WO2024028897A1 - Composition topique à base de bêta caryophyllène pour la gestion de la douleur et de l'inflammation - Google Patents

Composition topique à base de bêta caryophyllène pour la gestion de la douleur et de l'inflammation Download PDF

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WO2024028897A1
WO2024028897A1 PCT/IN2023/050742 IN2023050742W WO2024028897A1 WO 2024028897 A1 WO2024028897 A1 WO 2024028897A1 IN 2023050742 W IN2023050742 W IN 2023050742W WO 2024028897 A1 WO2024028897 A1 WO 2024028897A1
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composition
caryophyllene
pain
oil
minutes
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PCT/IN2023/050742
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English (en)
Inventor
Pirthi Pal SINGH PARTAP SINGH
Ashok Goyal
Bholaram JHA
Priyamvada ARUN
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Tirupati Medicare Ltd
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Publication of WO2024028897A1 publication Critical patent/WO2024028897A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

  • the present invention generally relates to pharmaceutical sciences. Specifically, the present invention is related to a topical composition comprising isolated P-caryophyllene, benzalkonium chloride, pharmaceutically acceptable excipients, and optionally an additional active component for the management of pain, inflammation, and other pain related disorders. Also, the present invention provides a method for producing the same and uses thereof.
  • Beta-Caryophyllene chemically represented as trans-(lR, 9S)-8- Methylene-4,l l,l l-trimethylbicyclo-7.2.0 undec-4-ene or lR-(lR4E.9S)-4,l l,l l-trimethyl- 8-methylene-bicyclo7.2.0 undec-4-ene
  • P-Caryophyllene chemically represented as trans-(lR, 9S)-8- Methylene-4,l l,l l-trimethylbicyclo-7.2.0 undec-4-ene or lR-(lR4E.9S)-4,l l,l l-trimethyl- 8-methylene-bicyclo7.2.0 undec-4-ene
  • trans-caryophyllene (E)-BCP) mixed with small amounts of its isomers, (Z)-P-caryophyllene (iso-caryophyllene) and a-humulene (a- caryophyllene), as well as its oxidation derivative — P-caryophyllene oxide (BCPO).
  • BCP mainly stands for (E)-BCP or the natural mixture of BCP isomers.
  • P-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.
  • GRAS Generally Recognized as Safe
  • EFSA European Food Safety Authority
  • 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 P-caryophyllene is as follows: BCP is one of the major active components of essential oils derived from large number of spice and food plants.
  • 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).
  • P-caryohyllene has several biological effects including anti-inflammatory, anticarcinogenic, antimicrobial, antioxidative, and analgesic activities.
  • P-caryophyllene is the primary sesquiterpene contributing to the spiciness of black pepper.
  • P-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 P-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 P-caryophyllene displays insensibly higher biding affinity to CB2 and do not bind to CB1. This implies that P-caryophyllene action is devoid of psychoactive side effects associated with CB1 activation and suggests its potential use in medicine.
  • 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 bum, 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.
  • 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].
  • 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.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • 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.
  • THC tetrahydrocannabinol
  • P-caryophyllene has potential as an efficient natural analgesic without any side effects like psychoactivity, dependence and sedation.
  • P-caryophyllene based analgesic compositions have been reported.
  • US20080280996 provides a composition comprising caryophyllenes including P- caryophyllene for the treatment of inflammatory conditions and inflammatory pain.
  • AU2020412501 provides a composition comprising terpenes including P- caryophyllene for the treatment of pain and anxiety.
  • topical composition comprising P-caryophyllene has limitation with respect to absorption of P-caryophyllene on the skin due to its low solubility in biological fluids. This restricts use of this highly safe natural analgesic in topical analgesic formulations. Therefore, an unmet need exists for a topical composition based on P-caryophyllene which is stable and has enhanced absorption on the skin for enhanced bioavailability of P- caryophyllene to generate sufficient and quick analgesic effect.
