WO2012127496A1 - Compositions pharmaceutiques stables de lornoxicam ou des sels de celui-ci - Google Patents

Compositions pharmaceutiques stables de lornoxicam ou des sels de celui-ci Download PDF

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Publication number
WO2012127496A1
WO2012127496A1 PCT/IN2012/000143 IN2012000143W WO2012127496A1 WO 2012127496 A1 WO2012127496 A1 WO 2012127496A1 IN 2012000143 W IN2012000143 W IN 2012000143W WO 2012127496 A1 WO2012127496 A1 WO 2012127496A1
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composition
lornoxicam
pharmaceutical composition
salts
salt
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PCT/IN2012/000143
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English (en)
Inventor
Sunilendu Bhushan Roy
Shafiq Sheikh
Jay Shantilal Kothari
Jitendra Dasharathlal Patel
Jinesh Suresh Pancholi
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Cadila Healthcare Limited
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Publication of WO2012127496A1 publication Critical patent/WO2012127496A1/fr

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    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • the present invention relates to stable pharmaceutical compositions of lornoxicam or salts thereof comprising nano size droplets of lornoxicam or salts thereof along with other pharmaceutically acceptable excipients. These compositions exhibit excellent permeability, and enhanced therapeutic efficacy.
  • the invention also relates to process for the preparation of such compositions.
  • Lornoxicam (also known as chlortenoxicam) [6-chloro-4-hydroxy-2-methyl-n- 2-pyridyl-5H-thieno(2,3-e)-[ l ,2]-thiazine-2-carboxamide-l , l -dioxide] is a nonsteroidal anti-inflammatory drug (NSA1D) that decreases prostaglandin synthesis by inhibiting cyclooxygenase and can be ⁇ used to treat acute and chronic pain conditions accompanied by inflammatory processes, e.g., post-operative pain, arthritis, rheumatism, injuries to soft parts, etc.
  • NSA1D nonsteroidal anti-inflammatory drug
  • Lornoxicam is available in form of quick release tablets as well as in formulations suitable for intramuscular and intravenous adm inistration.
  • the drug is absorbed rapidly and almost completely from the gastro-intestinal tract and approximately 2/3 rd of drug is eliminated via the liver and l /3 rd of drug via the kidneys as inactive substance. Since no unchanged form is detectable ⁇ in excreted material, lornoxicam appears to be eliminated predominantly by hepatic biotransformation.
  • the enzyme responsible for the main metabolic pathway, 5'-hydroxyIation of lornoxicam, is cytochrome P450 2C9 (CYP2C9) (Eur J Clin Pharmacol 49: 305-308).
  • lornoxicam Although a major portion of commercial lornoxicam is available in the form of oral medications, the drug causes subacute and chronic oral adverse effects in the gastrointestinal tract, which includes mortality, diarrhoea, prostration, decreased body weight gain and food consumption, faecal occult blood, anaemia, leucocytosis, hypoalbum inaemia, gastrointestinal erosions and ulcerations. Nausea and diarrhea are quite common side effects of oral lornoxicam.
  • lornoxicam parenteral route of administration for lornoxicam have also been suggested, however being invasive and thus painful to administer, such formulations are usually less preferred by large patient population. Since lornoxicam and its salts may scarcely absorbed percutaneously and thereby require higher quantity to be applied topically thus leading to increased frequency of application also. This leads to patient incompliance. Moreover, percutaneous drug delivery is complicated by the fact that the skin behaves as a natural barrier and therefore transport of agents through the skin is, eventually, a complex mechanism.
  • U. S. Patent No. 5,629,021 relates to micellar nanoparticles and methods of their production.
  • U. S. Patent No. 5,894,019 discloses topical compositions comprising lipid and essentially free of emulsifiers and surfactants.
  • EP 506197 B l discloses an aqueous suspension of solid lipid nanoparticles for topical use.
  • topically applied non-steroidal antiinflammatory drugs are safer than and at least as efficacious as oral NSAIDs in the treatment of rheumatic diseases.
  • Adverse drug reactions after topical administration of NSAID use are rare when compared to the incidence of serious GI events associated with oral NSAI Ds.
