Classifications

• • 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
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
• • 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
  • A61K47/30—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
  • 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
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• the present invention relates to the taste masking pharmaceutical orally dissolving strips of Lornoxicam comprising Lornoxicam or pharmaceutically acceptable salts thereof as an active ingredient, taste masking agent, surfactant, and at least one pharmaceutically acceptable excipient.
• the taste masking agent is preferably a carboxylic acid ion exchange resin comprising methacrylic acid cross-linked with divinyl benzene.
• the present invention also relates to the process of the preparation of taste masking pharmaceutical orally dissolving strips of Lornoxicam.
• Lornoxicam is a non-steroidal anti-inflammatory drug (NSAID) of the oxicam-dass-and-is-ased ⁇ f arth3 ⁇ 4 ⁇ ⁇ to the pain resulting from inflammatory diseases of the joints, osteoarthritis, surgery, sciatica, and other inflammations.
• the chemical name of Lornoxicam is (3£)-6-chloro-3- [hydroxy (pyridin-2-ylamino) methylene]-2-methyl-2, 3-dihydro- H-thieno [2, 3-e] [1, 2] thiazin-4-one 1, 1-dioxide and is structurally represented with the formula
• Lornoxicam mode of action is partly based on inhibition of prostaglandin synthesis (inhibition of the cyclooxygenase enzyme). The inhibition of cyclooxygenase does not result in an increase in leucotriene formation. Lornoxicam is available in Europe as film coated tablets 4 mg and 8 mg, rapid release film-coated tablets 8 mg, and as powder and solvent for intramuscular and intravenous 4 mg/ml injection.
• Lornoxicam has very low water solubility ⁇ lmg/100ml in 0.1N Hcl.
• US Patent 6,713,089B1 is directed to a quick release pharmaceutical composition of Lornoxicam, involving the reaction of the drug and alkali in the presence of water to increase the in vitro dissolution to atleast 50% in 20 minutes in 1300 ml 0.1 N HCl at 50 rpm.
• the reaction in the presence of water is stated to be essential to achieve the claimed dissolution which is not achieved in traditional tablet formulations.
• US Patent Application No. 20070218128A1 describes the co-milling or equivalent intimate mixing of drug and alkaline substances either without or with a minimum amount of liquid to achieve fast in vitro dissolution of at least 50% within the first 20 minutes.
• Such mixtures prepared without liquids produced tablets, which had water contents similar to batches of tablets prepared by wet granulation, and yet showed improved stability despite the comparable water content.
• US20070218128A1 discloses the intimate mixing of drug and alkaline agent is essential for fast dissolution which is not 'achieved-with-traditiona tablet-processing ⁇ hese-new-formulations-which-contain- 40 % bicarbonate were shown to reduce the median T max for Lornoxicam from 2.5 hours from standard tablets, to 0.5 hours demonstrating faster absorption when the Lornoxicam was co-processed intimately with the bicarbonate.
• WO2011077452A2 discloses the fast dissolving pharmaceutical composition containing Lornoxicam or pharmaceutically acceptable salts thereof, as an active ingredient along with at least one alkalinizer, at least one organic acid and at least one pharmaceutically acceptable excipient.
• orally dissolving strips may be used to carry active ingredients such as Lornoxicam that has the bitter taste. So, therefore there exists a need to develop a pharmaceutical dosage form such as taste masking orally dissolving strips and achieve the fast dissolution, to overcome the disadvantages as disclosed above.
• the present invention relates to the taste masking pharmaceutical orally dissolving strips of Lornoxicam comprising Lornoxicam or pharmaceutically acceptable salts thereof as an active ingredient, taste masking agent, surfactant, and at least one phar-maGeutiGally-aGGeptable-exGipient -
• Another object of the invention relates to the taste masking pharmaceutical orally dissolving strips of Lornoxicam comprising Lornoxicam or pharmaceutically acceptable salts thereof as an active ingredient, taste masking agent, surfactant, a water soluble polymer and at least one pharmaceutically acceptable excipient.
