EP2658576A1 - Medicated patch for improved transdermal permeation of diclofenac diethylammonium - Google Patents

Medicated patch for improved transdermal permeation of diclofenac diethylammonium

Info

Publication number
EP2658576A1
EP2658576A1 EP10798143.3A EP10798143A EP2658576A1 EP 2658576 A1 EP2658576 A1 EP 2658576A1 EP 10798143 A EP10798143 A EP 10798143A EP 2658576 A1 EP2658576 A1 EP 2658576A1
Authority
EP
European Patent Office
Prior art keywords
diclofenac
medicated patch
diclofenac diethylammonium
composition
transdermal permeation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP10798143.3A
Other languages
German (de)
French (fr)
Inventor
Francesco Cilurzo
Paola Minghetti
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
PHARMAFILM Srl
Original Assignee
PHARMAFILM Srl
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by PHARMAFILM Srl filed Critical PHARMAFILM Srl
Publication of EP2658576A1 publication Critical patent/EP2658576A1/en
Withdrawn legal-status Critical Current

Links

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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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

A medicated patch for improved transdermal permeation of diclofenac diethylammonium in a composition comprising an acrylic copolymer and a citric acid ester.

Description

MEDICATED PATCH FOR IMPROVED TRANSDERMAL PERMEATION OF DICLOFENAC DIETHYLAMMONIUM
The present invention relates to a medicated patch for improved transdermal permeation of diclofenac diethylammonium.
Numerous 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.
In particular 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.
Still preferably, 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.
The abovestated 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.
EXAMPLE 1 MEDICATED PATCH FOR THE TRANSDERMAL PERMEATION OF DICLOFENAC DIETHYLAMMONIUM DISPERSED IN A COMPOSITION CONTAINING TRIBUTYLCITRATE (Formulation 1 )
27.5 g of tributylcitrate, 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).
An aqueous dispersion of this type is known by the name of EudragitR NE 40. This EudragitR 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.
The 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 60QC 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/cm2 of diclofenac.
At the end of the process the medicated patch obtained is cut and stored in hermetic containers.
In vitro permeation method
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 -20QC 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 60QC for one minute the human epidermis section was carefully separated with tweezers from the remaining tissues. Before experimental use, 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 ParafilmR and fixed by means of a clip.
These vertical cells have a diffusion of about 5 ml by 0.636 cm2. 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 NaN3 as preservative.
Particular care was taken to prevent the presence of bubbles between the 0.9% NaCI solution and the epidermis in the receiving compartment. The Franz cells containing the buffer were maintained at 37QC with a circulating water bath during the entire experiment, such that the epidermis surface temperature is 32±1 QC. Only the receiving compartment was in contact with the water circulating at 37QC, 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).
Results
The diclofenac quantity which had permeated after 24 hours was 14.1 ±1 .8 g/cm2, the stationary flow being 0.8±0.0 g/cm2 per hour.
EXAMPLE 2
MEDICATED PATCH FOR THE TRANSDERMAL PERMEATION OF DICLOFENAC DIETHYLAMMONIUM DISPERSED IN A COMPOSITION CONTAINING DIBUTYLSEBACATE (Formulation 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 operations involved in the preparation and subsequent analysis are identical to those described in Example 1 .
Results
The diclofenac quantity which had permeated after 24 hours was 1 .0±0.6 g/cm2, the stationary flow being 0.1 ±0.1 g/cm2 per hour. EXAMPLE 3
MEDICATED PATCH FOR THE TRANSDERMAL PERMEATION OF DICLOFENAC DIETHYLAMMONIUM DISPERSED IN A COMPOSITION CONTAINING TRIACETIN
(Formulation 3)
Differently to that described in Example 1 , 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 operations involved in the preparation and subsequent analysis are identical to those described in Example 1 .
Results
The diclofenac quantity which had permeated after 24 hours was 1 .9±0.3 Mg/cm2, the stationary flow being 0.1 ±0.0 g/cm2 per hour.
EXAMPLE 4
MEDICATED PATCH FOR THE TRANSDERMAL PERMEATION OF DICLOFENAC DIETHYLAMMONIUM DISPERSED IN A COMPOSITION CONTAINING TRIBUTYLCITRATE (Formulations 4, 5 and 6)
Differently to that described in Example 1 , 34 g of tributylcitrate, 3.7 g of diclofenac diethylammonium and 62.3 g of an aqueous dispersion of ethylacrylate/methylmethacrylate copolymer (Formulation 4), 24 g of tributylcitrate, 3.5 g of diclofenac diethylammonium and 72.5 g of an aqueous dispersion of ethylacrylate/methylmethacrylate copolymer (Formulation 5), 27.1 g of tributylcitrate, 4.9 g of diclofenac diethylammonium and 68 g of an aqueous dispersion of ethylacrylate/methylmethacrylate copolymer (Formulation 6) are poured gradually in succession at ambient temperature into a mixer (agitating for two hours).
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.
Results
The diclofenac quantity which had permeated after 24 hours in the case of Formulation 4 was 15.8±2.3 pg/cm2, in the case of Formulation 5 was 13.1 ±3.3 Mg/cm2, and in the case of Formulation 6 was 17.1 ±1 .7 pg/cm2 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/cm2 per hour, in the case of Formulation 5 was 0.7±0.2 pg/cm2 per hour, and in the case of Formulation 6 was 1 .1 ±0.3 g/cm2 per hour.
Final comments
The results obtained from Examples 1 , 2 and 3 using epidermis originating from one and the same donor show that tributylcitrate (Formulation 1 ) is capable of improving permeation of diclofenac salt through the skin compared with triacetin (Formulation 3) and with dibutylsebacate (Formulation 2).
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).

