DESC:FIELD OF THE INVENTION
The present invention generally relates to pharmaceutical sciences. Specifically, the present invention is related to a composition of a phytocannabinoid useful for the treatment of pain, inflammation, and related disorders. Particularly, the invention relates to an oral composition comprising isolated ß-caryophyllene, an oil adsorbent, and one or more pharmaceutically acceptable excipients for the treatment 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. It 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). Its biological effects include anti-inflammatory, anticarcinogenic, antimicrobial, antioxidative, and analgesic activities. ß-caryophyllene is the primary sesquiterpene contributing to the spiciness of black pepper. BCP belongs to a class of cannabinoids (CBs), specifically phytocannabinoids (pCBs), which were identified as plant derivatives of Cannabis sativa L.

Natural and synthetic cannabinoids have ability to activate the cannabinoid receptors (CB1 and CB2), however BCP activates exclusively CB2 and exhibits no affinity to CB1. This implies that BCP action is devoid of psychoactive side effects associated with CB1 activation and suggests its potential use in medicine. This selective CB2 activation properties of BCP suggest it as a potential natural analgesic and exerts significant cannabimimetic anti-inflammatory effects. Klaudyna et al in a study, reported in Cancer Medicine 2016; 5(10):3007-3017, found in the quantitative radioligand binding experiments that E-BCP displays insensibly higher biding affinity to CB2 and does not bind to CB1.

Clayton et al. in a study published in Pain 96(2002) 253-260 concluded 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. Therefore, CB1 agonists are not suitable for the treatment of inflammation and pain. 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 a use of synthetic drugs, the natural products with strong analgesic activities and low side effects are still being 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 [Aust. Prescr. 38:212-215].

WO 2022047016 A1 discloses a combination of at least two active agents having BCP as one of them. This patent discloses composition containing BCP and THC or BCP and CBD for the treatment of pain and inflammation respectively. THC has been associated for long with pain relief. THC mediates through cannabinoid receptors CB1 and CB2. Expression of CB1 is predominantly in the CNS with high level of receptors expressed in brain and spinal cord. It has been found that CB1 activation is associated with psychoactive side effects leading to addiction. Therefore, there is a need to find an alternative natural product which is devoid of psychoactive side effects. On the other hand, BCP is a selective agonist of CB2, which is predominantly expressed on the periphery. Thereby pain modulation by BCP could be largely mediated through non-neuronal cells. BCP can diminish an acute and chronic pain not only through cannabinoid, but additionally through opioid system.

Pure or isolated beta-caryophyllene (BCP) displays similar analgesic activities as several essential oils, in which BCP is one of the active compounds. However, it should be noted that essential oils are mixture of various chemical compounds including THC, which may have psychoactive side effects and induce addiction. Hence there is a need to develop a composition in which isolated BCP is used instead of essential oil to avoid the psychotic side effect and development of addiction.

WO 2012104706 discloses a combination of beta-caryophyllene (BCA) and docosahexaenoic acid (DHA) for the treatment of pain. Fiorenzani et al. studied the antinociceptive activity of BCP in mixture with docosahexaenoic acid (DHA) and found that the combination of BCP and DHA, which was suspected to bring a double, analgesic and anti-inflammatory effect in the treatment of inflammation-associated pain, DHA did not exert an additional analgesic activity over that of BCP alone in animal model of formalin-induced pain. Further, the same study has revealed that DHA attenuated BCP toxicity in fibroblasts [Evid. Based Complement. Alternat. Med. 2014:596312].

To understand better the BCP-mediated analgesia, it is essential to get insight into the mechanism of its action. Cannabinoid receptors type 1 (CB1) and type 2 (CB2) are G-protein-coupled receptors (GPCR) and main components of endocannabinoid system (ECS). They play important roles not only in the maintenance of energy balance, metabolism, neurotransmission, and immune response, but are also engaged in pathological processes, for example, neuropathic pain. CB1 are mostly localized to the central nervous system (CNS), whereas CB2 are found predominantly in the peripheral tissues and immune cells. Both types of CB receptors are elements of numerous signaling pathways, mediating cellular responses to various bioactive molecules such as hormones, local mediators, or neurotransmitters. BCP binding to CB2 results in the activation of Gai/o protein, which leads to decline of cAMP production and in consequence inhibition of adenylyl cyclase. In addition, ligand-coupled CB2 activate G?ß proteins and stimulate both mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathways. In inflammatory hyperalgesia, indirect pain inhibition through CB2 localized on mast and immune cells is possibly achieved by the reduction of prostanoids or cytokines release, which are responsible for peripheral nociceptor sensitization. Fernandes et al. [Eur. J. Pharmacol. 569:228–236] found that BCP derived from essential oil of Cordia verbenacea exhibited anti-inflammatory properties, blocking release of proinflammatory molecules, such as TNFa and prostaglandin E2 (PGE2). The same report showed BCP-induced decrement in expression of COX-2 and inducible nitric oxide synthase (iNOS), which could suppress the NF-?B activation and in a consequence promote analgesia. In addition, Paula-Freire et al in Phytomedicine 21:356–362 reported a decreased level of IL-1ß in the injured sciatic nerve after BCP treatment, in a model of chronic pain.

Thus, a stable and effective composition for treatment of pain and inflammation, which overcome the associated side effects specifically the psychoactive side effects and addiction is highly desirable. The present inventors have surprisingly developed a composition of isolated ß-caryophyllene (BCP) for oral administration, which is natural and safe yet highly effective for the treatment of pain and inflammation.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides an oral pharmaceutical composition for the management of pain, inflammation, and related disorders. The said composition comprises 10% w/w to 60% w/w of an isolated ß-caryophyllene, 0.5% w/w to 60% w/w of at least one oil adsorbent, and 0.001% w/w to 40% w/w of at least one excipient.

The said composition is in a solid dosage form which can be administered as such or reconstituted before administration to obtain relief from pain and inflammation within 15 minutes and the analgesic effect imparted by the said composition sustains for about 2.5 hours.