  • the present invention provides a topical pharmaceutical composition for the management of pain, inflammation, and pain related disorders.
  • the said composition comprises 10% w/w to 60% w/w of an isolated P-caryophyllene, 0.01% w/w to 35% w/w of benzalkonium chloride, 30% w/w to 70% w/w of at least one excipient, and optionally 0.5% w/w to 30% w/w of an additional active component.
  • the said composition is in a topical dosage form which can be applied on the skin to obtain relief from pain and inflammation within 2 minutes and the analgesic effect imparted by the said topical composition sustains for about 8 hours.
  • the topical composition provided herein has enhanced absorption on the skin.
  • the present invention also provides simple process for the preparation of said topical pharmaceutical composition, method for the management of pain, inflammation, and related disorders in a subject by administering the said composition, and uses of said composition in the management of pain, inflammation, and related disorders.
  • the topical pharmaceutical composition provided herein is natural, safe, economic, and easy to prepare on industrial scale.
  • the topical analgesic composition provide herein has an analgesic effect equivalent to standard diclofenac -based analgesic topical compositions and has no side-effects like psychoactivity, dependence, and sedation.
  • Figure 1 illustrates response latency of the composition disclosed herein (20% w/w of P-caryophyllene, TruMove Gel) in comparison with a standard diclofenac -based analgesic gel (1% w/w of Diclofenac sodium).
  • Figure 2 illustrates % protection against acute pain imparted by the composition disclosed herein (20% w/w of P -caryophyllene, TruMove Gel) in comparison with a standard diclofenac -based analgesic gel (1% w/w of Diclofenac sodium).
  • Figure 3 illustrates WOMAC and McGill pain scores from baseline to Post study in both the groups: the composition disclosed herein (20% w/w of P-caryophyllene, TruMove Gel) in comparison with a standard diclofenac -based analgesic gel (1% w/w of Diclofenac sodium)
  • TruMove or “TruMove gel” used herein refers to a series of test products based on the topical pharmaceutical composition provided herein.
  • a topical pharmaceutical composition for the management of pain, inflammation, and pain related disorders comprising: a therapeutically effective amount of isolated P-caryophyllene; a pharmaceutically acceptable amount of benzalkonium chloride; a pharmaceutically acceptable excipient; and optionally an additional active component.
  • P-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-(lR, 9S)-8-Methylene-4,l 1,1 l-trimethylbicyclo-7.2.0 undec- 4-ene or lR-(lR4E.9S)-4,l l,l l-trimethyl-8-methylene-bicyclo7.2.0 undec-4-ene).
  • isolated P-caryophyllene refers to P-caryophyllene available commercially as mixture of oils, P-caryophyllene extracted from natural plants by conventional methods, or P-caryophyllene prepared by synthetic routes.
  • the topical pharmaceutical composition provided herein comprises a therapeutically effective amount of isolated P -caryophyllene.
  • the topical pharmaceutical composition provided herein comprises about 10% w/w to 60% w/w of isolated P-caryophyllene.
  • the isolated P-caryophyllene present in the topical pharmaceutical composition is in form of oil comprising about 70% w/w to 100% w/w of P-caryophyllene.
  • the isolated P-caryophyllene present in the topical pharmaceutical composition is in form of oil extracted from a group of plants comprising basil ⁇ Ocimum spp.), cinnamon ⁇ Cinnamomum spp.), black pepper Piper nigrum L.), cloves ⁇ Syzygium aromaticu i), cannabis Cannabis sativa L.), lavender ⁇ Lavandula angustifolia), oregano ⁇ Origanum vulgare L.), rosemary ⁇ Rosmarinus officinalis), hops ⁇ Humulus lupulus). and copaiba ⁇ Copaifera langsdorffii).
  • the isolated P-caryophyllene is extracted from cloves.
  • the isolated P-caryophyllene is extracted from clove leaves.