• Another object of the invention relates to the taste masking pharmaceutical orally dissolving strips of Lornoxicam comprising Lornoxicam or pharmaceutically acceptable salts thereof as an active ingredient, taste masking agent, surfactant, water soluble polymer and at least one pharmaceutically acceptable excipient devoid of alkalinizer and/or organic acid.
• the present invention relates to the taste masking pharmaceutical orally dissolving strips of Lornoxicam comprising Lornoxicam or pharmaceutically acceptable salts thereof as an active ingredient, taste masking agent, surfactant, and a pharmaceutically acceptable excipient.
• the taste masking agents used in the taste masking pharmaceutical orally dissolving strips of Lornoxicam are preferably selected from Ion exchange resins.
• Ion exchange resins preferred for use in the strips of the invention are water-insoluble and consist of a pharmacologically inert organic or inorganic matrix containing covalently bound functional groups that are ionic or capable of being ionized under the appropriate conditions of pH.
• the organic matrix may be synthetic (e.g., polymers or copolymers of acrylic acid, methacrylic acid, sulfonated styrene, sulfonated diviriylbenzene), or partially synthetic (e.g., modified cellulose and dextrans).
• the inorganic matrix can also be, e.g., silica gel modified by the addition of ionic groups.
• the covalently bound ionic groups may be strongly acidic (e.g., sulfonic acid), weakly acidic (e.g., carboxylic acid), strongly basic (e.g., quaternary ammonium), weakly basic (e.g., primary amine), or a combination of acidic and basic groups.
• ion exchangers suitable for use in ion exchange chromatography and for such applications as deionization of water are suitable for use in these controlled release drug preparations. Such ion exchangers are described by H. F. Walton in "Principles of Ion Exchange" (pp. 312 343).
• the resin is crosslinked with a crosslinking agent selected from difunctional compounds capable of crosslinking polystyrenes; these are commonly known in the art.
• the crosslinking agent is a divinyl or polyvinyl compound.
• the crosslinking agent is divinylbenzene.
• the resin is crosslinked to an extent of about 3 to about 20%, preferably about 4 to about 16%, more preferably about 6 to about 10%, and most preferably about 8% by weight based on the total resin.
• the resin is crosslinked with the crosslinking agent by means well known in the art.
• the size of the ion exchange resins should preferably fall within the range of about 20 to about 200 micrometers. Particle sizes substantially below the lower limit are difficult to handle in all steps of the processing. Particle sizes substantially above the upper limit, e.g., commercially available ion exchange resins having a spherical shape and diameters up to about 1000 micrometers, are gritty in liquid dosage forms and have a greater tendency to fracture when subjected to drying-hydrating cycles.
• the most preferred ion exchange resins include acidic low cross-linked carboxylic acid resins prepared from methacrylic acid and divinyl benzene such as Kyron T-114.
• the taste masking agent need not be an ion exchange resin.
• the taste masking agent can be, e.g., magnesium-trisilicaterSeereTgTrUTS ⁇
• Kyron T-114 (taste masking agent) desirably ranges from about 2% to 50% w/w of the total dosage form, preferably from about 10 to 40% w/w of the total dosage form and more preferably from about 20 to 30% w/w of the total weight of the dosage form.
• the examples of the surfactants used in the taste masked orally dissolving strips of Lornoxicam include, but not limited to, sodium docusate, polyoxyethylene ether, poloxamer, cremophore, polysorbates (Tween), polyoxyethylene stearates, sodium lauryl sulfate, sorbitan esters and combinations thereof.
• the most preferred surfactant used is sodium lauryl sulphate.
• surfactant desirably ranges from from about 1 to 10 % w/w of the total dosage form and preferably from about 2 to 8 % w/w of the total weight of the dosage form.
• the present invention further relates to the taste masking orally dissolving strips of Lornoxicam comprising Lornoxicam or pharmaceutically acceptable salts thereof as an active ingredient, taste masking agent, surfactant, a water soluble polymer and at least one pharmaceutically acceptable excipient.
• the present invention further relates to the taste masking pharmaceutical orally dissolving strips of Lornoxicam .