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

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

The oral analgesic composition provide herein has an analgesic effect comparable to diclofenac-based oral 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 (300 mg of ß-caryophyllene, Truemove-01 tablet) in comparison with vehicle (0.5 % CMC) and Novartis Voveran 50 (50 mg Diclofenac).
Figure 2 illustrates % protection against acute pain imparted by the composition disclosed herein (300 mg of ß-caryophyllene, Truemove-01 tablet) in comparison with vehicle (0.5 % CMC) and Novartis Voveran 50 (50 mg Diclofenac).
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.

In one aspect of the present invention, there is provided an oral pharmaceutical composition for the management of pain, inflammation, and related disorders comprising:
- a therapeutically effective amount of isolated ß-caryophyllene;
- a pharmaceutically acceptable oil adsorbent; and
- a pharmaceutically acceptable excipient.

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

In an embodiment of the present invention, the oral 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 oral 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 oral pharmaceutical composition is in form of oil extracted from 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 oral pharmaceutical composition disclosed herein is selected from about 1mg to 5 mg, about 1mg to 10 mg, about 5mg to 20 mg, about 10mg to 50 mg, about 20mg to 100 mg, about 50mg to 150 mg, about 100mg to 250 mg, about 150mg to 300 mg, and about 250mg to 500 mg.

In an embodiment of the present invention, the therapeutically effective amount of isolated ß-caryophyllene is in a range of about 1mg to 500mg.

In an embodiment of the present invention, the therapeutically effective amount of isolated ß-caryophyllene is in a range of about 10mg to 200mg.

In an embodiment of the present invention, the therapeutically effective amount of isolated ß-caryophyllene is in a range of about 50 mg to 150 mg.

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

The term “oil adsorbent” used herein refers to a material which adsorbs the fluid-like pharmaceutical ingredients on its surface and makes them easy to incorporate into a solid dosage form.

The oral pharmaceutical composition provided herein comprises a pharmaceutically acceptable oil adsorbent.

In an embodiment of the present invention, the oral pharmaceutical composition provided herein comprises an oil adsorbent in a concentration range of 0.5% w/w to 60% w/w of the composition.

In an embodiment of the present invention, the oral pharmaceutical composition provided herein comprises an oil adsorbent selected from a group comprising aluminosilicate-based adsorbent, silica-based adsorbent, carbohydrate-based adsorbent, calcium phosphate-based adsorbent, and a combination thereof.

In an embodiment of the present invention, the oral pharmaceutical composition provided herein comprises a carbohydrate-based adsorbent selected from a group comprising starch, cellulose, lactose, microcrystalline cellulose, and a combination thereof.

In an embodiment of the present invention, the oral pharmaceutical composition provided herein comprises an oil adsorbent selected from a group comprising Neusilin US2, MCC 102, Lactose Monohydrate (DC), Syloid, CompactCel, F-Melt, and a combination thereof.

The oral pharmaceutical composition provided herein has enhanced bioavailability of ß-caryophyllene. The oil adsorbent comprises numerous micro-capillaries having large surface area for adsorption of ß-caryophyllene oil globules. Efficient adsorption of ß-caryophyllene oil globules inside these micro-capillaries decreases the size of oil globules and increases effective surface area of the oil globules. The greater surface area of the oil globules leads to better or higher absorption i.e., higher bioavailability of ß-caryophyllene.

The oral 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 oral pharmaceutical composition provided herein comprises an excipient in a concentration range of 0.001% w/w to 40% w/w of the composition.

In an embodiment of the present invention, the oral pharmaceutical composition provided herein comprises an excipient selected from a group of commonly used excipients in oral pharmaceutical compositions comprising emulsifier, glidant, stabilizing agent, lubricant, diluent, disintegrant, anti-capping agent, binder, anti-caking agent, solubilizing agent, fragrance, sweetening agent, controlled-release agent, anti-adherent, carrier, and a combination thereof.

In an embodiment of the present invention, the oral pharmaceutical composition provided herein comprises a pharmaceutically acceptable diluent selected from a group of commonly used diluents comprising powdered cellulose; microcrystalline cellulose; silicified microcrystalline cellulose; starch; modified starch; dibasic calcium phosphate; tribasic calcium phosphate; calcium carbonate; dextrose; kaolin; magnesium carbonate; magnesium oxide; sugars such as lactose, sucrose etc.; sugar alcohols such as mannitol, sorbitol, erythritol, or like and a combination thereof.

In an embodiment of the present invention, the oral pharmaceutical composition provided herein comprises a pharmaceutically acceptable binder selected from a group of commonly used binders comprising hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, dextrin, ethyl cellulose, methylcellulose, gelatin, polymethacrylates, Carboxymethyl cellulose, polyvinylpyrrolidone, pregelatinized starch, sodium alginate, gums, synthetic resins, or like and a combination thereof.

In an embodiment of the present invention, the oral pharmaceutical composition provided herein comprises a pharmaceutically acceptable disintegrant selected from a group of commonly used disintegrant comprising croscarmellose sodium, sodium starch glycolate, starch, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, or like and a combination thereof.

In an embodiment of the present invention, the oral pharmaceutical composition provided herein comprises a pharmaceutically acceptable lubricant or glidant selected from a group of commonly used lubricant or glidant comprising talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, sodium stearyl fumarate, sodium benzoate, mineral oil, magnesium trisilicate, or like and a combination thereof.

In an embodiment of the present invention, the oral pharmaceutical composition provided herein comprises a pharmaceutically acceptable stabilizing agent selected from a group of commonly used stabilizing agent 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 oral pharmaceutical composition provided herein comprises a pharmaceutically acceptable anti-capping agent selected from a group of commonly used anti-capping agent comprising Polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), low substituted hydroxypropyl cellulose (L-HPC) bovine serum albumin (BSA), ethylene diamine tetra acetic acid (EDTA), chitosan, and a combination thereof.