  • terapéuticaally effective amount 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 P-caryophyllene in the topical pharmaceutical composition disclosed herein is in a range of about lOmg to 30mg.
  • the therapeutically effective amount of isolated P-caryophyllene is in a range of about 0.2g to 1g.
  • BAC Benzalkonium Chloride
  • the topical pharmaceutical composition provided herein comprises a pharmaceutically acceptable amount of benzalkonium chloride.
  • the topical pharmaceutical composition provided herein comprises benzalkonium chloride in a concentration range of 0.01% w/w to 35% w/w of the composition.
  • the topical pharmaceutical formulation disclosed herein has enhanced skin absorption due to incorporation of benzalkonium chloride.
  • the enhanced absorption of the composition disclosed herein is increasing the bioavailability of P-caryophyllene and enabling sufficient analgesic effect in highly safe manner through activation of only CB2 receptor.
  • the topical pharmaceutical composition provided herein comprises a pharmaceutically acceptable excipient.
  • pharmaceutically acceptable excipient 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.
  • an “intended subject” includes animals and/or humans.
  • patient and “subject” may be used interchangeably.
  • the topical pharmaceutical composition provided herein comprises an excipient in a concentration range of 30% w/w to 70% w/w of the composition.
  • the topical pharmaceutical composition provided herein comprises an excipient selected from a group of commonly used excipients in topical pharmaceutical compositions comprising rheology modifier, antioxidant, chelating agent, emulsifier, penetration enhancer, preservative, emollient, stabilizing agent, solvent, and a combination thereof.
  • the topical pharmaceutical composition provided herein comprises a pharmaceutically acceptable rheology modifier selected from a group of commonly used rheology modifiers comprising trihydroxystearin, dextrin fatty acid esters such as dextrin palmitate, cholesterol and derivatives such as lanosterol, silicone gellants such as organopolysiloxane elastomers, oil soluble cellulose derivatives such as methylcellulose, ethyl cellulose, and polymers or mixed copolymers, such as ethylene/methacrylic acid copolymer, ethylene/acrylic acid copolymer, organo-clays, such as bentone, polyamides(amine- terminated, ester-terminated, acid-terminated, silicone-modified and tertiary amine terminated), N-acyl amino acids, and esters or amides thereof, 12- hydroxystearic acid and esters or amides thereof, alkylamides of di- and tricarboxylic acids, or polyethylene
  • the topical pharmaceutical composition provided herein comprises a pharmaceutically acceptable emulsifier selected from a group of commonly used emulsifiers comprising non-ionic surface active agent e.g., polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, sucrose fatty acid ester, glycerin fatty acid ester, sorbitan fatty acid ester, anionic surface active agent e.g., alkyl phosphoric acid ester, alkyl sulfate ester, soap, polyoxyethylene alkyl phosphate acid ester, polyoxyethylene alkyl sulfate, and a combination thereof.
  • 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 este
  • the topical pharmaceutical composition provided herein comprises a pharmaceutically acceptable antioxidant selected from a group of commonly used antioxidants comprising amino acids and derivatives thereof, imidazoles, peptides such as carnosine and derivatives, carotenoids, carotenes (such as a-carotene, P- carotene, and lycopene), a-hydroxy acids (such as citric acid, lactic acid, or malic acid), tocopherols and derivatives (such as Vitamin E), vitamin A, co-enzyme Q10, bioflavonoids, glutathione, plant extracts (such as rosemary extract, olive leaf extracts), and green tea extracts, lignans, and aurones, and a combination thereof.
