Technical Field of the Invention
The present invention relates to a topical composition in the form of spray comprising aceclofenac, one or more penetration enhancers and a propellant.
Background of the invention
Aceclofenac ((2-[(2, 6-dichlorophenyl)amino]phenylacetoxyacetic acid (CAS RN: 89796-99-6) is a a phenylacetic acid-based anti-inflammatory analgesic drug showing an excellent effect for chronic joint diseases, including rheumatoid arthritis, osteoarthrosis ankylosing spondylitis and toothache, as well as acute conditions like post- operation or post- delivery pain. This drug shows an excellent treating effect as it is easily penetrated into inflammatory tissues in a joint and the like, and thus shows excellent action of inhibiting prostaglandin production, as compared to other anti-inflammatory analgesic drugs, including naproxen and diclofenac. On the other hand, when administered orally this drug shows weak inhibition of normal prostaglandin production in a gastric mucosa to reduce gastroenteric trouble so that it is suitable for long-term application Particularly, this drug is characteristic in that it inhibits the production of interleukin-1 causing the destruction of joint cartilage and accelerates the production of glycosaminoglycan found in joint cartilage, thereby preventing rheumatoid arthritis, osteoarthrosis and the like from being worse.
Aceclofenac has the following clinical advantages over other anti-inflammatory analgesic drugs: (i) It inhibits the production of interleukin-1 causing the destruction of joint cartilage and accelerates the production of glycosaminoglycan found in joint cartilage, so that it is suitable for the prevention of rheumatoid arthritis and osteoarthrosis, (ii) It has a reduced effect on normal prostaglandin production in a gastric mucosa such that gastroentric trouble is minimized and (iii) It is penetrated into an inflammatory site, such as a joint, at high concentration so that it has a powerful effect of inhibiting prostaglandin production in foci.
Aceclofenac is currently available in the form of tablets, capsules, powder, injectables, suppositories, suspension, creams and gels.
Topical routes of drug administration are often desirable, because problems associated with other drug delivery means can be avoided. For instance, oral administration of drugs is often associated with variable absorption and metabolism of the drug and gastrointestinal irritation. Oral NSAID administration may also result in other systemic adverse effects, such as headache,
dizziness, salt and fluid retention, and hypertension. Furthermore, a significant amount of the drug may be lost as a result of oral administration, due to partial metabolism of the drug by the liver prior to reaching the bloodstream. Further, aceclofenac has a low solubility property that led to poor dissolution, thereby absorption is delayed leading to lowering its bioavailability.
Although preferred over oral dosage forms in acute conditions, the available topical dosages have a series of disadvantages. Frequently numerous adjuvants must be added to these preparations, which leads to an unnecessary burden to the formulation. In spite of the many additives used, these formulations are not sufficiently stable at elevated temperatures. This leads to a "breaking" of the formulation, producing a non-homogeneous mixture of the different components of the preparation, and loss of therapeutic usefulness. This applies particularly to preparations in the form of emulsions or other dispersions.
With the currently customary topical dosage forms such as emulsions, suspensions, etc. the active material is involved in special transport and distribution processes before it can penetrate through the skin into the body and become effective. Many of these systems suffer from occlusion problems and cause skin irritation.
Topical spray formulations containing anti-inflammatory analgesic drugs are often desired when there is a need for instant pain relief, especially in conditions like sprain or strains, back pain, lower back pain, joint stiffness, etc.
US Patent 4,704,406 discloses a sprayable preparation for the treatment of traumatic and rheumatic diseases, containing a solvent mixture of one or more volatile solvents and one or more non-volatile solvents.
US Patent 6,635,674 discloses a topical gel composition containing non steroidal antiinflammatory agent for external use. The aqueous gel system contains oleic acid or oleyl alcohol as skin penetration enhancers.
US Patent 7,026,360 discloses pharmaceutical compositions containing non steroidal antiinflammatory drugs including diclofenac with enhanced absorption of active ingredients. Phosphatidylcholine is used for the enhancement of absorption of active ingredients. The enhancement of absorption of active ingredient is sought by incorporation of 0.1% - 20% by weight of phosphatidylcholine.
PCT application WO 09/047785 teaches a non-aqueous topical solution for diclofenac diethylamine salt. The topical solution composition is non-greasy, non-irritating and non-dehydrating when applied on the skin of a mammal and also exhibits enhanced transdermal penetration resulting in higher blood plasma levels.
US Patent 6,962,691 discloses a topical medicinal spray composition that forms films upon application. Primarily the composition is meant for delivering active substance topically for prolonged period of time.