In an embodiment of the present invention, the oral pharmaceutical composition provided herein comprises a pharmaceutically acceptable anti-caking agent selected from a group of commonly used anti-caking agent comprising tricalcium phosphate, powdered cellulose, magnesium stearate, magnesium oxide, calcium oxide, sodium bicarbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, calcium phosphate, sodium silicate, silicon dioxide, calcium silicate, magnesium trisilicate, talcum powder, sodium aluminosilicate, potassium aluminium silicate, calcium aluminosilicate, bentonite, aluminium silicate, stearic acid, polydimethylsiloxane, and a combination thereof.

In an embodiment of the present invention, the oral pharmaceutical composition provided herein comprises a pharmaceutically acceptable solubilizing agent selected from a group of commonly used solubilizing agent comprising alcohols; glycols; surfactants; essential oils such as mentha oil, crotamiton, methyl salicylate, glycol salicylate; fatty acid esters such as isopropyl myristate, and a combination thereof.

In an embodiment of the present invention, the oral pharmaceutical composition provided herein comprises a pharmaceutically acceptable fragrance or flavouring agent selected from a group of commonly used fragrance or flavouring agent 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 oral pharmaceutical composition provided herein comprises a pharmaceutically acceptable sweetening agent selected from a group of commonly used sweetening agent comprising cyclamate, aspartame, isomalt, mannitol, sorbitol, xylitol, erythritol, and a combination thereof.

In an embodiment of the present invention, the oral pharmaceutical composition provided herein comprises a pharmaceutically acceptable controlled-release agent selected from a group of commonly used controlled-release agent comprising hydroxyethyl cellulose, hydroxypropyl cellulose, alginic acid, sodium alginate, carbomer, sodium carboxymethyl cellulose, xanthan gum, guar gum, locust bean gum, karaya gum, poly vinyl acetate, hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, acrylic acid polymerisate, methacrylic acid copolymers, carrageenans, acacia, chitin derivates, carmellose sodium, carmellose calcium. and a combination thereof.

In an embodiment of the present invention, the oral pharmaceutical composition provided herein comprises a pharmaceutically acceptable carrier selected from a group of commonly used carriers comprising sugar, starch, cellulose, powdered tragacanth, malt, gelatin, talc, cocoa butter, suppository wax, oil, glycol, polyol, ester, agar, buffering agent, alginic acid, isotonic saline, Ringer’s solution, ethyl alcohol, polyester, polycarbonate, polyanhydride, and a combination thereof.

In an embodiment of the present invention, the oral pharmaceutical composition provided herein comprises a pharmaceutically acceptable anti-adherent selected from a group of commonly used anti-adherents comprising silicon dioxide, calcium silicate, magnesium stearate, talcum, colloidal silicon dioxide, salts of stearic acid, sodium stearyl fumarate, leucine, microcrystalline cellulose, starch, and a combination thereof.

The oral pharmaceutical composition provided herein is in a dosage form selected from a group comprising tablet, capsule, lozenge, lollipop, dragées, powder, granule, pellet, powder for reconstitution, granule for reconstitution, suspension, and pill.

The oral pharmaceutical composition provided herein is in a dosage form which has an in vivo release profile selected from a group comprising buccal, sublingual, effervescent, chewable, immediate-release, sustained-release, and enteric-coated.

In an embodiment of the present invention, the oral pharmaceutical composition provided herein is in a dosage form which disintegrates in the mouth, stomach, intestine or in the interconnecting part of the gastrointestinal tract (duodenum).

In an embodiment of the present invention, the oral pharmaceutical composition provided herein is in a dosage form wherein there is no controlled release of active ingredient of the composition i.e., ß-caryophyllene.

In an embodiment of the present invention, the oral pharmaceutical composition provided herein is in a dosage form wherein there is controlled release of active ingredient of the composition i.e., ß-caryophyllene. Controlled-release agent are present as excipient in the composition disclosed herein for immediate-release, sustained-release, delayed release, and site-specific release. Disintegrant are present as excipient in the composition disclosed herein for faster disintegration. Effervescent solid dosage forms containing an acid in solid form, typically citric acid, which acts in water on a base containing chemically combined carbon dioxide, for example sodium hydrogen carbonate or sodium carbonate, and releases carbon dioxide. Such effervescent solid dosage forms disintegrate rapidly to release ß-caryophyllene.

The oral pharmaceutical composition provided herein is orally administered once a day to four times a day to a patient or subject.

The oral pharmaceutical composition provided herein has an onset time between 5 minutes to 15 minutes.

The term "onset time" as used herein refers to the period of time between the administration of a dosage form comprising the composition of the present invention and the release of the active ingredient from a particular component thereof.

The oral pharmaceutical composition provided herein has analgesic effect for a duration of 2 hours to 2.5 hours from the onset time.

The oral 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 oral 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 oral pharmaceutical composition provided herein is useful in the management of pain due to skin inflammation.

In an embodiment of the present invention, the oral dosage forms of the pharmaceutical composition provided herein are in form of controlled-release dosage forms. Such controlled-release dosage forms are prepared by processes known in art.

The oral pharmaceutical composition provided herein is prepared either in powder form or granular form.

In another aspect of the present invention, a process for the preparation of composition provided herein in powder form is provided. The said process comprises steps of,
- sifting an isolated ß-caryophyllene and at least one oil adsorbent through a 0.2 mm mesh to obtain a first mixture;
- sifting at least one oil adsorbent and at least one excipient through a 0.4 mm mesh to obtain a second mixture;
- mixing the first mixture and the second mixture to obtain a third mixture;
- dry blending the third mixture in an octagonal blender for a time duration of 15 minutes to 30 minutes at a speed in range of 11 rpm to 15 rpm and retaining at room temperature for a duration of 15 minutes to 25 minutes to obtain the composition in powder form.

In an embodiment of the present invention, the process provided herein further comprises,
- adding a lubricant sifted through a 0.6 mm mesh into the composition to obtain a pre-blend mixture;
- dry blending the pre-blend mixture in an octagonal blender for a time duration of 4 minutes to 6 minutes at a speed in range of 11 rpm to 15 rpm to obtain a compression blend; and
- compressing the compression blend with a punch to obtain the composition.