Claims

1 . A medicated patch for improved transdermal permeation of diclofenac diethylammonium, consisting of a flexible support having a composition spread onto one surface thereof, said composition comprising a polymer layer having at least one diclofenac salt dispersed within its interior, characterised in that said composition comprises 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.
2. A medicated patch as claimed in claim 1 , characterised in that said citric acid ester is tributylcitrate.
3. A medicated patch as claimed in claims 1 and 2, characterised in that said acrylic polymer is a copolymer of ethylacrylate and methyl methacrylate with an average molecular weight of 800000, in aqueous dispersion.
EP10798143.3A 2010-12-29 2010-12-29 Medicated patch for improved transdermal permeation of diclofenac diethylammonium Withdrawn EP2658576A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2010/070882 WO2012089256A1 (en) 2010-12-29 2010-12-29 Medicated patch for improved transdermal permeation of diclofenac diethylammonium

Publications (1)

Publication Number Publication Date
EP2658576A1 true EP2658576A1 (en) 2013-11-06

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EP10798143.3A Withdrawn EP2658576A1 (en) 2010-12-29 2010-12-29 Medicated patch for improved transdermal permeation of diclofenac diethylammonium

Country Status (5)

Country Link
EP (1) EP2658576A1 (en)
CN (1) CN103384533A (en)
BR (1) BR112013016998A2 (en)
EA (1) EA201390980A1 (en)
WO (1) WO2012089256A1 (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10966936B2 (en) 2015-12-30 2021-04-06 Corium, Inc. Systems comprising a composite backing and methods for long term transdermal administration
WO2017223402A1 (en) 2016-06-23 2017-12-28 Corium International, Inc. Adhesive matrix with hydrophilic and hydrophobic domains and a therapeutic agent
CN116270551A (en) 2016-07-27 2023-06-23 考里安有限责任公司 Compositions, transdermal patches and applications via in situ conversion of salts to neutral drugs
US11173132B2 (en) 2017-12-20 2021-11-16 Corium, Inc. Transdermal adhesive composition comprising a volatile liquid therapeutic agent having low melting point
IT202000011686A1 (en) * 2020-05-20 2021-11-20 Fidia Farm Spa SLOW RELEASE MEDICATED PATCH

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61280426A (en) * 1985-06-04 1986-12-11 Ikeda Mohandou:Kk Anti-inflammatory and analgesic application agent
KR19990026792A (en) * 1997-09-26 1999-04-15 김윤 Matrix Patches Containing Diclofenac Diethylammonium Salt
DE29823343U1 (en) * 1998-03-20 1999-07-15 Schwarz Pharma Ag, 40789 Monheim Transdermal therapeutic system (TTS) containing oxybutynin

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
RAINSFORD K D ET AL: "Review of the pharmaceutical properties and clinical effects of the topical NSAID formulation, diclofenac epolamine", CURRENT MEDICAL RESEARCH AND OPINION,, vol. 24, no. 10, 1 October 2008 (2008-10-01), pages 2967 - 2992, XP009167984, ISSN: 1473-4877 *
See also references of WO2012089256A1 *

Also Published As

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CN103384533A (en) 2013-11-06
EA201390980A1 (en) 2013-11-29
WO2012089256A1 (en) 2012-07-05
BR112013016998A2 (en) 2016-10-25

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