US Patent 4,534,958 discloses a sprayable aersol composition which is a liquid in the aerosol container and forms a gel upon application to the skin. The composition contains polyoxyethylene-polyoxypropylene copolymer to gel upon application.
Even though the prior references teaches various topical dosage forms containing various antiinflammatory analgesic drugs, there is a need for topical composition for aceclofenac particularly useful for the relief of acute pain and inflammation that can overcome the above mentioned
limitations.
Summary of the Invention
In one aspect, the present invention relates to a topical composition in the form of spray comprising (i) aceclofenac or a pharmaceutically acceptable salt thereof, in a concentration from 0.1 to 10% by weight of the composition, (ii) one or more penetration enhancers, in a concentration from 0.1 to 10% by weight of the composition, (iii) at least one propellant, in a concentration from 20 to 60% by weight of the composition.
Embodiments of the composition may include one or more following features. For example, the composition optionally comprises one or more other anti-inflammatory agents. Some of these additional anti-inflammatory agents are capable of acting as penetration enhancers. The composition advantageously produces synergistic effects in combination with aceclofenac. These additional anti inflammatory agents can be selected from one or more of, vegetable oils, methyl salicylate, menthol, eugenol, thymol, carvacrol, boldine, alpha-pinene, beta-pinene, caryophyllene, caryophyllene oxide, cinnamaldehyde, delta-3-carene, quercitrin, limonene, herbs, steroid or other NSAIDs.
In another embodiment, the composition of the present invention further comprises one or more pharmaceutically acceptable excipients like solvents, cooling agents, surfactants, humectants,
skin freshener or lather stabilizers, preservatives, antioxidants, film formers, plasticizers, colorants, flavouring agents, buffering agents or a pH-adjusting agents.
In another aspect, the present invention relates to a topical composition in the form of spray comprising (i) aceclofenac or a pharmaceutically acceptable salt thereof, in a concentration from 0.1 to 10% by weight of the composition, (ii) one or more penetration enhancers, in a concentration from 0.1 to 10% by weight of the composition, (iii) one or more counter irritant, in a concentration from 0.1 to 10% by weight of the composition, and (iv) at least one propellant, in a concentration from 20 to 60% by weight of the composition.
In one embodiment, topical composition comprises (i) aceclofenac, in a concentration from 0.1 to 10% by weight of the composition, (ii) linseed oil, in a concentration from 0.1 to 10% by weight of the composition, (iii) methyl salicylate, in a concentration from 0.1 to 10% by weight of the composition, and (iv) liquified petroleum gas, in a concentration from 20 to 60% by weight of the composition.
It is yet another aspect to provide a method for treating acute conditions of pain and inflammation like, Back pain, Lower back pain, Knee pain, Sprain & Strains, Ankle sprain, Wrist sprain, Osteoarthritis Knee, Spondylosis, Cervical spondylosis, Athlete Injury, Arthritis, Knee Arthritis, Shoulder lesions, Frozen Shoulder, Prolapsed intervertebral disc, Thumb stiffness, knee stiffness, shoulder stiffness, Rheumatoid arthritis or Tennis elbow by applying to a person in need thereof, a composition in the form of spray comprising aceclofenac or a pharmaceutically acceptable salt thereof. The composition may further include one or more other anti-inflammatory agents.
The details of one or more embodiments of the inventions are set forth in the description below. Other features and objects of the invention will be apparent from the description and claims.
Detailed Description of the Invention
Various aceclofenac formulations are available for the treatment of inflammation and pain. However the conventional oral and systemic administration may lead to various side effects such as gastric irritation, particularly diarrhoea, nausea, abdominal pain and flatulence. Ointments are occlusive, placing an oleaginous covering over surface which prevents or restricts the ability of the underlying tissue to transpire. This results in maceration of tissue, which is further excerbated if the tissue is already irritated. In addition, being oily products which become more fluid at body temperature, ointments tend to soften and flow and stain clothing. Creams and lotions are either oil-in-water or water-in-oil emulsion systems. The water-in-oil emulsions have some of the same
disadvantages as do ointments since they have an oil external phase. Both classes of emulsions, however of necessity, contain surface active or emulsifying agents. These materials are irritating to the skin membranes. The irritation is compounded if the membranes are irritated or compromised.
On the contrary, the present invention provides a topical spray composition comprising aceclofenac which can overcome the above mentioned limitations. Further the spray composition is beneficial for acute therapy of pain and inflammation as it provides immediate onset of action and hence immediate relief. The topical spray composition of the present invention comprises aeclofenac or a pharmaceutically acceptable salt thereof, penetration enhancers and a propellant.