In another aspect of the present invention, a process for the preparation of composition provided herein in granular form is provided. The said process comprises steps of,
- sifting an isolated ß-caryophyllene and at least one oil adsorbent through a 0.2 mm mesh to obtain a first mixture;
- sifting at least one oil adsorbent and at least one excipient through a 0.4 mm mesh to obtain a second mixture;
- mixing the first mixture and the second mixture to obtain a third mixture;
- blending the third mixture in a rapid mixer granulator for a time duration of 10 minutes to 20 minutes with intermittent racking and adding aqueous solution of a binder gradually at an impeller speed of 45 rpm to 75 rpm to obtain a granulating mixture; and
- subjecting the granulating mixture to thermal drying at a temperature in range of 60 °C to 70 °C in a fluidized bed dryer to obtain the composition in granular form.

In an embodiment of the present invention, the composition in granular form obtained by the process disclosed herein has a Loss on Drying (LOD) in range of 0.5% w/w to 1.5% w/w.

The composition in granular form so obtained is milled and sifted through a 0.2 mm mesh and at least one lubricant sifted through a 0.6 mm mesh is added in the meshed composition to obtain a pre-blend mixture. The pre-blend mixture is then blended in an octagonal blender for a time duration of 15 minutes to 20 minutes at a speed of 11 rpm to 14 rpm and the blend so obtained is compressed with suitable punch to obtain compressed solid dosage forms.

In an embodiment of the present invention, the process for the preparation of the oral pharmaceutical composition in granular form disclosed herein used granulating solvent selected from a group comprising water, isopropyl alcohol, ethanol, methanol, acetone, methylene chloride, and combination thereof. The granulating solution may comprise any binder or mixture of binders in the granulating solvent.

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

The oral analgesic composition provide herein has analgesic effect comparable to diclofenac based oral analgesics. However, due to presence of natural analgesic ß-caryophyllene as major component, the oral analgesic composition provided herein is extremely safe and free from adverse reactions like abdominal pain, constipation, diarrhoea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal), and vomiting. abnormal renal function, anaemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes, tinnitus etc. reported for diclofenac-based analgesics.

The oral analgesic 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: IMMEDIATE RELEASE TABLETS
1.1. Immediate release tablets with 21.5% w/w of Syloid and 22.5% w/w of ß-caryophyllene
The immediate release tablets having composition as provided in Table-1 below are prepared by two methods: dry blending method and wet granulation method.
Table-1: Composition 1
Sr. No. Ingredients mg/tab Qty. for 1000 tabs (gm)
1. ß-caryophyllene 126.00 126.00
2. Syloid 120.00 120.00
3. Cremophor 8.00 8.00
4. Crospovidone XL-10 30.00 30.0
5. Microcrystalline Cellulose PH102 40.00 40.00
6. Lactose Monohydrate (DC) 121.50 121.50
7. Talc 2.80 2.80
8. Magnesium stearate 2.80 2.80
9. LHPC LH-11 90.0 90.0
10. PVPK-30 16.90 16.90

1.1.a. Preparation using dry blending method
Isolated ß-caryophyllene and Syloid are sifted through a #20 using a vibratory sifter. Cremophor, Crospovidone XL-10, Microcrystalline Cellulose PH102, Lactose Monohydrate (DC), LHPC LH-11 and Talc are sifted through a 40# using a vibratory sifter. The two mixtures thus obtained are blended in a blender e.g., octagonal blender for 20 minutes at 11 RPM. Magnesium Stearate is sifted through a #60 using a vibratory sifter and added to the mixture and the mixture is blended again for 5 minutes at 11 RPM. The mixture thus obtained is compressed with suitable punch into compressed dosage forms like tablets, pellets, pills etc.

1.1.b. Preparation using wet granulation method
Isolated ß-caryophyllene and Syloid are sifted through a #20 using a vibratory sifter. Cremophor, Crospovidone XL-10, Microcrystalline Cellulose PH102, Lactose Monohydrate (DC), LHPC LH-11 and Talc are sifted through a 40# using a vibratory sifter.The two mixtures thus obtained are blended in a rapid mixer granulator for 15 minutes with intermittent racking. PVP K-30 is dissolved in purified water and added to the mixture gradually at slow impeller speed and chopper off. The wet mass thus obtained is fed into a fluidized bed dryer and the wet mass is heated at a temperature of 65°C ± 5°C until granules with desired LOD are obtained. The desired LOD is 0.5% w/w to 1.5% w/w. The granules thus obtained are sifted through a #20 SS sieve using Vibro sifter and milled the oversized granules through 2.0 mm screen with slow speed and forward direction. Talc sifted through a 60# is added to the granules and the mixture is blended in an Octagonal Blender for 20 minutes at 11 RPM. Magnesium Stearate sifted through 60# is added to mixture and the mixture is blended again for 5 minutes. The blend thus obtained is compressed with suitable punch to obtain solid compressed dosage forms.

1.2. Immediate release tablets with 26% w/w of Syloid and 38% w/w of ß-caryophyllene
The immediate release tablets having composition as provided in Table-2 below are prepared by two methods: dry blending method and wet granulation method as explained in Example-1 above.
Table-2: Composition 2
Sr. No. Ingredients mg/tab Qty. for 1000 tabs (gm)
1. ß -caryophyllene 150.00 150.00
2. Syloid 216.0 216.0
3. Cremophor 8.00 8.00
4. Crospovidone XL-10 30.00 30.00
5. Microcrystalline Cellulose PH102 20.00 20.00
6. Lactose Monohydrate (DC) 21.50 21.50
7. Talc 2.80 2.80
8. Magnesium stearate 2.80 2.80
9. LHPC LH-11 90.0 90.0
10. PVPK-30 16.90 16.90

