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
  • A61K9/0014—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
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
  • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• • 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
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/08—Antiseborrheics
• • 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]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • 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
  • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• • 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
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones

Definitions

• Topical Formulations Comprising Skin Penetration Agents and the Use Thereof
• the present invention relates to topical pharmaceutical compositions comprising a pharmaceutically active agent, laurocapram, and one or more diols, particularly propylene glycol
• the invention further relates to the use of the topical pharmaceutical compositions
• U S Patent No 4,552,872 discloses topical pharmaceutical compositions comprising a pharmaceutically active corticosteroid together with a penetration enhancing vehicle containing a C 3 -C 4 diol, and a cell-envelope disordering compound such as oleic acid
• the vehicle is substantially free of saturated, straight chain C 16 -C 20 alcohols and C 4 -C 20 mono- or dicarboxylic acids.
• U S Patent No 4,557,934 discloses topical pharmaceutical compositions containing a pharmaceutically active agent, the penetrating enhancing agent 1- dodecylazacycloheptan-2-one (laurocapram), in combination with certain C 3 -C 4 diols
• a pharmaceutically active agent 1- dodecylazacycloheptan-2-one (laurocapram)
• laurocapram dodecylazacycloheptan-2-one
• a preferred diol is propylene glycol
• Preferred pharmaceutically active agents include corticosteroids such as triamcinolone acetonide, vitamins, antifungal agents, blood calcium regulators, etc
• U S Patent Nos 4,552,872, and 4,557,934 also teach that certain straight chain, saturated C 16 -C 20 normal fatty alcohols may interfere with penetration of the pharmaceutically active agents in the diol formulations, particularly, the propylene glycol formulations, and should be avoided if such interference is too great.
• the patents teach that cetyl (C 16 ) and stearyl (C 18 ) n-alcohols are capable of significant interference with the penetration enhancement of the formulation.
• the compositions are substantially free of such compounds and preferably contain less than 0.5% of cetyl or stearyl alcohol.
• Example 9 of the '934 patent shows that the skin penetration of the pharmaceutically active agent triamcinolone acetonide from a propylene glycol vehicle is reduced 39% upon the addition of cetyl alcohol at a concentration of 3% by weight.
• topical formulations comprising significant amounts of a pharmaceutically active agent such as a corticosteroid, cetyl alcohol, stearyl alcohol, laurocapram and a diol, preferably propylene glycol, are very effective in treating dermatological conditions.
• a pharmaceutically active agent such as a corticosteroid, cetyl alcohol, stearyl alcohol, laurocapram and a diol, preferably propylene glycol
• the invention relates to a pharmaceutical composition for topical administration, comprising:
• a diol selected from the group consisting of 1,2-propanediol, 1,2-butanediol, 1,3-butanediol, 2,3-butanediol, and mixtures thereof;
• the invention also relates to a process for preparing a topical pharmaceutical composition, comprising: (a) admixing water, a diol and sodium lauryl sulfate at about 70°-80°C at least until the diol and sodium lauryl sulfate dissolve to give an Aqueous Phase Mixture Part A, wherein said diol is selected from the group consisting of 1,2- propanediol, 1,2-butanediol, 1,3-butanediol, 2,3-butanediol, and mixtures thereof,
• the pharmaceutically active agent may be added to the Aqueous Phase in step (a) or to the Oil (non-aqueous) Phase in step (d) depending upon the solubility of the pharmaceutically active agent.
• the invention also relates to a pharmaceutical composition obtained by the process of the invention
• the invention also relates to a method of treating an inflammatory skin condition in an animal in need thereof, comprising administering an effective amount of the inventive pharmaceutical composition to said animal, wherein the pharmaceutically active agent in the composition is an anti-inflammatory agent, preferably, a corticosteroid, more preferably, triamcinolone, most preferably, triamcinolone acetonide.
• an anti-inflammatory agent preferably, a corticosteroid, more preferably, triamcinolone, most preferably, triamcinolone acetonide.
• the invention relates in part to the discovery that topical pharmaceutical compositions containing pharmaceutically active agents such as corticosteroids, and substantial amounts of cetyl alcohol and stearyl alcohol are very effective topical therapeutic agents, e.g., for treating dermatological conditions.
• the pharmaceutical composition of the invention comprising 0 05% triamcinolone acetonide as the pharmaceutically active agent was found to potently induce vasoconstriction, and to provide relief from the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses
• the present invention provides for substantial cost savings due to a reduction in the required level of pharmaceutically active agent, results in a rapid onset of pharmacological effects, and is stable and non-irritating In addition, preservatives are not required and the inventive compositions have acceptable cosmetic and aesthetic properties
• the invention relates to a pharmaceutical composition for topical administration, comprising
• the preferred diol is 1 ,2-propanediol, i e , propylene glycol
• the preferred source of glyceryl monostearate is CERASYNT ® SD which is a non-compendial emulsifier available from Van Dyk & Co , Inc , although other self-emulsifying grades of glyceryl monostearate may be employed