  • formulation may have a dramatic impact on depth of penetration at the site of application, retention of drug molecules within the layers of skin, concentrations achieved in the muscle tissue, synovial fluid and in systemic circulation.
  • compositions of the invention overcome all the commonly encountered problems as exemplified above.
  • a pharmaceutical composition comprising nano size droplets of lornoxicam or salts thereof.
  • D90 particle size of droplets of lornoxicam or salts thereof in the compositions of the invention is about 500nm, preferably about 200nm, and more preferably about l OOnm or less.
  • composition comprising nano sized droplets of lornoxicam or salts thereof and methyl salicylate or salts thereof.
  • composition comprising nano size droplets of lornoxicam or salts thereof, wherein the " amount of lornoxicam or salt thereof in the composition ranges from about 0. 01 % to about 2.0% w/w of the composition:
  • a stable topical pharmaceutical composition comprising nano size droplets of lornoxicam or salts thereof, wherein said composition comprises oil in amount ranging from about 5 to about 25% w/w of the composition.
  • a stable topical pharmaceutical composition comprising nano size droplets of lornoxicam or salts thereof, wherein said composition comprises one or more emulsifier/s in amount ranging from about 0.1 to about 10% w/w of the composition.
  • a stable topical pharmaceutical composition comprising nano size droplets of lornoxicam or salts thereof, wherein said composition comprises one or more emulsifier/s and oil in the weight ratio ranging from about 0.1 :20 to about 0. t : 1 .
  • composition comprising nano size droplets of lornoxicam or salts thereof in the form suitable for topical administration.
  • a stable pharmaceutical composition comprising nano size droplets of lornoxicam or salts thereof, wherein the composition exhibits a significant difference in one or both of the rate and extent of absorption of lornoxicam or salts thereof as compared to topical formulation containing diclofenac or salts thereof.
  • composition comprising nano size droplets of lornoxicam or salts thereof and one or more pharmaceutically acceptable excipients comprising oils, lipids, stabilizers, thickening agents and initiators.
  • a stable pharmaceutical composition comprising nano size droplets of lornoxicam or salts thereof, wherein the composition retains at least 80% potency of lornoxicam or salts thereof after 3 months when stored at 40°C and 75% relative humidity.
  • Embodiments of the pharmaceutical composition may include one or more of the following features.
  • the pharmaceutical composition may further include one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients may include one or more of oils, lipids, stabilizers, emulsifiers, pH adjusting agents, emol lients, humectants, preservatives, stabilizers, antioxidants, chelating agents, initiators, thickening agents, and the like.
  • composition of the invention exhibits significantly low skin irritation.
  • a stable pharmaceutical composition comprising nano size droplets of lornoxicam or salts thereof, wherein the composition exhibits significantly greater percent inhibition of rat paw volume and/or edema as compared to topical formulation containing diclofenac or salts thereof.
  • Embodiments of the pharmaceutical composition may include one or more of the following features.
  • the pharmaceutical composition may further include one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients may include one or more of oils, lipids, stabilizers, emulsifiers, pH adjusting agents, emollients, humectants, preservatives, stabilizers, antioxidants, chelating agents, initiators, thickening agents, and the like.
  • a method of improving patient compliance to lornixicam therapy by administering the stable pharmaceutical composition comprising nano size droplets of lornoxicam or salts thereof.
  • composition of the invention is safe and effective for dermal application at the dose levels of 0.1 , 0.5 and 1.0% w/w.
  • Embodiments of the pharmaceutical composition may include one or more of the following features.
  • the pharmaceutical composition may further include one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients may include one or more of oils, lipids, stabilizers, emulsifiers, pH adjusting agents, emollients, humectants, preservatives, stabilizers, antioxidants, chelating agents, initiators, thickening agents, and the like.
  • a stable pharmaceutical composition comprising nano size droplets of lornoxicam or salts thereof, wherein the composition exhibits a percent inhibition of rat paw edema of at least 10% in 1 hour.
  • a stable pharmaceutical composition comprising nano size droplets of lornoxicam or salts thereof, wherein the composition exhibits a percent inhibition of rat paw edema of at least 5% in 5 hours.
  • Embodiments of the pharmaceutical composition may include one or more of the following features.
