryophyllene and insufficient analgesic effect. This limits exploitation of this readily available, natural, and safe analgesic to its fullest potential.

Therefore, need exists for the development of a ß-caryophyllene-based analgesic topical spray composition which has enhanced skin absorption and bioavailability of ß-caryophyllene for faster and efficient pain relief without any side effects like sedation, addiction, and psychoactivity.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides a topical spray composition for the management of pain, inflammation, and related disorders. The said composition comprises 2% w/w to 98% w/w of an isolated ß-caryophyllene, 0.01% w/w to 3.5% w/w of benzalkonium chloride, 10% w/w to 70% w/w of a propellant, 30% w/w to 70% w/w of at least one excipient, and optionally 0.05% w/w to 40% w/w of an additional active component.

The said composition is in form of a topical spray which can be sprayed on the skin to obtain relief from pain and inflammation within 2 minutes and the analgesic effect imparted by the said topical spray composition sustains for about 18 hours. The topical spray composition provided herein has enhanced absorption on the skin.

The present invention also provides simple process for the preparation of said topical spray composition.

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

The topical spray composition provided herein has analgesic effect better than the standard diclofenac-based analgesic sprays 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 onset time through evaluation of response latency of the composition disclosed herein (20% w/w of ß-caryophyllene, TruMove Spray) in comparison with standard pain relief spray based on diclofenac (1% w/w of Diclofenac sodium).
Figure 2 illustrates duration of analgesic effect through evaluation of % protection against acute pain imparted by the composition disclosed herein (20% w/w of ß-caryophyllene, TruMove Spray) in comparison with standard pain relief spray based on diclofenac (1% w/w of Diclofenac sodium).
Figure 3 illustrates Visual Analogue Scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and McGill pain scores from baseline to Post study in both the groups by the composition disclosed herein (20% w/w of ß-caryophyllene, TruMove Spray) in comparison with standard pain relief spray based on diclofenac (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 spray” used herein refers to a series of test products based on the topical spray composition provided herein.

In one aspect of the present invention, there is provided a topical spray 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 amount of a propellant;
- 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 spray composition provided herein comprises a therapeutically effective amount of isolated ß-caryophyllene.

In an embodiment of the present invention, the topical spray composition provided herein comprises about 2% w/w to 98% w/w of isolated ß-caryophyllene.

In an embodiment of the present invention, the isolated ß-caryophyllene present in the topical spray 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 spray 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 spray composition disclosed herein is in a range of about 20mg to 980mg.

In an embodiment of the present invention, the therapeutically effective amount of isolated ß-caryophyllene is in a range of about 10mg to 70mg.

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 spray composition provided herein comprises a pharmaceutically acceptable amount of benzalkonium chloride.

In an embodiment of the present invention, the topical spray composition provided herein comprises benzalkonium chloride in a concentration range of 0.01% w/w to 3.5% w/w of the composition.

The topical spray composition provided 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 spray 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 spray 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 spray composition provided herein comprises an excipient selected from a group of commonly used excipients in topical spray compositions comprising emulsifier, preservative, penetration enhancer, emollient, stabilizing agent, solvent, fragrance, and a combination thereof.

In an embodiment of the present invention, the topical spray 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 spray composition provided herein comprises a pharmaceutically acceptable stabilizing agent selected from a group of commonly used stabilizing agents comprising 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 spray 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 spray 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 spray 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 Valero lactone, 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 spray composition provided herein comprises ethanol as solvent.
In an embodiment of the present invention, the topical spray 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 spray 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 spray composition provided herein comprises a propellant.

The propellant used in the topical spray provided herein can be any pharmaceutically acceptable propellant which provides a suitable pressure within an aerosol dispenser, preferably a pressure in range of 20 pounds per square inch gauge (psig) to 130 pounds per square inch gauge (psig).

In an embodiment of the present invention, the topical spray composition provided herein comprises a propellant in a concentration range of 10% w/w to 70% w/w of the composition.

In an embodiment of the present invention, the topical spray composition provided herein comprises a propellant selected from a group comprising nitrogen, carbon dioxide, hydrocarbons, and a combination thereof.