  • a pharmaceutically acceptable antioxidant selected from a group of commonly used antioxidants comprising amino acids and derivatives thereof, imidazoles, peptides such as carnosine and derivatives, carotenoids, carotenes (such as a-carotene, P- carotene, and lycop
  • the topical pharmaceutical composition provided herein comprises a pharmaceutically acceptable chelating agent selected from a group of commonly used chelating agents selected from aminocarboxylic acids or salts thereof, polyphosphoric acids or salts thereof, diphosphonic acids, salts of diphosphonic acids, tertiary amines, aminopho sphonic acids, iminodiacetic acid derivatives, azines, hydroxyquinolines, amino acid esters, ethylene diamine tetra acetic acid, salt of ethylene diamine tetraacetic acid, sodium pyrophosphate, sodium tripolyphosphate, 8- hydroxyquinoline, DL-(Methylene)dinitrolo tetra acetic acids, trans-decahydronaphthylene- trans-2, 3-bis-iminodiacetic, aminophenyl methylene diphosphonic acid, ethylene-bis-N ⁇ Nl- (2,6-carboxyl) piperdine, adenosine triphosphate, L-cy
  • the topical pharmaceutical composition provided herein comprises a pharmaceutically acceptable stabilizing agent selected from a group of commonly used stabilizing agents comprising sorbitan oleate, sorbitan stearate, sorbitan sesquioleate, cetomacrogol, glycerol monostearate, sodium alginate, sodium carboxymethyl cellulose (CMC), guar gum, locust bean gum, carrageenan, gelatin, pectin, and a combination thereof.
  • a pharmaceutically acceptable stabilizing agent selected from a group of commonly used stabilizing agents comprising sorbitan oleate, sorbitan stearate, sorbitan sesquioleate, cetomacrogol, glycerol monostearate, sodium alginate, sodium carboxymethyl cellulose (CMC), guar gum, locust bean gum, carrageenan, gelatin, pectin, and a combination thereof.
  • the topical pharmaceutical composition provided herein comprises a pharmaceutically acceptable preservative selected from a group of commonly used preservatives comprising benzalkonium chloride, diazolidinyl urea; iodopropnyl butylcarbamate; vitamin E (alpha- tocopherol) and its derivatives including vitamin E acetate (alpha-tocopherol acetate); vitamin C (ascorbic acid); butylated hydroxytoluene (BHT); butylated hydroxyanisole (BHA); esters of p-hydroxy benzoic acid such as methylparaben (p-hydroxybenzoic acid methyl ester), ethylparaben (p- hydroxybenzoic acid ethyl ester), propylparaben (p-hydroxybenzoic acid n- propyl ester), and butylparaben (p-hydroxybenzoic acid n-butyl ester), and a combination thereof.
  • a pharmaceutically acceptable preservative selected
  • the topical pharmaceutical composition provided herein comprises a pharmaceutically acceptable emollient selected from a group of commonly used emollients comprising oils, waxes, natural oils derived from plants, silicone oil, polyunsaturated fatty acid, lanoline, dicaprylic ether, isopropyl palmitate, dicaprylyl carbonate, C12-C15 alkyl benzoate, isopropyl isononate, sucrose palmitate, sucrose oleate, isostearyl lactate, glyceryl behenate, triglycerol-4 isostearate, lauryl pirrolidone carboxylic acid, pantenyl triacetate, and a combination thereof.
  • 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, dicap
  • the topical pharmaceutical composition provided herein comprises a pharmaceutically acceptable solvent selected from a group of commonly used solvents comprising ketones such as acetone, diacetone alcohol, dihydroxyacetone, ethyl butyl valerolactone, methyl ethyl ketone etc., aliphatic or aromatic alcohols such as methanol, ethanol, propanol, benzyl alcohol, butyl alcohol, t-butyl alcohol, butylene glycol, diethylene glycol, abietyl alcohol, propylene carbonate, hexyl alcohol, isopropanol etc., glycol ethers such as butoxyethanol, butoxypropanol, 3-methyl-3-methoxy- butanol, methoxypropanol etc., esters such as butyl acetate, ethyl acetate, 1 -methoxylpropanol acetate etc., benzoates, siloxanes, cyclic silicones, and a
  • the topical pharmaceutical composition provided herein comprises a pharmaceutically acceptable fragrance or flavouring agent selected from a group of commonly used fragrances or flavouring agents selected from a group comprising natural oils, synthetic oils, alcohols, aldehydes, ketones, esters, lactones, hydrocarbons, and a combination thereof.