  • the pharmaceutical composition may further include one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients may include one or more of oils, lipids, stabilizers, emulsifiers, pH adjusting agents, emollients, humectants, preservatives, stabilizers, antioxidants, chelating agents, initiators, thickening agents, and the like.
  • a stable pharmaceutical composition of lornoxicam or salts thereof prepared by a process comprising:
  • step b) reducing the particle size of emulsion of step a) to a droplet size having D90 particle size of about 500nm or less;
  • step b) mixing other pharmaceutically acceptable excipients to the emulsion obtained in step b) and converting it into a suitable finished dosage form.
  • Embodiments of the pharmaceutical composition may include one or more of the following features.
  • the pharmaceutical composition may further include one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients may include one or more of oils, lipids, stabilizers, emulsifiers, pH adjusting agents, emollients, humectants, preservatives, stabilizers, antioxidants, chelating agents, initiators, thickening agents, and the like.
  • a method of treating prostaglandin associated acute and chronic pain conditions comprising topically applying the pharmaceutical composition comprising nano size droplets of lornoxicam or salts thereof.
  • lornoxicam or salts thereof when lornoxicam or salts thereof is formulated into nano size droplets in pharmaceutically acceptable emulgel (emulsion gel) system which includes optimized ratios of oils and/or emulsifiers, it leads to highly stable compositions of lornoxicam or salts thereof. Further, such compositions have enhanced permeability characteristics, improved biovailability and greater therapeutic anti-inflammatory effect as compared to topical formulations of diclofenac. Moreover, said such compositions may enhance the curative effect of the medicament, reduce the toxicity and side effects, and avoid the shortcomings of oral and parenteral administration.
  • emulgel emulsion gel
  • composition of the invention results in immediate and sustained action and covers large surface area with less quantity and good spreadability, non-irritant to skin and mucous membranes, reduced frequency of application leading to improved patient compliance and offers cosmetic benefits like non-stickiness, and non- greasy feel.
  • lornoxicam used throughout the specification refers to not only lornoxicam per se, but also its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable
  • t enantiomers pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof. It is also possible to use ' any salts and free base form of lornoxicam, including polymorphs, hydrates, solvates or amorphous forms.
  • the pharmaceutical composition comprises nano size droplets of lornoxicam or salts thereof.
  • the nano size droplets of lornoxicam or salts thereof possess a D90 particle size of about 500nm or less.
  • the nano size droplets of lornoxicam or salts thereof possess a D 90 particle size of about 400nm or less.
  • the nano size droplets of lornoxicam or salts thereof possess a D90 partic le size of about 300nm or less. In a preferred embodiment, the nano size droplets of lornoxicam or salts thereof possess a D90 particle size of about 200nm or less.
  • the nano size droplets of lornoxicam or salts thereof possess a D90 particle size of about l OOnm or less.
  • the pharmaceutical composition is in the form suitable for topical administration.
  • the amount of lornoxicam in the composition may range from about 0.01 % to about 2% by weight of the composition. Preferably, the amount of lornoxicam ranges from about 0.05% to about 1 % by weight of the composition.
  • the amount of lornoxicam or salts thereof in the pharmaceutical composition is about 0.1 % by weight of the composition.
  • the pharmaceutical composition remains stable over the storage period.
  • the composition retains at least 80% potency of lornoxicam or salts thereof after 3 months when stored at 40°C /75% RH.
  • composition of the present invention may comprise combination of lornoxicam and one or more additional active agents selected from NSAIDs and methyl salicylate.
  • the composition also retains at least 80% potency of additional active agents or salts thereof when stored for at least three months at 40°C and 75% relative humidity.
  • Suitable NSAIDs which can be used include one or more of aspirin, benoxaprofen, benzofenac, bucloxic acid, butibufen, carprofen, cicloprofen, cinmetacin, clidanac, clopirac, diclofenac, fenbufen, fenclofenac, fenclorac, fenoprofen, fentiazac, flunoxaprofen, furaprofen, flurbiprofen, furobufen, furofenac, ibuprofen, ibufenac, indomethacin, indoprofen, isoxepac, ketoprofen, lactorolac, lonazolac, metiazinic, miroprofen, naproxen, oxaprozin, oxepinac, phenacitin, pirprofen, pirazolac, protizinic acid, sulinda
  • the amount of methyl salicylate or salt thereof in the composition may range from about 10.0% to about 20.0% w/w (based on 1 00% total weight of the composition).