In an embodiment of the present invention, the topical spray composition provided herein comprises a propellant selected from a group comprising LPG, propane, butane, isobutane, dimethylether, hydrofluorocarbons, hydrochlorofluorocarbons, nitrogen, air, and a combination thereof.

The topical spray 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 spray composition provided herein comprises optionally an additional active component in a concentration range of 0.05% w/w to 40% w/w of the composition.

In an embodiment of the present invention, the topical spray composition provided herein comprises optionally an additional active component selected from a group comprising Gaultheria fragrantissima leaf oil, Mentha arvensis crystals, Syzygium aromaticum flower bud oil, Syzygium aromaticum (Lavang), Standaradized clove extract (containing ß Caryophyllene), Pinus roxburghii heart wood oil, Eucalyptus globulus leaf oil, Cinnamomum zeylanicum dried inner bark oil, capsicum annuum, capsaicin, and a combination thereof.

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

The topical spray 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 spray composition provided herein has analgesic effect for a duration of 17 hours to 18 hours from the onset time.

The topical spray 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 spray 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 spray 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 spray composition provided herein is disclosed. The said process comprises steps of,
- preparing a mixture of Mentha arvensis crystals and a solvent in a mixer by stirring Mentha arvensis crystals and a solvent at a speed in range of 10 rpm to 500 rpm for a duration of 15 minutes to 25 minutes to obtain a first mixture;
- adding isolated ß-caryophyllene, at least one excipient, and at least one additional active component into the first mixture and stirring the first mixture at a speed in range of 10 rpm to 500 rpm for a duration of 10 minutes to 15 minutes to obtain a second mixture;
- adding isopropyl myristate and polysorbate 80 (Tween 80) into the second mixture and stirring the second mixture at a speed in range of 10 rpm to 500 rpm for a duration of 5 minutes to 10 minutes to obtain a third mixture;
- preparing a solution of benzalkonium chloride in a solvent, adding the solution into the third mixture and stirring the third mixture at a speed in range of 10 rpm to 500 rpm for a duration of 5 minutes to 10 minutes to obtain a fourth mixture;
- diluting the fourth mixture with solvent and stirring the fourth mixture at a speed in range of 10 rpm to 500 rpm for a duration of 5 minutes to 10 minutes to obtain a fifth mixture;
- filtering the fifth mixture and filling the fifth mixture in a spray bottle with a propellant to obtain the composition.

The topical spray composition provided herein may be filled in an aluminium aerosol container without a propellant to obtain a topical spray.

In one of the embodiments of the present invention, the process for preparation of topical spray composition disclosed herein, ethanol is used as solvent.

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

The topical spray composition provided herein has analgesic effect better than diclofenac based topical analgesic sprays. Due to presence of natural analgesic ß-caryophyllene as major component, the topical spray 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 sprays. The safety associated with the topical spray composition provided herein will lead to better patient compliance.

The topical spray 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 SPRAY [TRUMOVE SPRAY]
1.1. Preparation of 20% TruMove spray 01
In main manufacturing vessel, a mixture of Mentha arvensis crystals and ethanol is prepared by stirring Mentha arvensis crystals and ethanol at a speed in range of 10 rpm to 500 rpm for a duration of 15 minutes to 20 minutes. In the mixture so obtained, Lavang (Syzygium aromaticum), Gandhapura (Gaultheria fragrantissima) Lf. Oil, Lavang (Syzygium aromaticum) Fl. Bud Oil, Sarala (Pinus roxburghii) Ht.Wd. Oil, Nilgiri (Eucalyptus globulus) Lf. Oil, and Dalchini (Cinnamomum zeylanicum) Dr. lnner Bk. Oil are added and stirred at a speed in range of 10 rpm to 500 rpm for a duration of 10 minutes to 15 minutes. Thereafter, isopropyl myristate and polysorbate 80 (Tween 80) are added into the mixture so obtained followed by stirring at a speed in range of 10 rpm to 500 rpm for a duration of 5 minutes to 10 minutes. An ethanolic solution of benzalkonium chloride is prepared in a separate container by stirring ethanol and benzalkonium chloride at a speed in range of 10 rpm to 500 rpm for a duration of 5 minutes to 10 minutes. The ethanolic solution of benzalkonium chloride so prepared is then added into the mixture in main manufacturing vessel and stirred for 5 minutes at a speed in range of 10 rpm to 500 rpm. The mixture so obtained is then diluted with ethanol, stirred, and filtered to obtain a concentrate. The concentrate is then filled inside a spray bottle with a propellant to obtain 20% TruMove spray 01 of composition provided in Table-1 below.
Table-1: Composition of 20% TruMove spray 01
S. No.Sl. No. Ingredients %w/w
1. Gandhapura (Gaultheria fragrantissima) Lf. Oil 15.0
2. Pudina Satwa (Mentha arvensis) Lf 5.0
3. Lavang (Syzygium aromaticum) Fl. Bud Oil 0.5
4. Sarala (Pinus roxburghii) Ht.Wd. Oil 3.0
5. Nilgiri (Eucalyptus globulus) Lf. Oil 2.0
6. Dalchini (Cinnamomum zeylanicum) Dr. lnner Bk. Oil 0.5
7. Lavang (Syzygium aromaticum) Standardized Clove hydroalcoholic extract (Contains ß-Caryophyllene) 20.0
8. Excipient & propellant q.s.
9. Benzalkonium Chloride 0.05%