• Lornoxicam or pharmaceutically acceptable salts thereof as an active ingredient, taste masking agent, surfactant, water soluble polymer and at least one pharmaceutically acceptable excipient devoid of alkalinizer and/or organic acid.
• water soluble polymer refers to a polymer that is at least partially soluble in water and fully or predominantly soluble in water or swellable in water.
• the "water soluble polymer” may be partially water soluble polymer or predominantly water soluble polymer, water swellable polymer or a combination of water soluble and water swellable polymer.
• the polymers may include cellulose or cellulose derivatives. Suitable examples of water soluble polymer includes but are not limited to, polyethylene oxide, pullulan, hydroxypropylmethyl cellulose (HPMC), Hydroxypropyl cellulose (HPC), carboxymethyl cellulose, polyvinyl alcohol, Water- swellable polysaccharides such as starch, starch derivatives such as polymers of dextrose like maltodextrin, carrageenan, xanthan gum, locus bean gum, acacia gum, chitosan, alginates, hyaluronic acid, pectin and combinations thereof.
• water soluble polymer desirably ranges from about 0% to 40%w/w of the total dosage form, preferably from about 10 to 35 w/w of the total dosage form and more preferably from about 15% to 30% w/w of the total weight of the dosage form.
• cellulosic polymer preferably used is Hydroxypropylmethyl cellulose (HPMC).
• a particular embodiment of the invention incorporates a plasticizer to impart flexibility, enhance elasticity and decrease brittleness.
• Preferred plasticizers include triacetine, citrate derivatives (such as triethyl, tributyl, acetyl tributyl, acetyl triethyl, trioctyl, acetyl trioctyl, trihexyl citrate, etc.), and dibutyl sebacate, glycerol, polyethylene glycol or combinations thereof.
• plasticizer desirably ranges from about 0% to 20% w/w of the total dosage form, preferably from about 5 to 15 % w/w of the total dosage form and more preferably from about 7.5 to 12.5% w/w of the total dosage form.
• the present invention further includes pharmaceutical additives such as fillers and/or disintegrants.
• the amount of filler ranges from about 1 to 20% w/w of the total dosage form.
• the filler includes at least one selected from group consisting of mannitol, microcrystalline cellulose, lactose.
• the amount of the disintegrant ranges from about 1 to 10% w/w of the total dosage form. Examples of disintegrants include crospovidone, crosscarmellose sodium, sodium starch glycolate and pre-gelatinized starch.
• Flavours may be chosen from natural and synthetic flavouring liquids.
• An illustrative list of such agents includes volatile oils, synthetic flavour oils, flavouring aromatics, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof.
• a non-limiting representative list of examples includes mint oils, cocoa, and citrus oils such as lemon, orange, grape, lime and grapefruit and fruit essences including apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot or other fruit flavours.
• aldehydes and esters such as benzaldehyde (cherry, almond), citral i.e., alphacitral (lemon, lime), neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehyde C-12 (citrus fruits), tolyl aldehyde (cherry, almond), 2,6-dimethyloctanol (green fruit), and 2-dodecenal (citrus, mandarin), combinations thereof and the like.
• aldehydes and esters such as benzaldehyde (cherry, almond), citral i.e., alphacitral (lemon, lime), neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus fruits), aldeh
• the sweeteners may be chosen from the following non-limiting list: glucose (corn syrup), dextrose, invert sugar, fructose, and combinations thereof; saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiapa (Stevioside); chloro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, xylitol, and the like.
• hydrogenated starch hydrolysates and the synthetic sweetener 3,6-dihydro-6-methyl-l-l-l,2,3-oxathiazin-4-one-2,2-dioxide particularly the potassium salt (acesulfame-K), and sodium and calcium salts thereof.
• a colouring agent which may be provided in a dosage form of the present invention, includes pharmaceutically acceptable natural or artificially synthesized dyes.
• pharmaceutically acceptable dyes include pharmaceutically acceptable natural or artificially synthesized dyes.