Medicament in the composition may be present in a solubilized or suspended or dispersed form. After application, the medicament is available locally or transdermally. The compositions are preferably in a form suitable for application by spraying from an aerosol or pump spray container.
In order to deliver effective amounts of active agent, the composition comprises aceclofenac or its pharmaceutically acceptable salt thereof, in a concentration from 0.1 to 10% by weight of the composition, more preferably, in a concentration from 0.1 to 5% by weight of the composition.
The term "pharmaceutically acceptable salt" of aceclofenac means any salts of aceclofenac having an acidic groups like e.g. an alkali metal or alkaline earth metal salt, e.g. the sodium, potassium, magnesium or calcium salt, an aluminium salt or a transition metal salt, e.g. the zinc or copper salt, or a corresponding salt with ammonia or organic amines. Organic amines that come into consideration are, for example, the following: alkylamines, such as mono-, di- or tri-lower alkylamines, e.g. ethylamine, tert-butylamine, diethylamine, diisopropylamine, trimethylamine or triethylamine, alkylenediamines, such as lower alkylenediamines, e.g. ethylenediamine, alkylamines substituted by phenyl, such as mono- or di-phenyl-lower alkylamines, e.g. benzylamine or 1 - or 2-phenylethylamine, hydroxy-alkylamines, such as mono-, di- or tri- hydroxy-lower alkylamines, e.g. mono-, di- or tri-ethanolamine or diisopropanolamine, oligohydroxy-lower alkylamines, e.g. tris- (hydroxymethyl) - methyl amine, hydroxy-lower alkyl-di-lower alkylamines, e.g. N, N-dimethylamino- or N,N-diethylamino-ethanol, amino sugars, such as those in which the amino group is optionally substituted by at least one lower alkyl group, e.g. D-glucosamine, D-galactosamine or marmosamine (derived from monosaccharides in which an alcoholic hydroxy group is replaced by an amino group) or N-methyl-Dglucosamine (an N-lower alkylated amino sugar), cycloalkylamines, such as mono- or dicycloalkylamines, e.g. cyclohexylamine or dicyclohexylamine, basic amino acids, e.g. arginine, histidine, lysine or ornithine, or cyclic amines, such as lower alkyleneamines or lower alkenyleneamines, e.g. azirine, pyrrolidine, 1 - ethyl -pyrrolidine, 2-hydroxyethylpyrrolidine, piperidine, 1 -ethyl- pipeddine, 2-
hydroxyethyl-pipeddine or pyrroline, or lower alkyleneamines or lower alkenyleneamines in which the carbon chain is interrupted by aza (-NH-), N-lower alkylaza [-N(-lower alkyl)], oxa (-0-) and/or thia (-S-), eg imidazoline, 3methylimidazoline, piperazine, 4-methyl-or 4-ethylpiperazine, morpholine or thiomorpholine.
Penetration enhancers increase the permeability of active agents into the skin. The composition of the present invention comprises one or more penetration enhancers, in a concentration from 0.1 to 10% by weight of the composition. Preferably, present in the concentration from 0.1 to 8% by weight of the composition.
Examples of suitable penetration enhancers include, but are not limited to, sulfoxides, alcohols, fatty acids, fatty acid esters, polyols, amides, surfactants, terpenes, alkanones, organic acids and mixtures thereof.
Specific examples of suitable sulfoxides include, but are not limited to, dimethylsulfoxide (DMSO) and decylmethylsulfoxide.
Specific examples of alcohols include, but are not limited to, higher mono- and poly-functional alcohols and fatty alcohols, such as caprylic alcohol, decyl alcohol, lauryl alcohol, 2-lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, linoleyl alcohol, and linolenyl alcohol.
Specific examples of suitable fatty acids include, but are not limited to, linear fatty acids such as valeric acid, heptanoic acid, pelagonic acid, caproic acid, capric acid, lauric acid, myristic acid, stearic acid, oleic acid, and caprylic acid; and branched fatty acids, such as isovaleric acid, neopentanoic acid, neoheptanoic acid, neononanoic acid, trimethyl hexanoic acid, neodecanoic acid, and isostearic acid.
Specific examples of suitable fatty acid esters include, but are not limited to, aliphatic fatty acid esters such as isopropyl n- butyrate, isopropyl n-hexanoate, isopropyl n-decanoate, isopropyl myristate, isopropyl palmitate, and octyldodecyl myristate; alkyl fatty acid esters such as ethyl acetate, butyl acetate, methyl acetate, methylvalerate, methylpropionate, diethyl sebacate, and ethyl oleate; and diisopropyl adipate and dimethyl isosorbide.