1.2. Preparation of 20% TruMove spray 02
20% TruMove spray 02 having composition as provided in Table-2 below is prepared using method detailed in Example 1.1.
Table-2: Composition of 20% TruMove spray 01
S. No.Sl. No. Ingredients %w/w
1. Lavang (Syzygium aromaticum) Standardized Clove hydroalcoholic extract (Contains ß-Caryophyllene) 20.0
2. Excipient & propellant q.s.
3. Benzalkonium Chloride 0.05%

1.3. Preparation of 20% TruMove spray 03
20% TruMove spray 03 having composition as provided in Table-3 below is prepared using method detailed in Example 1.1.
Table-3: Composition of 20% TruMove spray 03
S. No.Sl. No. Ingredients %w/w
1. Pudina Satwa (Mentha arvensis) Lf 5.0
2. Nilgiri (Eucalyptus globulus) Lf. Oil 2.0
3. Dalchini (Cinnamomum zeylanicum) Dr. lnner Bk. Oil 0.5
4. Lavang (Syzygium aromaticum) Standardized Clove hydroalcoholic extract (Contains ß-Caryophyllene) 20.0
5. Excipient & propellant q.s.
6. Benzalkonium Chloride 0.05%

EXAMPLE 2: STABILITY STUDIES
A topical spray 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 spray 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 85 % 98.00% 94.70% 91.40% 97.80% 94.60%
Methyl Salicylate NLT 85 % 98.90% 95.30% 92.40% 99.90% 97.50%
Menthol NLT 85 % 98.60% 96.50% 93.89% 99.80% 96.40%
Tarpin Ka Tel NLT 85 % 97.00% 101.50% 100.20% 98.10% 97.30%
Eucalyptus Oil NLT 85 % 98.10% 96.80% 93.86% 99.60% 97.20%
Cinnamon Oil NLT 85 % 135.30% 128.50% 119.70% 137.90% 129.50%
Clove Oil NLT 85 % 96.70% 89.40% 88.70% 97.70% 95.40%

Conclusion: All the physical and chemical parameters of the spray 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 SPRAY]
A comparative study is performed to evaluate the analgesic efficiency of the composition disclosed herein in form of a spray comprising 20% w/w of ß-caryophyllene (TruMove Spray) in comparison with a standard pain relief spray 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 spray and the standard pain relief spray were measured in Eppendorf tube by spraying twice and mist volume of both sprays are found to be 500µl. Volume is kept same for all 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 significantly fast onset of action with Trumove spray (45 seconds) when compared to standard pain relief spray (56 seconds) in all the Musculo-skeletal pain conditions like low back ache, knee joint pain and other joint pain disorders. Also, the onset of pain relief is also fast (2.13 minutes) with Trumove spray when compared to standard pain relief spray (5.27 minutes) as illustrated in Figure-1. The pain relief action sustains for around 18 hours in Trumove spray and for around 15 hours in standard pain relief spray as illustrated in Figure-2. Further, the VAS, WOMAC and McGill pain scores from baseline to Post study in Trumove spray and standard pain relief spray are comparable as reflected in Table-5 and Table-6 below and illustrated in Figure 3.
Table-5: WOMAC score
WOMAC score Standard spray TruMove spray p-value
Mean SD Mean SD
Baseline 29.2 (12.28) 26.27 (0.09) 0.464
Post Study 11.87 (9.71) 8.6 (4.38) 0.246
p-value 0.0001 0.0001