• a great variety of such pharmaceutically acceptable dyes have been known to be suitable for use in pharmaceutical compositions, for example natural dyes such as annatto extract, anthocyanins, beta-carotene, beta APO 8, carotenal, black currant, burnt sugar, canthaxanthin, caramel, carbo medicinalis, carmine, carmine blue, carminic acid, carrot, chlorophyll, chlorophyllin, cochineal extract, copper-chlorophyll, copper- chlorophyllin, curcumin, curcumin/CU-chloro, elderberry, grape, hibiscus, lutein, mixed carotenoids, paprika, riboflavin, spinach, stinging nettle, titanium dioxide, turmeric, natural colors, aronia/red fruit, bee
• a method for preparation of the taste masking pharmaceutical orally dissolving strips of Lornoxicam according to the present invention comprising the below mentioned steps.
• the second solution is deareated under vacuum and homogenized.
• the homogenized solution is introduced into a layering machine to form a strip.
• the temperature of the layering machine ranges from 60°C to 90°C and produces the strip.
• the dried strip is cut into desired sizes followed by putting them into aluminium foils.
• a taste masking pharmaceutical orally dissolving strips of Lornoxicam comprising Lornoxicam or pharmaceutically acceptable salts thereof, taste masking agent, surfactant, and at least one pharmaceutically acceptable excipient.
• Lornoxicam or pharmaceutically acceptable salts thereof is present in the range of 6-12 % w/w of the total weight of the dosage form
• the taste masking agent is present in the range of 20 to 30 % w/w of the total weight of the dosage form
• the surfactant is present in the range of 2 to 8% w/w of the total weight of the dosage form.
• the said taste masking agent is carboxylic acid ion exchange resin comprising methacrylic acid cross-linked with divinyl benzene.
• the said surfactant is selected from the group of but not limiting to sodium docusate, polyoxyethylene ether, poloxamer, cremophore, polysorbates, polyoxyethylene stearates, sodium lauryl sulfate, sorbitan esters and combinations thereof.
• the said surfactant is preferably sodium lauryl sulphate.
• the said the strip is devoid of alkalinizer and/or organic acid.
• a taste masking pharmaceutical orally dissolving strips of Lprnoxicam comprising Lornoxicam or pharmaceutically acceptable salts thereof, taste masking agent, surfactant, water soluble polymer and at least one pharmaceutically acceptable excipient.
• the water soluble polymer is present in the range of 15 to 30% w/w of the total weight of the dosage form.
• the water soluble polymer is at least partially soluble in water and fully or predominantly soluble in water or swellable in water.
• the water soluble polymer component is selected from Hydroxypropylmethylcellulose, maltodextrin and polyethylene oxide or combinations thereof.
• the water soluble polymer is 10 to 15% w/w solution with purified water.
• Example-1 Taste masking orally dissolving strip 8mg
• compositions per dosage unit Composition per dosage unit
• the process for the preparation of the taste masking orally dissolving strip of Lornoxicam involves the following steps:
• First solution preparation 35 g of hydroxypropylmethyl cellulose (HPMC) is dissolved in 234g of boiling water (13% w/w HPMC solution) to prepare the first solution.
• HPMC hydroxypropylmethyl cellulose
• Second solution preparation 8g of Lornoxicam is added to 140g of purified water and stirred for 5 to 25 minutes to prepare the active ingredient containing solution.
• Kyron T-114 35g is added and stirred for 15 - 45 minutes to prepare the Kyron T- 114 solution.
• the first solution (13% HPMC solution) is added to the Kyron T- 114 solution under stirring.
• lactose (7g) sodium lauryl sulphate (5.6g), vanilla flavour (14g), sucralose (8.4g), crosscarmellose sodium (5.9g), propylene glycol (14g), Banana flavour (6.9g) and Tartrazine (0.2g) are added to the above solution and stirred for 40 - 80 minutes to prepare the second solution.
• the homogenized solution is introduced into a layering machine to form a strip.
• the temperature of the layering machine ranges from 60°C to 90°C to produce the strip.
• the above dried film is cut into desired sizes to form the strips followed by putting them into aluminium foils.

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• 2013
  • 2013-03-14 WO PCT/IN2013/000159 patent/WO2013136346A2/fr not_active Ceased

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