Specific examples of suitable polyols include, but are not limited to, propylene glycol, butylene glycol, polyethylene glycol, ethylene glycol, diethylene glycol, triethylene glycol, dipropylene glycol, ethoxydiglycol, pentylene glycol, glycerol, propanediol, butanediol, pentanediol, hexanetriol, and glycerin.
Specific examples of suitable amides include, but are not limited to, urea, dimethylacetamide, diethyltoluamide, dimethylf ormamide (DMF) , dimethyloctamide, dimethyldecamide, biodegradable cyclic urea (e.g., l-alkyl-4-imidazoline-2-one) , pyrrolidone derivatives, biodegradable pyrrolidone derivatives (e.g., fatty acid esters of N- (2- hydroxyethyl) -2-pyrrolidone) , cyclic amides, hexamethylenelauramide and its derivatives, diethanolamine, and triethanolamine . Examples of pyrrolidone derivatives include 1-methyl-2-pyrrolidone, 2-pyrrolidone, 1-lauryl-2-pyrrolidone, 1-methyl-4- carboxy-2 -pyrrolidone, 1-hexyl-4-carboxy-2 -pyrrolidone, 1-lauryl- 4-carboxy-2 -pyrrolidone, 1-methyl-4-methoxycarbonyl-2-pyrrolidone, 1-hexyl-4-methoxycarbonyl- 2-pyrrolidone, 1-lauryl -4-methoxycarbonyl -2-pyrrolidone, N-cyclohexylpyrrolidone, N- dimethylaminopropylpyrrolidone, N-cocoalkypyrrolidone, N -tallowalkylpyrrolidone, and N-methylpyrrolidone.
Specific examples of cyclic amides include, but are not limited to, 1- dodecylazacycloheptane-2-one (e.g., Azone®) , 1- geranylazacycloheptan-2-one, 1-famesylazacycloheptan-2- one, 1-geranylgeranylazacycloheptan-2-one, 1-(3,7- dimethyloctyl) azacycloheptan-2-one, 1- (3, 7,11-trimethyldodecyl) azacyclohaptane-2-one, 1- geranylazacyclohexane-2-one, 1-geranylazacyclopentan-2, 5-dione, and 1-farnesylazacyclopentan-2-one.
Examples of suitable surfactants include, but are not limited to, anionic surfactants, cationic surfactants, nonionic surfactants, and mixtures thereof.
Specific examples of suitable anionic surfactants include, but are not limited to, sodium laurate, sodium lauryl sulfate, and sodium laureth sulfate.
Specific examples of cationic surfactants include, but are not limited to, cetyltrimethyl ammonium bromide, tetradecyltrimethylammonium bromide, benzalkonium chloride, octadecyltrimethylammonium chloride, cethylpyridinium chloride, dodecyltrimethylammonium chloride, and hexadecyultrimethylammonium chloride.
Specific examples of nonionic surfactants include, but are not limited to, poloxamer 231, poloxamer 182, poloxamer 184, Brij® 30 (polyoxyethylene (4) lauryl ether), Brij® 93 (polyoxyethylene (2) oleyl ether), Brij® 96 (polyoxyethylene (20) oleyl ether), Brij® 99 (polyoxyl (10) oleyl ether), Span® 20 (sorbitan monolaurate) , Span® 40 (sorbitane monopalmitate), Span® 60 (sorbitane monostearate), Span® 80 (sorbitane monooleate) , Span® 85 (sorbitane trioleate) , TWEEN® 20 (polyethylene glycol sorbitan monolaurate; polyoxyethylene (20) sorbitan monolaurate), TWEEN® 40 (polyoxyethylene (20) sorbitan monopalmitate) , TWEEN® 60
(polyethylene glycol sorbitan monostearate; polyoxyethylene (20) sorbitan monostearate), TWEEN® 80 (polyethylene glycol sorbitan monooleate; polyoxyethylene (20) sorbitan monooleate), Myrj® 45 (polyoxyethylene (8) stearate), Myrj® 51 (polyoxyethylene stearate), Myrj® 52 (polyoxyethylene stearate), and Miglyol 840 (propylene glycol dicaprylate/dicaprat), among others.
Specific examples of suitable bile salts include, but are not limited to, sodium cholate, and sodium salts of taurocholic, glycholic, and desoxycholic acids.