1.3. Immediate release tablets with 11% w/w of Syloid and 53.7% w/w of ß-caryophyllene
The immediate release tablets having composition as provided in Table-3 below are prepared by two methods: dry blending method and wet granulation method as explained in Example-1 above.
Table-3: Composition 3
Sr. No. Ingredients mg/tab Qty. for 1000 tabs (gm)
1. ß -caryophyllene 300.00 300.00
2. Syloid 66.00 66.00
3. Cremophor 8.00 8.00
4. Crospovidone XL-10 30.00 30.00
5. Microcrystalline Cellulose PH102 20.00 20.00
6. Lactose Monohydrate (DC) 21.50 21.50
7. Talc 2.80 2.80
8. Magnesium stearate 2.80 2.80
9. LHPC LH-11 90.00 90.00
10. PVPK-30 16.90 16.90

1.4. Immediate release tablets with 16.12% w/w of CompactCel and 53.76% w/w of ß-caryophyllene
The immediate release tablets having composition as provided in Table-4 below are prepared by two methods: dry blending method and wet granulation method as explained in Example-1 above except that CompactCel is used instead of Syloid.
Table-4: Composition 4
Sr. No. Ingredients mg/tab Qty. for 1000 tabs (gm)
1. ß -caryophyllene 300.0 300.0
2. CompactCel 90.0 90.0
3. Cremophor 8.00 8.00
4. Crospovidone XL-10 30.0 30.0
5. Microcrystalline Cellulose PH102 17.50 17.50
6. Talc 2.80 2.80
7. Magnesium stearate 2.80 2.80
8. LHPC LH-11 90.0 90.0
9. PVPK-30 16.90 16.90

1.5. Immediate-release tablets with 35.8 % w/w of CompactCel and 22.58.% w/w of ß-caryophyllene
The immediate release tablets having composition as provided in Table-5 below are prepared by two methods: dry blending method and wet granulation method as explained in Example-1 above except that CompactCel is used instead of Syloid.
Table-5: Composition 5
Sr. No. Ingredients mg/tab Qty. for 1000 tabs (gm)
1. ß -caryophyllene 126.0 126.0
2. Compact Cel 200.0 200.0
3. Cremophor 8.00 8.00
4. Crospovidone XL-10 30.00 30.00
5. Microcrystalline Cellulose PH102 40.0 40.0
6. Lactose Monohydrate (DC) 41.50 41.50
7. Talc 2.80 2.80
8. Magnesium stearate 2.80 2.80
9. LHPC LH-11 90.00 90.00
10. PVPK-30 16.90 16.90

1.6. Immediate release tablets with 8.96% w/w of F-MELT and 53.76% w/w of ß-caryophyllene
The immediate release tablets having composition as provided in Table-6 below are prepared by two methods: dry blending method and wet granulation method as explained in Example-1 above except that F-MELT is used instead of Syloid.
Table-6: Composition 6
Sr. No. Ingredients mg/tab Qty. for 1000 tabs (gm)
1. ß –caryophyllene 300.0 300.0
2. F-MELT 50.00 50.00
3. Cremophor 8.00 8.00
4. Crospovidone XL-10 30.0 30.0
5. Microcrystalline Cellulose PH102 40.0 40.0
6. Lactose Monohydrate (DC) 17.50 17.50
7. Talc 2.80 2.80
8. Magnesium stearate 2.80 2.80
9. LHPC LH-11 90.0 90.0
10. PVPK-30 16.90 16.90

1.7. Immediate-release tablets with 53.76.% w/w of F-MELT and 22.58% w/w of ß-caryophyllene
The immediate release tablets having composition as provided in Table-7 below are prepared by two methods: dry blending method and wet granulation method as explained in Example-1 above except that F-MELT is used instead of Syloid.
Table-7: Composition 7
Sr. No. Ingredients mg/tab Qty. for 1000 tabs (gm)
1. ß -caryophyllene 126.0 126.0
2. F-MELT 300.0 300.0
3. Cremophor 8.00 8.00
4. Crospovidone XL-10 30.0 30.0
5. Talc 2.80 2.80
6. Magnesium stearate 2.80 2.80
7. LHPC LH-11 71.5 71.5
8. PVPK-30 16.90 16.90

1.8. Immediate-release tablets with 32% w/w Syloid and 11.1% w/w ß-caryophyllene
The immediate release tablets having composition as provided in Table-8 below are prepared by two methods: dry blending method and wet granulation method as explained in Example-1 above.
Table-8: Composition 8
Sr. No. Ingredients mg/tab Qty. for 1000 tabs (gm)
1. ß-caryophyllene 62.00 62.00
2. Syloid 184.00 184.00
3. Cremophor 8.00 8.00
4. Crospovidone XL-10 30.0 30.0
5. Microcrystalline Cellulose PH102 40.00 40.00
6. Lactose Monohydrate (DC) 121.50 121.50
7. Talc 2.80 2.80
8. Magnesium stearate 2.80 2.80
9. LHPC LH-11 90.0 90.0
10. PVPK-30 16.90 16.90

1.9. Immediate-release tablets with 3% w/w Syloid and 10.75% w/w ß-caryophyllene
The immediate release tablets having composition as provided in Table-9 below are prepared by two methods: dry blending method and wet granulation method as explained in Example-1 above.
Table-9: Composition 9
Sr. No. Ingredients mg/tab Qty. for 1000 tabs (gm)
1. ß-caryophyllene 60.00 60.00
2. Syloid 17.00 17.00
3. Cremophor 8.00 8.00
4. Crospovidone XL-10 30.0 30.0
5. Microcrystalline Cellulose PH102 209.00 209.00
6. Lactose Monohydrate (DC) 121.50 121.50
7. Talc 2.80 2.80
8. Magnesium stearate 2.80 2.80
9. LHPC LH-11 90.0 90.0
10. PVPK-30 16.90 16.90

1.10. Immediate-release tablets with 50% w/w Syloid and 10.75% w/w ß-caryophyllene
The immediate release tablets having composition as provided in Table-10 below are prepared by two methods: dry blending method and wet granulation method as explained in Example-1 above.
Table-10: Composition 10
Sr. No. Ingredients mg/tab Qty. for 1000 tabs (gm)
1. ß-caryophyllene 60 60
2. Syloid 279 279
3. Cremophor 8 8
4. Crospovidone XL-10 30 30
5. Microcrystalline Cellulose PH102 47 47
6. Lactose Monohydrate (DC) 21.5 21.5
7. Talc 2.8 2.8
8. Magnesium stearate 2.8 2.8
9. LHPC LH-11 90 90
10. PVPK-30 16.9 16.9