• Examples of pharmaceutically active agents useful in the present invention include, without limitation, corticosteroids such as hydroxytriamcinolone, alpha methyl dexamethasone, dexamethasone acetate, betamethasone, beclomethasone dipropionate, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, clobetasol valerate, clobetasol propionate, desonide, desoxymethasone, dexamethasone, difluorosone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, flumethasone pivalate, fluocinolone acetonide, fluocinonide, flucortine butylester, flucortolone, fluprednidine (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone buty
• compositions include agents, synthetic and natural, which have a pharmaceutical effect at the surface of the skin and/or in the subcutaneous layers of the skin such as antimicrobials, antivirals, antibiotics, anthelmintics, anti-inflammatory agents, histamine H 2 -receptor agonists and antagonists, hormones, vitamins, neoplastic agents, immune-response agents, antithrombotics, sulfones, sunscreens, local anesthetics, muscle relaxants, antitussives, blood regulators, anticoagulants, hemostatics, sedatives, analgesics, adrenergics, antispasmodics, bone-active agents, prostaglandins, antipsychotics, anorexigenics, cholinergics, anticholinergics and sulfonamides
• pharmaceutically active agent also includes pharmaceuticals used to treat arthritis, thyroid conditions, hypertension, cardiac conditions, depression, hyperlipidemia, ulcers, malaria, cancer and anxiety Mixtures of
• the pharmaceutical composition of the present invention has the following composition:
• the pharmaceutical composition of the present invention has the following composition:
• the corticosteroid is triamcinolone acetonide.
• the pharmaceutical composition of the present invention has the following composition: Ingredients Percent (%w/w)
• Triamcinolone Acetonide USP 0 05
• CERASYNT ® SD (comprising glyceryl monostearate) 3 50
• the invention also relates to a process for preparing a topical pharmaceutical composition, comprising
• the pH of the pharmaceutical composition is adjusted with either aqueous sodium hydroxide or hydrochloric acid to give a pH of about 5 0 to about 7 0, more preferably, about 5 5 to about 6 5
• the invention also relates to a pharmaceutical composition obtained by the process of the invention
• the pharmaceutical compositions of the present invention may contain additional ingredients including antimicrobials, excipients, dyes, perfumes, fragrances, preservatives, anti-oxidants, opacifiers, thickening agents, preservatives, stabilizers and the like.
• additional ingredients including antimicrobials, excipients, dyes, perfumes, fragrances, preservatives, anti-oxidants, opacifiers, thickening agents, preservatives, stabilizers and the like.
• Such materials when added, should not unduly interfere with the activity of the pharmaceutically active agent nor possess irritating properties.
• Such formula modifications to improve cosmetic acceptability are well within the skill in the art.
• the pharmaceutical composition of the invention may be provided in ajar, tube or other suitable container as is well known in the art.
• the invention also relates to a method of treating the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses in an animal in need thereof, comprising administering topically an effective amount of a pharmaceutical composition of the invention to said animal.
• the animal is a mammal, more preferably, a human.
• the dermatosis is psoriasis, seborrheic dermatitis, atopic dermatitis, contact dermatitis, eczema or any skin condition characterized by dermal and inflammatory pruritis.
• the individual dosage is determined according to the particular condition being treated.
• the compositions may be applied from one to six times daily or otherwise as is necessary to treat the skin condition. If the pharmaceutically active agent is a corticosteroid, then the composition is preferably applied one to four times daily, more preferably, once or twice daily. In the most preferred application, the corticosteroid-containing composition is applied as a thin layer to the affected area twice daily and rubbed into the skin completely.
• Any animal which will benefit from the pharmaceutical composition of the invention is within the scope of animals that may be treated according to the present invention.
• animals include humans and veterinary animals.
• STEP 1 Inspect processing rooms and equipment listed to insure they are clean and ready for use.
• Part A Aqueous Phase
• STEP 3 Add the appropriate amount of purified water USP, to a clean stainless steel steam-jacketed mixing kettle equipped with a turbine mixer and scraper blade mixer Begin mixing and heat the water to 70°-80°C Maintain at 70°-80°C through Step 12 (cooling emulsion).
• STEP 4 Add propylene glycol USP Cover the mixing kettle and mix until the propylene glycol dissolves. Mix for at least 5 minutes.
• STEP 5 Add sodium lauryl sulfate NF Cover the mixing kettle and mix on low speed until the sodium lauryl sulfate powder dissolves. Continue mixing at low speed.
• Part B Triamcinolone Acetonide/Laurocapram Premix
• Step 6 Add laurocapram (AZONE ® ) to a clean stainless steel mixing vessel equipped with an appropriate mixer Cover the mixing vessel and heat, using an appropriate heater, the AZONE ® to 70°- 80 °C while stirring at low speed Maintain the temperature at 70°-80°C through Step 12
• Part C Oil (non-aqueous) Phase
• STEP 8 Add glyceryl monostearate (preferably, CERASYNT ® SD from
• STEP 10 Increase the speed of the mixer for Part A, the aqueous phase in
• Step 5 to high Slowly add combined Parts B and C (from Step 9) to Part A (Step 5) Cover and continue to mix
• STEP 11 Turn off the steam, drain the steam jacket, and continue mixing
• Step 12 Rinse the kettle used in Step 9 with a appropriate amount of purified water USP, and add the rinse solution to Step 10
• STEP 13 Cover and continue mixing using a propeller and side sweep Cool the batch to 55°-60°C, using cooling water in the jacket if necessary
• STEP 14 Check and record the pH of a 1 10 mixture in purified water, USP
• STEP 15 Process the emulsion from Step 13 through the homogenizer using two medium and one fine generator Continue homogenizing the emulsion for at least 45 minutes
• STEP 16 Pump the product through the homogenizer into poly-lined plastic drums
• STEP 17 Take beginning, middle and end samples during the pumping operation for bulk drug product