Specific examples of terpenes include, but are not limited to, hydrocarbons (e.g., D-limonene, a-pinene, P-carene, etc.), alcohols (e.g. a-terpineol, terpinen-4-ol, carvol, etc.), ketones (e.g., carvone, pulegone, piperitone, menthone, etc.), oxides (e.g., cyclohexene oxide, limonene oxide, opinene oxide, cyclopentene oxide, 1,8-cineole, etc.), and oils (e.g., ylang ylang, anise, chenopodium, eucalyptus, peppermint, etc.).
Examples of suitable alkanones include, but are not limited to, N- heptane, N-octane, N-nonane, N-decane, N-undecane, N- dodecane, N-tridecane, N-tetradecane, and N-hexadecane, among
others.
Examples of suitable organic acids include, but are not limited to, salicylic acid and salicylates (including their methyl, ethyl, and propyl glycol derivatives), citric acid, and succinic acid, among others.
Other examples of suitable skin penetration enhancers are known in the art and include, but are not limited to, monoglycerides, polyglycosylated glycerides, glyceryl monoethyl ether, polysorbates, beta- cyclodextrin, cyclopentadecalactone, alkyl-2- (N, N- disubstituted amino) -alkanoate ester, 2- (n-nonyl) -1, 3- dioxolane, isopropyl myristate, terpinol, menthol, cineol, monoolein, sodium oleate, oleyl oleate, laurylcapram, bisabolol and capaicin.
Propellants in the composition greatly help in dispensing the composition in the spray form. Generally propellant is a substance that is gas under atmospheric conditions but liquid under pressure, that is used to generate a fine mist spray. The composition of the present invention comprises at least one propellant, in a concentration from 20 to 60% by weight of the composition. Preferably, present in the concentration from 25 to 50% by weight of the composition.
Examples of propellants used in the composition include, but are not limited to, liquefied gas propellants, such as hydrocarbons, for example, propane, butane, isobutane, or dimethylether; hydrofluorocarbons and hydrochlorofluorocarbons, for example, dichlorodifluoromethane (P12), trichloromonofluoromethane (P11), dichlorofluoroethane, monochlorodifluoromethane (P22), dichlorotetrafluoroethane (P114), difluoroethane (P152a), tetrafluoroethane (134a), heptafluoropropane (P227b); compressed gas propellants with a vapour pressure of greater than 101.3 kPa (14.7 psi), such as compressed carbon dioxide or nitrogen gas; and mixtures thereof.
In an aerosol dispenser using liquefied gas-type propellants, the container is loaded with the liquid product and propellant to a pressure approximately equal to, or slightly greater than, the vapor pressure of the propellant. Thus filled, the container still has a certain amount of space that is not occupied by liquid. This space is referred to as the "head space" of the dispenser assembly. Since the container is pressurized to approximately the vapor pressure of the propellant, some of the propellant is dissolved or emulsified in the liquid product. The remainder of the propellant is in the vapor phase and fills the head space. As the product is dispensed, the pressure in the container remains approximately constant as liquid propellant evaporates to replenish discharged vapor. Liquefied gas propellants keep the pressure constant in the aerosol can until the contents are exhausted, thus ensuring a consistent spray performance throughout the lifetime of the can. It is common to use a blend of propellant components to achieve best combination of solubility, economics, pressure and safety.
In contrast, compressed gas propellants (C02, N20, N2) are not liquid in conventional aerosol containers; that is, they are present entirely in the vapor phase. The internal vapour pressure drops as the contents are depleted, causing changes in the rate and characteristics of the spray.
Hydrocarbon aerosol propellants are relatively inexpensive, non-toxic, and environmentally friendly (since they are not damaging to the ozone layer and are not greenhouse gases). Preferably the propellant used in the present composition is selected from liquefied gas propellants, more preferably hydrocarbon such as butane, propane, isobutane or mixtures thereof. The hydrocarbons may be deodourized by a suitable procedure prior to use as a propellant.
The composition of the invention may also include a counterirritant. A counterirritant is a substance which creates inflammation in one location with the goal of lessening the inflammation in another location. A counterirritant produces a blister, a pustular eruption or other irritation in some part of the body, in order to relieve an existing irritation in some other part. Counter irritants are of as great use in moral as in physical diseases. Counterirritants used in the composition
include, but are not limited to, salicylates, capsaicin, camphor, eucalyptus oil, phenol and menthol.