1.11. Immediate-release tablets with 3% w/w Syloid and 54.83% w/w ß-caryophyllene
The immediate release tablets having composition as provided in Table-11 below are prepared by two methods: dry blending method and wet granulation method as explained in Example-1 above.
Table-11: Composition 11
Sr. No. Ingredients mg/tab Qty. for 1000 tabs (gm)
1. ß-caryophyllene 306 306
2. Syloid 16.75 16.75
3. Cremophor 8 8
4. Crospovidone XL-10 30 30
5. Microcrystalline Cellulose PH102 63.25 63.25
6. Lactose Monohydrate (DC) 21.5 21.5
7. Talc 2.8 2.8
8. Magnesium stearate 2.8 2.8
9. LHPC LH-11 90 90
10. PVPK-30 16.9 16.9

1.12. Immediate-release tablets with 22.00% w/w Syloid and 40.00% w/w ß-caryophyllene
The immediate release tablets having composition as provided in Table-12 below are prepared by two methods: dry blending method and wet granulation method as explained in Example-1 above.
Table-12: Composition 12
Sr. No. Ingredients mg/tab Qty. for 1000 tabs (gm)
1. ß-caryophyllene 223.2 223.2
2. Syloid 122.76 122.76
3. Cremophor 8 8
4. Crospovidone XL-10 30 30
5. Microcrystalline Cellulose PH102 40.04 40.04
6. Lactose Monohydrate (DC) 21.5 21.5
7. Talc 2.8 2.8
8. Magnesium stearate 2.8 2.8
9. LHPC LH-11 90 90
10. PVPK-30 16.9 16.9

1.13. Immediate-release tablets with 7.00% w/w Syloid and 40.00% w/w ß-caryophyllene
The immediate release tablets having composition as provided in Table-13 below are prepared by two methods: dry blending method and wet granulation method as explained in Example-1 above.

Table-13: Composition 13

Sr. No. Ingredients mg/tab Qty. for 1000 tabs (gm)
1. ß-caryophyllene 223.2 223.2
2. Syloid 39.06 39.06
3. Cremophor 8 8
4. Crospovidone XL-10 30 30
5. Microcrystalline Cellulose PH102 123.74 123.74
6. Lactose Monohydrate (DC) 21.5 21.5
7. Talc 2.8 2.8
8. Magnesium stearate 2.8 2.8
9. LHPC LH-11 90 90
10. PVPK-30 16.9 16.9

1.14. Immediate-release tablets with 7.00% w/w Syloid and 40.00% w/w ß-caryophyllene
The immediate release tablets having composition as provided in Table-14 below are prepared by two methods: dry blending method and wet granulation method as explained in Example-1 above.
Table-11: Composition 14
Sr. No. Ingredients mg/tab Qty. for 1000 tabs (gm)
1. ß-caryophyllene 223.2 223.2
2. Syloid 156.24 156.24
3. Cremophor 8 8
4. Crospovidone XL-10 30 30
5. Microcrystalline Cellulose PH102 6.56 6.56
6. Lactose Monohydrate (DC) 21.5 21.5
7. Talc 2.8 2.8
8. Magnesium stearate 2.8 2.8
9. LHPC LH-11 90 90
10. PVPK-30 16.9 16.9

EXAMPLE 2: POWDER FOR SUSPENSION OR SUSPENSION
2.1. Powder for suspension or suspension with 16.75% w/w of Syloid and 20% w/w of ß-caryophyllene
Isolated ß-caryophyllene and Syloid are sifted through a #20 using a vibratory sifter. Cremophor, Xanthan Gum, Mannitol, Sucralose, Orange Flavor (Powder) and Ascorbic Acid, Colour Sunset Yellow, Sodium Benzoate are sifted through a 40# using a vibratory sifter. The two mixtures thus obtained are blended in a blender e.g., octagonal blender for 20 minutes at 11 RPM. Magnesium Stearate is sifted through a #60 using a vibratory sifter and added to the mixture and the mixture is blended again for 5 minutes at 11 RPM. The blended mixture is dispersed in purified water and mixed well to obtain a suspension having composition as provided in Table-15 below:

Table-15: Composition 15
Sr. No. Ingredients g/100ml
1. ß-caryophyllene 20
2. Syloid 16.75
3. Cremophor 8
4. Xanthan Gum 0.2
5. Mannitol 40
6. Sucralose 0.2
7. Orange Flavor (Powder) 1.0
8. Ascorbic Acid 0.10
9 Color Sunset Yellow 0.20
10 Sodium Benzoate 0.02
11 Purified Water Q.s.

EXAMPLE 3: SUSTAINED RELEASE TABLETS
3.1 Sustained release tablets with 10.75% w/w of ß-caryophyllene and 50% w/w of Syloid
Isolated ß-caryophyllene and Syloid are sifted through a #20 using a vibratory sifter, Microcrystalline Cellulose PH102, HPMC K4M, PVPK-30 and Talc are sifted through a 40# using a vibratory sifter. The two mixtures thus obtained are blended in a blender e.g., octagonal blender for 20 minutes at 11 RPM. Magnesium Stearate is sifted through a #60 using a vibratory sifter and added to the mixture and the mixture is blended again for 5 minutes at 11 RPM. The mixture thus obtained is compressed with suitable punch into compressed dosage forms like tablets, pellets, pills etc. having composition as provided in Table-16 below.
Table-16: Composition 16
Sr. No. Ingredients mg/tab Qty. for 1000 tabs (gm)
1. ß-caryophyllene 60 60
2. Syloid 279 279
3. Microcrystalline Cellulose PH102 175 175
4. HPMC K4M 21.5 21.5
5. Talc 2.8 2.8
6. Magnesium stearate 2.8 2.8
7. PVPK-30 16.9 16.9