  • composition of the invention exhibits significantly low and preferably no skin irritation.
  • composition of the present invention comprises one or more pharmaceutically acceptable excipients selected from, but not limited to lipids, oils, emulsifiers, stabilizers, initiators, pH adjusting agents, emollients, humectants, preservatives, antioxidants and chelating agents.
  • Suitable lipids which can be used include one or more of hydrocarbons, fatty alcohols, fatty acids, glycerides or esters of fatty acids with C
  • Hydrocarbons may include paraffin or petroleum jelly.
  • Fatty alcohols may include decanoi, dodecanol, tetradecanol, hexadecanol or octadecanol.
  • Fatty acids may include C6-C24 alkanoic acids such as hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid, unsaturated fatty acids such as oleic acid and linoleic acid.
  • Glycerides may include olive oil, castor oil, sesamfe oil, caprylic/capric acid triglyceride or glycerol mono-, di- and tri-esters with palmitic and/or stearic acid.
  • Esters of fatty acids may include C 1 -C36 alkanols such as beeswax, carnauba wax, cetyl palmitate, lanolin, isopropyl myristate, isopropyl stearate, oleic acid decyl ester, ethyl oleate and C6-C12 alkanoic acid esters and the like.
  • C 1 -C36 alkanols such as beeswax, carnauba wax, cetyl palmitate, lanolin, isopropyl myristate, isopropyl stearate, oleic acid decyl ester, ethyl oleate and C6-C12 alkanoic acid esters and the like.
  • Suitable oils may include one or more of almond oil, apricot seed oil, borage oil, canola oil, coconut oil. corn oil, cotton seed oil, fish oil, jojoba bean oil, lard oil, linseed oil, boiled macadamia nut oil, mineral oil, olive oil, peanut oil, safflower oil, sesame oil, soybean oil, squalane, sunflower seed oil, tricaprylin (1 ,2,3 trioctanoyl
  • the preferred quantity of oil used is in the range of about 5 to about 25% w/w, and more preferably in the range of about 5% to about 20% w/w of the composition..
  • Suitable stabilizers may include one or more of ionic polysorbate surfactant, Tween ® 20, Tween ® 40, Tween ® 60, Tween ® 80, Nonylphenol Polyethylene Glycol Ethers, (alkylphenol-hydroxypolyoxyethylene), Poly(oxy- l ,2-ethanediyl), alpha-(4L nonylphenol)-omega-hydroxy-, branched (i.e. Tergitol ® NP-40 Surfactant), Nonylphenol Polyethylene Glycol Ether mixtures (i.e.
  • Tergitol NP-70 (70% AQ) Surfactant Tergitol NP-70 (70% AQ) Surfactant
  • phenoxypolyethoxyethanols and polymers thereof such as Triton ® , Poloxamer ® , Spans ® , Tyloxapol®, different grades of Brij, sodium dodecyl sulfate and the like.
  • the preferred quantity of the stabilizer used is in the range of about 0.1 % to about 10% w/w of the composition.
  • the ratio of stabilizer to oil in the pharmaceutical composition of the present invention ranges from about 0.1 :20 to about 0.1 : 1 , preferably about ⁇ . 1 : 10 to about 0.1 : 1.
  • Suitable initiators may include one or more of alcohols like C
  • the amount of initiator may range from about 3.0% to about 7.0% w/w of the total weight of the composition.
  • Suitable pH adjusting agents which can be used include one or more of organic or inorganic acids and bases including sodium hydroxide, potassium hydroxide, ammonium hydroxide, phosphate buffers, citric acid, acetic acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid and the like.
  • the pH of the composition of the invention may range from about 3.5 to about 7.0.