  • the topical pharmaceutical composition provided herein comprises a pharmaceutically acceptable penetration enhancer selected from a group comprising pyrrolidone, alcohol especially, ester, water, ester sulfoxide (such as dimethyl sulfoxide) and their derivatives, hydrocarbon, terpene and derivatives, benzalkonium chloride, azone and its analogs, amide (including urea and its derivatives), fatty acids, surfactants, oleodendrimers, ionic liquids, and deep eutectic solvents, and a combination thereof.
  • 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
  • the topical pharmaceutical composition provided herein comprises an optional additional active component.
  • active component 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.
  • the topical pharmaceutical composition provided herein comprises optionally an additional active component in a concentration range of 0.5% w/w to 30% w/w of the composition.
  • the topical pharmaceutical composition provided herein comprises optionally an additional active component selected from a group comprising methyl salicylate, pudina crystals, terpene oil, eucalyptus oil, capsaicin, clove oil, and a combination thereof.
  • the topical pharmaceutical composition provided herein is in a dosage form selected from a group liquid, ointment, foam, lotion, cream, gel, paste, ointment, patch, emugel, emulsion, solution, oil, suspension, poultice, plaster, paint, liniment, collodion, and roll-on.
  • the topical pharmaceutical composition provided herein is applied topically on the skin once a day to four times a day to a patient or subject.
  • the topical pharmaceutical composition provided herein has an onset time between 2 minutes to 15 minutes.
  • onset time refers to the period of time between the topical application of the topical dosage form comprising the composition of the present invention and the release of the active ingredient thereof.
  • the topical pharmaceutical composition provided herein has analgesic effect for a duration of 7.5 hours to 8 hours from the onset time.
  • the topical pharmaceutical composition provided herein is used for the management of pain, inflammation, and related disorders.
  • 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 bum, 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.
  • pain or inflammation which persists beyond the time necessary for resolution of an acute condition is defined as chronic pain or inflammation.
  • the topical pharmaceutical composition provided herein is useful in the management of pain in medical conditions selected from a group comprising arthralgia, backache, neuralgia, ischialgia, fibromyalgia, musculo -skeletal pain, pelvic pain, and related disorders.
  • the topical pharmaceutical composition provided herein is useful in the management of pain in medical conditions selected from a group comprising atopic dermatitis, contact dermatitis, allergic dermatitis, pruritic dermatitis, solar (UVB -induced) dermatitis, chemical-induced dermatitis, bacterial and viral skin inflammation, acne, psoriasis, and related disorders.
  • a process for the preparation of topical composition comprises steps of, mixing the isolated P-caryophyllene and at least one excipient and heating the mixture with continuous stirring at a temperature in range of 50 °C to 60 °C to obtain an oil phase; mixing purified water, an emulsifier, and a preservative in a stainless-steel container at a temperature in range of 50 °C to 60 °C to obtain an aqueous phase; mixing the oil phase and the aqueous phase in a homogenizer at a speed in range of 2000 rpm to 28000 rpm for a duration of 2 minutes to 12 minutes maintaining the temperature in range of 50 °C to 60 °C to obtain an emulsified mixture; mixing purified water and a viscosity modifier with continuous stirring and soaking for a duration of 45 minutes to 50 minutes to obtain a gel of viscosity modifier; mixing the emulsified mixture and the gel of viscosity
  • emulsifier is Tween 80
  • preservative is sodium methyl paraben
  • viscosity modifier is Carbopol
  • excipient is selected from a group comprising methyl salicylate, pudina crystals, terpene oil, eucalyptus oil, clove oil, capsaicin, glycerol monostearate, span 80, cetostearyl alcohol, and a combination thereof.