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Epidemiology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Dermatology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Immunology (AREA)
• Rheumatology (AREA)
• Pain & Pain Management (AREA)
• Pulmonology (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Cosmetics (AREA)

Priority Applications (9)

Applications Claiming Priority (2)

Publications (1)

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Country Status (15)

Cited By (8)

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• 1999
  • 1999-09-28 BR BRPI9917389-1A patent/BR9917389B1/pt not_active IP Right Cessation
  • 1999-09-28 AT AT99973935T patent/ATE273682T1/de active
  • 1999-09-28 WO PCT/US1999/022313 patent/WO2001000139A1/en not_active Ceased
  • 1999-09-28 NZ NZ516765A patent/NZ516765A/xx not_active IP Right Cessation
  • 1999-09-28 CA CA002376850A patent/CA2376850C/en not_active Expired - Fee Related
  • 1999-09-28 PT PT99973935T patent/PT1194109E/pt unknown
  • 1999-09-28 AU AU60607/99A patent/AU769079B2/en not_active Ceased
  • 1999-09-28 KR KR1020017016610A patent/KR100623534B1/ko not_active Expired - Fee Related
  • 1999-09-28 DK DK99973935T patent/DK1194109T3/da active
  • 1999-09-28 EP EP99973935A patent/EP1194109B1/en not_active Expired - Lifetime
  • 1999-09-28 ES ES99973935T patent/ES2224755T3/es not_active Expired - Lifetime
  • 1999-09-28 MX MXPA01013460A patent/MXPA01013460A/es active IP Right Grant
  • 1999-09-28 DE DE69919597T patent/DE69919597T2/de not_active Expired - Lifetime
  • 1999-09-28 US US09/406,918 patent/US6271219B2/en not_active Expired - Lifetime
  • 1999-09-28 JP JP2001515895A patent/JP2003506462A/ja active Pending

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