  • Suitable emollients which can be used include one or more of caprylic/capric triglyerides, castor oil, ceteareth-20, ceteareth-30, cetearyl alcohol, ceteth 20, cetostearyl alcohol, cetyl alcohol, cetyl stearyl alcohol, cocoa butter, diisopropyl adipate, glycerin glyceryl monooleate, glyceryl monostearate, glyceryl stearate, isopropyl myristate, isopropyl palmitate, lanolin, lanolin alcohol, hydrogenated lanolin, liquid paraffins, linoleic acid, mineral oil, oleic acid, white petrolatum, polyethylene glycol, polyoxyethylene glycol fatty alcohol ethers, polyoxypropylene 1 -stearyl ether, propylene glycol stearate, squalane, steareth-2 or - 100, stearic acid, stearyl alcohol
  • Suitable preservatives which can be used include one or more of phenoxyethanol.
  • parabens such as methylparaben and propylparaben
  • propylene glycols propylene glycols
  • sorbates urea derivatives (such as diazolindinyl urea), and the like.
  • Suitable antioxidants which can be used include one or more of ascorbic acid, alpha-tocopherol (vitamin-E), butylated hydroxyanisole, butylated hydroxytoluene,, glutathione, sodium metabisulphite and the like.
  • Suitable humectants which can be used include one or more of propylene glycol, glycerin, butylene glycol, sorbitol, triacetin and the like.
  • Suitable chelating agents which can be used include one or more of disodium EDTA, edetate trisodium, edetate tetrasodium, diethyleneamine pentaacetate and the like.
  • composition of the invention may be prepared by a) combining an oily phase comprising lornoxicam or salts thereof along with other pharmaceutically acceptable excipierits with an aqueous phase to form an emulsion; b) reducing the particle size of emulsion of step a) to a droplet size having D90 particle size of 500nm or less; and c) mixing other pharmaceutically acceptable excipients to emulsion obtained in step b) and converting it into a suitable finished dosage form.
  • the nano size droplets may be produced with reciprocating syringe instrumentation, continuous flow instrumentation, high speed mixing or high pressure homogenization.
  • any known method of reducing the size of droplet may be adopted to serve the purpose of the present invention.
  • Small droplets of the nano emulsion may be formed by passing the emulsion through a homogenizer under different pressures ranging from 3,500-21 ,500 psi.
  • the emulsion may be passed between 4-5 times under the same conditions to get a final D 0 droplet size of about 500 nm.
  • the nano droplets formed may be filtered through 0.2 to 0.4 micron filter. 1
  • the gel base may be used in the present invention to form a gel matrix for the preparation of nanogel from nanoemulsion.
  • the gel base comprises of one or more of thickening agents.
  • Suitable thickening agents may include one or more of cellulose polymer, a carbomer polymer, a carbomer derivative, a cellulose derivative, polyvinyl alcohol, poloxamers, polysaccharides and the like.
  • Preferred thickening agent is carbomer polymer or derivatives thereof.
  • the amount of the thickening agent that used is in composition may range from about 0.01 % to about 10% w/w of the composition.
  • composition of the present invention is provided in the form suitable for topical administration, such as in the form of cream, gel, ointment, lotion, and emulsion.
  • composition is developed in the form of gel.
  • the invention provides a method of improving patient compliance to lornoxicam therapy by administering a stable pharmaceutical composition of lornoxicam or salts thereof comprising nano size droplets of lornoxicam or salts thereof.
  • the invention also provided a method of treating prostaglandin associated acute and chronic pain conditions comprising topically applying the pharmaceutical composition comprising nano size droplets of lornoxicam or salts thereof.
  • Example 2 Stability study on lornoxicam nanogel composition of Example 1
  • Table 2 provides stability data of lornoxicam nanogel composition of Example 1 when stored at 40°C and 75% relative humidity for three months and indicates that the composition remains stable and retains at least 80% potency of lornoxicam over the storage period.
  • Anti-inflammatory activity of lornoxicam nano gel was evaluated in two studies conducted using male Wistar rats. In each of the studies, animals were divided into 4 groups, each group comprised of six animals. In each of the study lornoxicam was tested in two different concentrations :(0.05 and 0.1 %), first study and (0.5 and 1 %) in the second study. In both the studies, one group received diclofenac ( 1 % gel) as reference standard at the left hind paw before the subplanter carrageenan injection. Control group animals received placebo cream only. Paw edema was measured at 0, 3 and 5 hour of carrageenan injection.