An optional additional anti-inflammatory agent present in the composition may include, but are not limited to vegetable oil such as linseed oil, emu oil, eucalyptus oil, cottonseed oil, castor oil, sesame oil, arachis oil, barage oil, clove oil, camphor oil, Ocimum sanctum oil, almond oil, jojoba oil, mustard oil, olive oil; methyl salicylate, phenyl salicylate , menthol, eugenol, thymol, carvacrol, boldine, alpha-pinene, beta-pinene, caryophyllene, caryophyllene oxide, cinnamaldehyde, delta-3-carene, quercitrin ; herbs including hyssop, ginger, turmeric, Arnica montana , cannabis & willow bark, steroids (glucocorticoid) or any other non-steroidal anti-inflammatory drugs.
Examples of non-steroidal anti-inflammatory drugs include, but are not limited to, salicylic acid or a derivative thereof, e.g. acetaminosalol, aspirin, benorylate, bromosaligenin, calcium acetylsalicylate, diflunisal, etersalate, fendosal, gentisic acid, glycol salicylate, imidazole salicylate, lysine acetylsalicylate, mesalamine, morpholine salicylate, 1 -naphthyl salicylate, olsalazine, parsalmide, phenyl acetylsalicylate, phenyl salicylate, salacetamide, salicylamide O-acetic acid, salicylsulfuric acid, salsalate or sulfasalazine; an aminoary carboxylic acid or a derivative thereof, e.g. enfenamic acid, etofenamate, flufenamic acid, isonixin, meclofenamic acid, metenamic acid, niflumic acid, talniflumate, terofenamate or tolfenamic acid; an (aryl or heteroaryl)-alkylcarboxylic acid or a derivative thereof, such as acemetacin, alclofenac, amfenac, bufexamac, cinmetacin, clopirac, diclofenac, etodolac, felbinac, fenclofenac, fenclorac, fenclozic acid, fentiazac, glucametacin, ibutenac, indomethacin, isotezolac, isoxepac, lonazolac, metiazinic acid, oxametacine, pirazolac, proglumetacin, sulindac, tiaramide, tolmetin, zomepirac, bumadizon, butifen, fenbufen, xenbucin, clidanac, ketorolac, tinoridine, alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenoprofen, flunoxaproten, flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen, miroproten, naproxen, oxaprozin, piketoprofen, pirprofen, pranaprofen, protizinic acid, suprofen or tiaprofenic acid; a thiazinecarboxamide, e.g. droxicam, isoxicam, piroxicam ortenoxicam; a pyrazole derivative, e.g. difenamizole orepirizole; a pyrazolone derivative, e.g. apazone, benzpiperylon, febrazone, mofebutazone, morazone, oxyphenbutazone, phenylbutazone, pipebuzone, propyphenazone, ramifenazone, suxibuzone or thiazolinobutazone; or a non-steroidal antiinflammatory drug of another structure, e.g. epsilon-acetamidocaproic acid, S-adenosylmethionine, 3- amino-4-hydroxybutyric acid, amixetrine, bendazac, benzyclamine, bucolome, difenpiramide, ditazol, emorfazone, guaiazulene, nabumetone, nimesulide, orgotein, oxaceprol, paranyline, perisoxal, pifoxime, proquazone, proxazole, tenidap and mixtures thereof.
A number of anti-inflammatory agents listed above are also capable of acting as penetration enhancers. For instance a number of vegetable oils such as linseed oil, emu oil, eucalyptus oil, cottonseed oil, castor oil, sesame oil, arachis oil, barage oil, clove oil, camphor oil, Ocimum sanctum oil, almond oil, babassu oil, coconut oil, jojoba oil, mustard oil, olive oil, olive oil, palm oil, safflower oil, soyabean oil, sunflower seed oil, wheat oil; and other agents like, methyl salicylate, menthol, eugenol, thymol, carvacrol, alpha-pinene, beta-pinene, limonene can also act as penetration enhancer. The composition containing these agents in combination with aceclofenac advantageously produces synergistic effects.
The composition of the present invention further include one or more pharmaceutically acceptable excipients like solvents, cooling agents, surfactants, humectants, skin freshener or lather stabilizers, preservatives, antioxidants, film formers, plasticizers, colorants, flavouring agents, buffering agents or a pH-adjusting agents.
Solvents used in the composition may include volatile solvents, non volatile solvents or mixtures thereof. When a blend of volatile and non volatile solvent is used, the volatile solvent gets evaporated and the active ingredient remains on the skin, dissolved in the non-volatile solvent, in an enriched form. While volatile solvent used alone, provide drug delivery without leaving a residue or film.
