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
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
  • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
  • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
  • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
  • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• • 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
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • 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
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
  • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
  • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
  • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
  • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
  • A61K9/7061—Polyacrylates

Definitions

• the present invention relates to a medicated patch for improved transdermal permeation of diclofenac diethylammonium.
• diclofenac salts are known, of which diclofenac diethylammonium has demonstrated a particular pharmacological interest; however it has low permeation through the skin.
• the object of the present invention is to provide a medicated patch which facilitates transdermal permeation of diclofenac diethylammonium.
• This object is attained by dispersing said diclofenac diethylammonium salt in a polymer matrix spread onto a flexible support applicable to the human skin.
• said polymer matrix consists of a composition comprising from 39% to 55% of an acrylic polymer, from 4% to 12% of diclofenac diethylammonium and from 42% to 55% of a citric acid ester, said percentages being calculated by weight on the total weight of said composition.
• said citric acid ester is tributylcitrate, said polymer matrix consisting of a copolymer of ethylacrylate and methylmethacrylate with average molecular weight 800000, in aqueous dispersion.
• composition has proved very effective in promoting transdermal permeation of diclofenac diethylammonium.
• the medicated patch of the present invention will be better understood from the non-limiting examples given below.
• Eudragit R NE 40 An aqueous dispersion of this type is known by the name of Eudragit R NE 40.
• This Eudragit R NE 40 is an aqueous polymer dispersion with a concentration of 40 wt%.
• the resultant aqueous polymer system is left to stand, to enable the air to be completely removed.
• composition obtained in this manner is spread with a doctor blade (by a Matris spreading machine model LTE-S) on a silicone-coated protective sheet and dried for a time of 15 minutes at a temperature of 60 Q C and then coupled to a flexible support formed from a non-woven fabric or weft and warp fabric.
• the distance between the doctor blade and the protective sheet is such as to obtain a medicated patch containing 1 mg/cm 2 of diclofenac.
• the medicated patch obtained is cut and stored in hermetic containers.
• the skin used in the transdermal permeation studies was obtained from the abdomen of a patient undergoing cosmetic surgery.
• the total skin harvested was sealed in plastic vacuum bags and cooled to -20 Q C within 24 hours of removal. Before preparation, the skin was restored to ambient temperature and the excess fat was carefully removed.
• the skin section was cut into squares, then after immersing the skin in water at 60 Q C for one minute the human epidermis section was carefully separated with tweezers from the remaining tissues.
• the sample was carefully inspected to check for the presence of defects; said operation was carried out before mounting the sample on Franz diffusion cells with the corneal layer facing upwards in contact with the patch sample.
• the top and bottom parts of the Franz cell were sealed with Parafilm R and fixed by means of a clip.
• These vertical cells have a diffusion of about 5 ml by 0.636 cm 2 .
• the receiving volume of each cell is sized individually.
• the receiving compartment was filled with a fresh degassed 0.9% NaCI solution containing l OOpg/ml NaN 3 as preservative.
• the Franz cells containing the buffer were maintained at 37 Q C with a circulating water bath during the entire experiment, such that the epidermis surface temperature is 32 ⁇ 1 Q C. Only the receiving compartment was in contact with the water circulating at 37 Q C, each Franz cell being equipped with a magnetic stirrer. At a predetermined time (1 , 2, 6, 8, 24 hours) 0.2 ml of sample were withdrawn from the receiving compartment. The withdrawn samples were analyzed directly by HPLC to determine the concentration of the components which had permeated through the epidermis. The permeation data were calculated as the total drug quantity permeated through the skin as a function of time. All values were determined as the mean of experiments carried out in triplicate.
• the diclofenac concentration was determined by HPLC analysis (HP 1 100, Chemstation, Hewlett Packard). A 20 ml sample was injected at ambient temperature into a reverse phase column C18 (C18 Nova-Pak, 4.6 - 150 mm; Waters Spa, Milan, Italy). The eluent composition was acetonitrile/water/acetic acid (50/46/4 v/v). The throughput was 1 .5 ml/min. The wavelength was set at 254 nm. The drug concentration was determined by standard sodium diclofenac curves (0.3-20 pg/ml).
• the diclofenac quantity which had permeated after 24 hours was 14.1 ⁇ 1 .8 g/cm 2 , the stationary flow being 0.8 ⁇ 0.0 g/cm 2 per hour.
• Example 2 Differently to that described in Example 1 , 27.5 g of dibutylsebacate, 3.5 g of diclofenac diethylammonium and 69 g of an aqueous dispersion of ethylacrylate/methylmethacrylate copolymer with average molecular weight 800000 are poured gradually in succession at ambient temperature into a mixer (agitating for two hours).
• the diclofenac quantity which had permeated after 24 hours was 1 .0 ⁇ 0.6 g/cm 2 , the stationary flow being 0.1 ⁇ 0.1 g/cm 2 per hour.
• Example 27.5 g of triacetin, 3.5 g of diclofenac diethylammonium and 69 g of an aqueous dispersion of ethylacrylate/methylmethacrylate copolymer with average molecular weight 800000 are poured gradually in succession at ambient temperature into a mixer (agitating for two hours).
• the diclofenac quantity which had permeated after 24 hours was 1 .9 ⁇ 0.3 Mg/cm 2 , the stationary flow being 0.1 ⁇ 0.0 g/cm 2 per hour.
• Said aqueous dispersion has an average molecular weight of 800000.
• the operations involved in the preparation and subsequent analysis are identical to those described in Example 1 .
• the diclofenac salt is dissolved in tributylcitrate.
• the diclofenac quantity which had permeated after 24 hours in the case of Formulation 4 was 15.8 ⁇ 2.3 pg/cm 2
• in the case of Formulation 5 was 13.1 ⁇ 3.3 Mg/cm 2
• in the case of Formulation 6 was 17.1 ⁇ 1 .7 pg/cm 2
• the stationary flow, determined by the slope of the linear portion of the graph in the case of Formulation 4 was 0.9 ⁇ 0.1 g/cm 2 per hour
• in the case of Formulation 5 was 0.7 ⁇ 0.2 pg/cm 2 per hour
• in the case of Formulation 6 was 1 .1 ⁇ 0.3 g/cm 2 per hour.
• Example 4 Statistically, in Example 4 the different tributylcitrate quantities do not significantly reduce (Formulation 5) or increase (Formulation 4) the permeated diclofenac quantity; the same result is achieved by increasing the drug concentration within the polymer system (Formulation 6).

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• 2010
  • 2010-12-29 WO PCT/EP2010/070882 patent/WO2012089256A1/en active Application Filing
  • 2010-12-29 EA EA201390980A patent/EA201390980A1/ru unknown
  • 2010-12-29 CN CN201080071026.5A patent/CN103384533A/zh active Pending
  • 2010-12-29 EP EP10798143.3A patent/EP2658576A1/de not_active Withdrawn
  • 2010-12-29 BR BR112013016998A patent/BR112013016998A2/pt not_active IP Right Cessation

Non-Patent Citations (2)

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