  • N 6 The percent inhibition of edema produced by each formulation-treated group was calculated against the respective control group. The results of anti-inflammatory activity were compared using the Dunnett test of 1 -way ANOVA.
  • composition of the invention demonstrated greater percentage inhibition of paw edema compared to diclofenac formulation. .
  • Dermal dose toxicity study was carried out to characterize the full range of potential action of the composition of the present invention that is, to determine the dose at which effects occur and a dose which is without such effects.
  • composition of the present invention was appl ied by dermal route to rats at three different concentrations for a minimum period of 28 days. Recovery groups were - maintained to determine the persistence or reversibility or delayed toxic effects at high concentration along with a vehicle control group for 14 days treatment free period. To check the effects of placebo, additional untreated control group was maintained.

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Abstract

La présente invention concerne des compositions pharmaceutiques de lornoxicam pour le traitement d'états inflammatoires, qui présentent une plus grande perméabilité et une efficacité thérapeutique améliorée. Elle concerne également un procédé de préparation de telles compositions.
PCT/IN2012/000143 2011-03-01 2012-03-01 Compositions pharmaceutiques stables de lornoxicam ou des sels de celui-ci WO2012127496A1 (fr)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993018752A1 (fr) * 1992-03-26 1993-09-30 Pharmos Corp. Systeme d'apport topique et transdermique utilisant des spheres d'huile aux dimensions de l'ordre du sous-micron
US5629021A (en) 1995-01-31 1997-05-13 Novavax, Inc. Micellar nanoparticles
WO1998009654A1 (fr) 1996-09-03 1998-03-12 Nycomed Austria Gmbh Composition pharmaceutique contenant du lornoxicam et un sel disodique de l'acide ethylenediamine tetracetique
EP0506197B1 (fr) 1991-03-25 1998-06-17 Yamanouchi Europe B.V. Préparation topique contenant une suspension de particules lipidiques solides
US5894019A (en) 1995-03-17 1999-04-13 Gebro Broschek Gesellschaft M.B.H. Topically applied pharmaceutical composition, method of preparing it and its use
US20060241175A1 (en) * 2002-09-27 2006-10-26 Joseph Schwarz Vehicle for topical delivery of anti-inflammatory compounds
US20070036831A1 (en) * 2005-08-09 2007-02-15 Nanobio Corporation Nanoemulsion compositions having anti-inflammatory activity
WO2010116382A2 (fr) * 2009-04-08 2010-10-14 Cadila Healthcare Limited Compositions pharmaceutiques stables de diclofénac

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0506197B1 (fr) 1991-03-25 1998-06-17 Yamanouchi Europe B.V. Préparation topique contenant une suspension de particules lipidiques solides
WO1993018752A1 (fr) * 1992-03-26 1993-09-30 Pharmos Corp. Systeme d'apport topique et transdermique utilisant des spheres d'huile aux dimensions de l'ordre du sous-micron
US5629021A (en) 1995-01-31 1997-05-13 Novavax, Inc. Micellar nanoparticles
US5894019A (en) 1995-03-17 1999-04-13 Gebro Broschek Gesellschaft M.B.H. Topically applied pharmaceutical composition, method of preparing it and its use
WO1998009654A1 (fr) 1996-09-03 1998-03-12 Nycomed Austria Gmbh Composition pharmaceutique contenant du lornoxicam et un sel disodique de l'acide ethylenediamine tetracetique
US20060241175A1 (en) * 2002-09-27 2006-10-26 Joseph Schwarz Vehicle for topical delivery of anti-inflammatory compounds
US20070036831A1 (en) * 2005-08-09 2007-02-15 Nanobio Corporation Nanoemulsion compositions having anti-inflammatory activity
WO2008051186A2 (fr) 2005-08-09 2008-05-02 Nanobio Corporation Compositions de nano-émulsion ayant une activité anti-inflammatoire
WO2010116382A2 (fr) * 2009-04-08 2010-10-14 Cadila Healthcare Limited Compositions pharmaceutiques stables de diclofénac

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
EUR J CLIN PHARMACOL, vol. 49, pages 305 - 308

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