3.2 Sustained release tablets with 20.6% w/w of ß-caryophyllene and 50% w/w of Syloid
The sustained release tablets having composition as provided in Table-17 below are prepared by dry blending method as detailed in 3.1 above.
Table-17: Composition 17
Sr. No. Ingredients mg/tab Qty. for 1000 tabs (gm)
1. ß-caryophyllene 115 115
2. Syloid 279 279
5. Microcrystalline Cellulose PH102 86.5 86.5
6. HPMC K4M 55 55
7. Talc 2.8 2.8
8. Magnesium stearate 2.8 2.8
10. PVPK-30 16.9 16.9

3.3 Sustained release tablets with 30% w/w of ß-caryophyllene and 50% w/w of Syloid
Isolated ß-caryophyllene and Syloid are sifted through a #20 using a vibratory sifter. Cremophor, Microcrystalline Cellulose PH102, HPMC K4M are sifted through a 40# using a vibratory sifter. The two mixtures thus obtained are blended in a rapid mixer granulator for 15 minutes with intermittent racking. PVP K-30 is dissolved in Isopropyl Alcohol and added to the mixture gradually at slow impeller speed and chopper off. The wet mass thus obtained is fed into a fluidized bed dryer and air dry the wet mass for 10 minutes after that heated at a temperature of 60°C ± 5°C until granules with desired LOD are obtained. The desired LOD is 0.5% w/w to 1.5% w/w. The granules thus obtained are sifted through a #20 SS sieve using Vibro sifter and milled the oversized granules through 2.0 mm screen with slow speed and forward direction. Talc sifted through a 60# is added to the granules and the mixture is blended in an Octagonal Blender for 20 minutes at 11 RPM. Magnesium Stearate sifted through 60# is added to mixture and the mixture is blended again for 5 minutes. The blend thus obtained is compressed with suitable punch to obtain solid compressed dosage forms having composition as provided in Table-18 below:

Table-18: Composition 18
Sr. No. Ingredients mg/tab Qty. for 1000 tabs (gm)
1. ß-caryophyllene 167 167
2. Syloid 165.5 165.5
3. Microcrystalline Cellulose PH102 120 120
4. HPMC K4M 83 83
5. Talc 2.8 2.8
6. Magnesium stearate 2.8 2.8
7. PVPK-30 16.9 16.9

EXAMPLE 4: ENTERIC COATED TABLETS
4.1 Enteric coated tablets with 30% w/w of ß-caryophyllene and 30% w/w of Syloid
Isolated ß-caryophyllene and Syloid are sifted through a #20 using a vibratory sifter, Microcrystalline Cellulose PH102, Cremophor, PVPK-30 and Talc are sifted through a 40# using a vibratory sifter. The two mixtures thus obtained are blended in a blender e.g., octagonal blender for 20 minutes at 11 RPM. Magnesium Stearate is sifted through a #60 using a vibratory sifter and added to the mixture and the mixture is blended again for 5 minutes at 11 RPM. The mixture thus obtained is compressed with suitable punch into compressed dosage forms like tablets, pellets, pills etc. having composition as provided in Table-19 below.
For Seal Coat – Opadry II (Seal Coat) Dissolved in Isopropyl Alcohol and Methylene Di Chloride. Coat the tablets and desired weight gain is achieved.
For Enteric Coating - Opadry Enteric Coat Dissolved in Isopropyl Alcohol and Methylene Di Chloride. Coat the tablets and desired weight gain is achieved.
Table-19: Composition 19
Sr. No. Ingredients mg/tab Qty. for 1000 tabs (gm)
1. ß-caryophyllene 167 167
2. Syloid 165.5 165.5
3. Cremophor 8 8
5. Microcrystalline Cellulose PH102 97 97
6. Opadry II (Seal Coat) 15 15
7. Opadry Enteric Coat 83 83
8. Talc 2.8 2.8
9. Magnesium stearate 2.8 2.8
10. PVPK-30 16.9 16.9

EXAMPLE 5: CHEWABLE TABLETS
5.1 Chewable tablets with 10% w/w of ß-caryophyllene and 3% w/w of Syloid
Isolated ß-caryophyllene and Syloid are sifted through a #20 using a vibratory sifter, Mannitol, Xylitol Cremophor, Sucralose, Xanthan Gum and Orange Flavour are sifted through a 40# using a vibratory sifter. The two mixtures thus obtained are blended in a blender e.g., octagonal blender for 20 minutes at 11 RPM. Magnesium Stearate is sifted through a #60 using a vibratory sifter and added to the mixture and the mixture is blended again for 5 minutes at 11 RPM. The mixture thus obtained is compressed with suitable punch into compressed dosage forms like tablets, pellets, pills etc. having composition as provided in Table-20 below:
Table-20: Composition 20
Sr. No. Ingredients mg/tab Qty. for 1000 tabs (gm)
1. ß-caryophyllene 75 75
2. Syloid 6 6
3. Mannitol 36.5 36.5
4. Xylitol 70.0 70.0
5. Cremophor 1.0 1.0
6. Sucralose 0.5 0.5
7. Xanthan Gum 2.0 2.0
8. Orange Flavour 5.0 5.0
9. Magnesium stearate 4.0 4.0

EXAMPLE 6: STABILITY STUDIES
Tablets comprising not less than 85% 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-18 below:
Table-18: Stability studies results
ß-caryophyllene Tablets Initial 40°C± 2°C/75%±5% 30°C± 2°C/75%±5%
Test Specification 0 Day 3 M 6M 3 M 6M
Assay of Beta Caryophyllene NLT 85 % 99.30% 97.60% 94.90% 98.40% 95.70%
Disintegration time (DT) NMT 15 min. 6-7 min. 7-8 min. 6-7 min. 7-8 min. 7-8 min.
Average Weight of tablet 1200 mg ± 5.0 % 1213 mg 1209 mg 1211 mg 1217 mg 1215 mg