Preferably the solvents used in the composition include, but are not limited to, water, ethanol, isopropyl alcohol, higher mono- and poly-functional alcohols such as propanol, butanol, pentanol, hexanol, octanol, n-octanol, nonanol, decanol, 2-butanol, 2-pentanol, and esters of polyhydroxy acids.
The composition of the invention can also include one or more cooling agents. The cooling agents used in the composition include, but are not limited to, menthol; an isomer of menthol, a menthol derivative; 4-Methyl-3-(1-pyrrolidinyl)-2[5H]-furanone; WS-23, Icilin, Icilin Unilever Analog, 5-methyl-4-(1-pyrrolidinyl)-3-[2H]-furanone; 4,5-dimethyl-3-(1-pyrrolidinyl)-2[5H]-furanone; isopulegol, 3-(l-menthoxy)propane-1 ,2-diol, 3-(l-menthoxy)-2-methylpropane-1 ,2-diol, p-menthane-2,3-diol, p-menthane-3,8-diol, 6- isopropyl-9-methyl-1 ,4-dioxas- piro[4,5]decane-2-methanol, menthyl succinate and its alkaline earth metal salts, trimethylcyclohexanol, N-ethyl-2-isopropyl-5- methylcyclohexanecarb-oxamide, Japanese mint (Mentha arvensis) oil, peppermint oil, menthone, menthone glycerol ketal, menthyl lactate, 3-(l-menthoxy)ethan-1-ol, 3-(l-menthoxy)propan-1-ol, 3-(l-menthoxy)butan-1-ol, l-menthylacetic acid N-ethylamide, I- menthyl-4-
hydroxypentanoate, l-menthyl-3-hydroxybutyrate, N,2,3-trimethyl-2-(1- methylethyl)-butanamide and spearmint oil. The menthol derivative is selected from the group consisting of: menthol ethylene glycol carbonate, which is now known as Frescolat® type MGC, menthol Propylene Glycol Carbonate (Frescolat® type MPC), menthyl lactate (Frescolat ML®) and Menthone Glycerin Acetal (Frescolat MGA®) and 3- (/-Menthoxy)-1 ,2-propanediol.
Humectants are substance that promotes retention of moisture and mostly used in topical compositions. Humectants used in the composition include, but are not limited to, polyhydric alcohols and polyvinyl pyrrolidone. Preferred polyhydric alcohols are propylene glycol, butylene glycol, polyethylene glycol, glycerol and sorbitol.
Skin fresheners or lather stabilizers may also be used in the composition include, but are not limited to, lanolin or its derivatives, lecithin, higher alcohols, dipelargonate ethers or esters, coconut oil and other fatty esters and mixtures thereof.
The composition of the invention can also include preservative. Preservatives are used in the topical composition to prevent the growth of microorganisms (e. g., bacteria, fungi, yeasts) therein. Preferably, the preservative must be effective at relatively low concentrations against a broad spectrum of microorganisms. In addition, the preservative must be non-toxic at the required concentration, compatible with other ingredients in the topical composition, stable to the expected preparation and storage conditions, and approved by global regulatory agencies. The composition of the present invention can include more than one preservative. A blend of preservatives can facilitate a broader spectrum of antimicrobial activity if the individual preservatives of the blend are effective against different microorganisms.
Suitable preservatives used in the composition include, but are not limited to, quaternary ammonium compounds, such as benzalkonium chloride, benzethonium chloride, cetrimide, dequalinium chloride, and cetylpyridinium chloride; mercurial agents, such as phenylmercuric nitrate, phenylmercuric acetate, and thimerosal; alcoholic agents, for example, chlorobutanol, phenylethyl alcohol, and benzyl alcohol; antibacterial esters, for example, esters of parahydroxybenzoic acid; and other anti-microbial agents such as chlorhexidine, chlorocresol, benzoic acid and polymyxin.
Oxidative stress damages cellular elements of the skin, which can be repaired with most known antioxidants. Appropriate antioxidants used in the composition may include, but are not limited to, synthetic antioxidants, such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate (PG), and tert-butylhydroquinone (TBHQ), and natural antioxidants, such as flavonoids, polyphenols, ascorbic acid (Vitamin C) or tocopherols (Vitamin E).
Film formers refer to compounds, preferably polymers that form stable films on a surface when applied. Film formers used in the composition may include, but are not limited to, acrylic polymers or copolymers, including methacrylic polymers and copolymers, polyvinyl acetate, cellulose acetate, polyvinyl alcohol, povidone, povidone vinyl acetate, hydroxypropyl methyl cellulose, hydroxyl ethyl cellulose, methyl cellulose & ethyl cellulose.