Table-6: McGill Pain score comparison.
McGill Pain score Standard spray TruMove spray p-value
Mean SD Mean SD
Baseline 10.87 (5.30) 10.73 (4.59) 0.942
Post Study 4.2 (4.49) 3.87 (3.13) 0.815
p-value 0.0001 0.0001

The study also reflects that there is significant reduction in the inflammatory biomarkers ESR and Hs-CRP from baseline to Post study in both the groups, but ESR reduction is more prominent in Trumove spray group as reflected in Table-7 and Table-8 below.
Table-7: ESR reduction
ESR Standard spray TruMove spray p-value
Mean SD Mean SD
Baseline 24.07 (19.3) 30.33 (20.94) 0.398
Post Study 16.47 (10.33) 19.27 (10.71) 0.472
p-value 0.01 0.002

Table-8: Hs-CRP reduction
Hs-CRP Standard spray TruMove spray p-value
Mean SD Mean SD
Baseline 4.507 (2.16) 5.02 (3.28) 0.617
Post Study 4.133 (1.80) 4.5 (2.55) 0.654
p-value 0.024 0.04

Conclusion: Pain relief is faster and better in TruMove spray than standard pain relief spray.
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:We claim:
1. A topical spray 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 amount of a propellant,
- 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 2% w/w to 98% 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 3.5% w/w of the composition.

6. The composition as claimed in claim 1, wherein the propellant is in a concentration range of 10% w/w to 70% w/w of the composition.

7. 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.

8. The composition as claimed in claim 1, wherein the additional active component is in a concentration range of 0.05% w/w to 40% w/w of the composition.

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

10. The composition as claimed in claim 1, wherein the additional active component is selected from a group comprising Gaultheria fragrantissima leaf oil, Mentha arvensis crystals, Syzygium aromaticum flower bud oil, Syzygium aromaticum (Lavang), Standaradized clove extract (containing ß Caryophyllene), Pinus roxburghii heart wood oil, Eucalyptus globulus leaf oil, Cinnamomum zeylanicum dried inner bark oil, capsicum annuum, capsaicin, and a combination thereof.

11. The composition as claimed in claim 1, wherein the propellant is selected from a group comprising liquified petroleum gas, propane, butane, isobutane, dimethyl ether, hydrofluorocarbons, hydrochlorofluorocarbons, nitrogen, air, and a combination thereof.

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

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 for a duration of 17 hours to 18 hours from the onset time.

15. A process for the preparation of composition as claimed in claim 1, wherein the process comprises step of:
- preparing a mixture of Mentha arvensis crystals and solvent in a mixer by stirring Mentha arvensis crystals and a solvent at a speed in range of 10 rpm to 500 rpm for a duration of 15 minutes to 25 minutes to obtain a first mixture;
- adding isolated ß-caryophyllene, at least one excipient, and at least one additional active component into the first mixture and stirring the first mixture at a speed in range of 10 rpm to 500 rpm for a duration of 10 minutes to 15 minutes to obtain a second mixture;
- adding isopropyl myristate and polysorbate 80 (Tween 80) into the second mixture and stirring the second mixture at a speed in range of 10 rpm to 500 rpm for a duration of 5 minutes to 10 minutes to obtain a third mixture;
- preparing a solution of benzalkonium chloride in a solvent, adding the solution into the third mixture and stirring the third mixture at a speed in range of 10 rpm to 500 rpm for a duration of 5 minutes to 10 minutes to obtain a fourth mixture;
- diluting the fourth mixture with a solvent and stirring the fourth mixture at a speed in range of 10 rpm to 500 rpm for a duration of 5 minutes to 10 minutes to obtain a fifth mixture;
- filtering the fifth mixture and filling the fifth mixture in a spray bottle with a propellant to obtain the composition.

16. A process as claimed in claim 15, wherein the solvent is ethanol.