  • topical composition provided by the present invention in the management of pain, inflammation, and related disorders.
  • the topical pharmaceutical composition provided herein is natural, safe, economic, and easy to prepare on industrial scale.
  • the topical pharmaceutical composition provided herein has analgesic effect equivalent to diclofenac based topical compositions. Due to presence of natural analgesic P- caryophyllene as major component, the topical composition provided herein is extremely safe and free from adverse reactions like application site dermatitis which is generally experienced by patients in long term usage of diclofenac based topical compositions. The safety associated with the topical composition provided herein will lead to better patient compliance.
  • the topical pharmaceutical composition provided herein has no side-effects like psychoactivity, 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.
  • cannabinoid analgesic e.g., THC which activates both CB1 and CB2 receptors to trigger undesirable psychoactivity.
  • Isolated P-caryophyllene, Methyl Salicylate, Pudina crystals, Taarpeen ka Tel, Eucalyptus Oil, Clove Oil, Capsaicin, Glycerol monostearate, Span 80, and Cetostearyl Alcohol are mixed together and heated between 50 °C to 60 °C with constant stirring to obtain a clear oil phase solution.
  • purified water, Tween 80, and sodium methyl paraben are mixed and heated between 50 °C to 60 °C to obtain aqueous phase solution.
  • the oil phase solution and the aqueous phase solution are mixed in a high-speed homogenizer between 50 °C to 60 °C to obtain an emulsified mixture.
  • Table-2 Composition of analgesic gel [20% TruMove Gel 021
  • TruMove Gel 03 having composition provided in Table-3 below is prepared using method detailed in Example 1.1 Table-3: Composition of analgesic gel [20% TruMove Gel 031
  • An analgesic gel comprising not less than 20% w/w of beta-caryophyllene is evaluated for stability at 40 °C ⁇ 2 °C /75 ⁇ 5 % RH and 30 °C ⁇ 2 °C / 75 ⁇ 5 % RH for initial, 3 months’ and 6 months’ .
  • the result of the study is provided in Table-4 below:
  • a comparative study is performed to evaluate the analgesic efficiency of the composition disclosed herein in form of a gel comprising 20% w/w of P-caryophyllene (TruMove Gel) in comparison with a standard pain relief gel comprising 1% w/w of Diclofenac sodium.
  • a comparative study is performed to evaluate the analgesic efficiency of the composition disclosed herein in form of a gel comprising 20% w/w of P-caryophyllene (TruMove Gel) in comparison with a standard pain relief gel comprising 1% w/w of Diclofenac sodium.

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Abstract

La présente invention concerne une composition topique basée sur le phytocannabinoïde β-caryophyllène (BCP) pour la gestion de la douleur, de l'inflammation et de troubles associés. La composition comprend du β-caryophyllène sous forme isolée, du chlorure de benzalkonium, au moins un excipient pharmaceutiquement acceptable, et éventuellement un composant actif supplémentaire. La composition topique a une absorption améliorée sur la peau et confère une protection efficace contre la douleur, l'inflammation et les troubles associés. La composition est spécifiquement utile dans le traitement de troubles inflammatoires chroniques car elle est exempte d'effets secondaires indésirables tels que la psycho-activité, la dépendance et la sédation. La présente invention concerne également un procédé de production de celle-ci et ses utilisations.
PCT/IN2023/050742 2022-08-01 2023-08-01 Composition topique à base de bêta caryophyllène pour la gestion de la douleur et de l'inflammation WO2024028897A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108420789A (zh) * 2018-04-16 2018-08-21 海南皇隆制药股份有限公司 一种苯扎氯铵外用溶液及其制备方法
US20200030252A1 (en) * 2018-07-18 2020-01-30 John Enrique Mata Multifunctional topical cream comprising beta-caryophyllene, essential oils, in a phospholipid and triglyceride base

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