Conclusion: All the physical and chemical parameters of the tablet 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 7: ANALGESIC EFFECT OF TRUMOVE01 TABLETS
A comparative study is performed to evaluate the analgesic efficiency of a solid dose composition comprising 300 mg of ß-caryophyllene (TueMove01 tablet) disclosed herein in comparison with vehicle composition (0.5 % CMC) and commercially available analgesic tablet Voveran 50 (50 mg Diclofenac) sold by Novartis.
15 healthy male Wistar rats aged between 10 weeks to 12 weeks and weighing between 220 grams to 250 grams are divided into three groups of 5 animals. TruMove01 tablet comprising 300mg of ß-caryophyllene and Voveran 50 tablet comprising 50 mg of Diclofenac are triturated in mortar and pestle in 0.5% w/w of CMC in distilled water separately. Single dose is administered orally to the rats of the three test solutions and hot-plate test is performed. The dosages administered to three groups of rats is provided in Table-19 below:
Table-19: Dosage during the hot-plate test
Animal group Dose No. of animals
TruMove01 [300mg ß-caryophyllene] 300 mg HED 5
Voveran 50 [50mg Diclofenac 50 mg HED 5
Vehicle [0.5% w/w CMC] 1ml/animal 5

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-20 below provides the results of the study.
Table-20: Results of comparative analgesic efficiency evaluation
Group Group details Baseline 0 min 15 min 30 min 60 min 120 min
1 TruMove01 0 0 50 57 59 66
2 Voveran 50 0 8 56 60 65 68
3 Vehicle 0 0 0 6.25 6.25 0

Conclusion: The study shows that % protection increased from 50% at 15 min to 66% at 120 min for ß-caryophyllene Tablet and, % protection increased from 56% at 15 min to 68 % at 120 min for Diclofenac. It indicates that ß-caryophyllene Tablet and diclofenac, both provides similar protection against heat from 15 min to 120 min and may be after 120 min to some extent.
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:and related disorders comprising:
- a therapeutically effective amount of an isolated ß-caryophyllene;
- a pharmaceutically acceptable oil adsorbent; and
- a pharmaceutically acceptable excipient.

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 oil adsorbent is in a concentration range of 0.5% w/w to 60% w/w of the composition.

6. The composition as claimed in claim 1, wherein the excipient is in a concentration range of 0.001% w/w to 40% w/w of the composition.

7. The composition as claimed in claim 1, wherein the oil adsorbent is selected from a group comprising aluminosilicate-based adsorbent, silica-based adsorbent, carbohydrate-based adsorbent, calcium phosphate-based adsorbent, and a combination thereof.

8. The composition as claimed in claim 7, wherein the carbohydrate-based adsorbent is selected from a group comprising starch, cellulose, lactose, microcrystalline cellulose, and a combination thereof.

9. The composition as claimed in claim 1, wherein the excipient is selected from a group comprising emulsifier, glidant, stabilizing agent, lubricant, diluent, disintegrant, anti-capping agent, binder, anti-caking agent, solubilizing agent, fragrance, sweetening agent, anti-adherent, carrier, coating agent, and a combination thereof.

10. The composition as claimed in claim 1, wherein the composition is in a dosage form selected from a group comprising tablet, capsule, dragées, lozenge, lollipop, powder, granule, pellet, powder for reconstitution, granule for reconstitution, suspension, and pill.

11. The composition as claimed in claim 10, wherein the dosage form has an in vivo release profile selected from a group comprising buccal, sublingual, effervescent, chewable, immediate-release, sustained-release, and enteric-coated.

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

13. The composition as claimed in claim 1, wherein the composition on administration has an onset time from 5 minutes to 15 minutes.

14. The composition as claimed in claim 1, wherein the composition has analgesic effect of 2 hours to 2.5 hours from the onset time.

15. A process for the preparation of composition as claimed in claim 1, comprising steps of,
- sifting an isolated ß-caryophyllene and at least one oil adsorbent through a 0.2 mm mesh to obtain a first mixture;
- sifting at least one oil adsorbent and at least one excipient through a 0.4 mm mesh to obtain a second mixture;
- mixing the first mixture and the second mixture to obtain a third mixture;
- dry blending the third mixture in an octagonal blender for a time duration of 15 minutes to 30 minutes at a speed in range of 11 rpm to 15 rpm; and retaining at room temperature for a duration of 15 minutes to 25 minutes to obtain the composition.

16. The process as claimed in claim 15, wherein the process further comprises,
- adding a lubricant sifted through a 0.6 mm mesh into the composition to obtain a pre-blend mixture;
- dry blending the pre-blend mixture in an octagonal blender for a time duration of 4 minutes to 6 minutes at a speed in range of 11 rpm to 15 rpm to obtain a compression blend; and
- compressing the compression blend with a punch to obtain the composition.

17. A process for the preparation of composition as claimed in claim 1, wherein the process comprises steps of,
- sifting an isolated ß-caryophyllene and at least one oil adsorbent through a 0.2 mm mesh to obtain a first mixture;
- sifting at least one oil adsorbent and at least one excipient through a 0.4 mm mesh to obtain a second mixture;
- mixing the first mixture and the second mixture to obtain a third mixture;
- blending the third mixture in a rapid mixer granulator for a time duration of 10 minutes to 20 minutes with intermittent racking and adding aqueous solution of a binder gradually at an impeller speed of 40 rpm to 75 rpm to obtain a granulating mixture; and
- subjecting the granulating mixture to thermal drying at a temperature in range of 60 °C to 70 °C in a fluidized bed dryer to obtain the composition.

18. The process as claimed in claim 17, wherein the composition obtained has a Loss on drying (LOD) in range of 0.5% w/w to 1.5% w/w.

19. The process as claimed in claim 17, wherein the process further comprises steps of,
- milling and sifting the composition through a 0.2 mm mesh and adding at least one lubricant sifted through a 0.6 mm mesh to obtain a pre-blend mixture;
- dry blending the pre-blend mixture in an octagonal blender for a time duration of 15 minutes to 20 minutes at a speed of 11 rpm to 15 rpm to obtain a compression blend; and
- compressing the compression blend with a punch to obtain the composition.