The composition of the present invention may also include one or more plasticizers, which include, but are not limited to, citrate esters, dimethyl isosorbide, castor oil, propylene glycol and polyethylene glycol.
It may also be desirable to include FDA approved fragrances and/or coloring agents in the present composition. Additives of such types which are appropriate for cosmetic products are well-known in the art and need not be described.
The composition of the present invention may also include a buffering system that helps in providing a stable composition. Buffers used in the composition include, but are not limited to, EDTA, a citrate buffer, or a mixture thereof. It can also be an organic acid, a carboxylic acid, a fatty acid an amino acid, an aromatic acid, an alpha or beta hydroxyl acid an organic base or a nitrogen containing compound.
The topical composition of the present invention can be used for the external treatment of pain and inflammation associated with traumatic and musculoskeletal disorders such as tendonitis, tenosynovitis, sprains and strains, dislocations, periarthritis, distention, lumbago, stiff neck, back pain, lower back pain, knee pain, ankle sprain, wrist sprain, osteoarthritis knee, spondylosis, cervical spondylosis, athlete Injury, arthritis, knee Arthritis, shoulder lesions, frozen shoulder, prolapsed intervertebral disc, thumb stiffness, knee stiffness, shoulder stiffness, rheumatoid arthritis or tennis elbow. It can also be used for the supportive treatment of muscle rheumatism, painful degenerative joint diseases (arthritis), inflammatory rheumatic diseases of the joints and vertebrae, swelling, etc.; inflammation of soft tissues associated with joints (e.g. sinovial membrane, ligament, sinovial capsule, tendon and cartilage), shoulder stiffness and lower back pain.
The present invention is illustrated below by reference to the following example. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention.
EXAMPLE:
Composition

(Table Removed)
Procedure: 1. Dissolve aceclofenac in the isopropyl alcohol with continuous stirring to form a clear
solution. 2 Add linseed oil, menthol, methyl salicylate and then benzyl alcohol to the solution formed in step 1, with continuous stirring to get a clear solution.
3. Make up the weight of solution with isopropyl alcohol and transfer the mixture into uncrimped cans to required volume; and
4. Crimp the cans with the approved spray valve and charge the filled can with liquefied petroleum gas.

WE CLAIM:
1. A topical composition in the form of spray comprising:
(i) aceclofenac or its pharmaceutically acceptable salt thereof, in a concentration from 0.1 to
10% by weight of the composition, (ii) one or more penetration enhancers, in a concentration from 0.1 to 10% by weight of the
composition, and (iii) a propellant, in a concentration from 20 to 60% by weight of the composition.
2. The composition according to claim 1, wherein the composition further comprises one or more counter irritants.
3. The composition according to claim 2, wherein the counter irritant is present in a concentration from 0.1 to 10% by weight of the composition.
4. The composition according to claim 2, wherein the counter irritant comprises one or more of salicylates, capsaicin, camphor, eucalyptus oil, phenol, menthol.and mixtures thereof.
5. The composition according to claim 1, wherein the penetration enhancer comprises one or more of sulfoxides, alcohols, fatty acids, fatty acid esters, polyols, amides, surfactants, terpenes, alkanones, organic acids and mixtures thereof.
6. The composition according to claim 1, wherein the propellant comprises one or more
of hydrocarbons, hydroflurocarbons, hydrochloroflurocarbons, dimethyl ether and mixtures
thereof.
7. The composition according to claim 1, wherein the composition further comprises one or more pharmaceutically acceptable excipients in the capacity of solvents, cooling agents, surfactants, humectants, skin freshener or lather stabilizers, preservatives, antioxidants, film formers, plasticizers, colorants, flavouring agents, buffering agents or pH-adjusting agents and mixtures thereof.
8. The composition according to claim 1, wherein the composition optionally comprises one or more other anti-inflammatory agents.
9. The composition according to claim 8, wherein the anti- inflammatory agents comprises one or more of vegetable oils, methyl salicylate, menthol, eugenol, thymol, carvacrol, boldine, alpha-
pinene, beta-pinene, caryophyllene, caryophyllene oxide, cinnamaldehyde, delta-3-carene, quercitrin, limonene, herbs, steroid and NSAID's.
10. A topical composition in the form of spray comprising aceciofenac or its pharmaceutically acceptable salt thereof, one or more penetration enhancers and a propellant, substantially as described and illustrated herein.