WO2003097021A2 - Use of transdermal topical systems for the prevention and treatment of primary dysmenorrhea - Google Patents

Use of transdermal topical systems for the prevention and treatment of primary dysmenorrhea Download PDF

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WO2003097021A2
WO2003097021A2 PCT/IB2003/002048 IB0302048W WO03097021A2 WO 2003097021 A2 WO2003097021 A2 WO 2003097021A2 IB 0302048 W IB0302048 W IB 0302048W WO 03097021 A2 WO03097021 A2 WO 03097021A2
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use according
nsaids
transdermal
ketoprofen
days
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PCT/IB2003/002048
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French (fr)
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WO2003097021A3 (en
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Stefano Camponovo
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Technipharma L.L.C.
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Priority to AU2003230136A priority Critical patent/AU2003230136A1/en
Publication of WO2003097021A2 publication Critical patent/WO2003097021A2/en
Publication of WO2003097021A3 publication Critical patent/WO2003097021A3/en

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    • 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
    • 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
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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

Definitions

  • the present invention relates to a new therapeutic use of transdermal topical systems comprising at least a non-steroidal anti-inflammatory drug and, more particularly, it relates to the use of said systems in the prevention and treatment of painful symptoms associated with primary dysmenorrhea.
  • Dysmenorrhea is clinically defined as "painful menstruation". In its essential or primary form, that is the one not depending on a specific pathological reason, it is believed to involve, at least for some period of life, about 50% of women in their fertile age.
  • NSAIDs non-steroidal anti- inflammatory drugs
  • the preferred pharmacological therapy of the painful symptoms of primary dysmenorrhea is represented by the oral administration of non-steroidal anti- inflammatory drugs (NSAIDs) that, by inhibiting the synthesis of prostaglandins, reduce their local or systemic effects [Clinical Therap. (1990), 12, 398-409].
  • NSAIDs non-steroidal anti- inflammatory drugs
  • physicians are particularly oriented towards NSAIDs having a good analgesic effect.
  • the oral NSAIDs are only suitable for short periods of treatment and for the reduction of painful symptoms after they have appeared.
  • several other methods for treating dysmenorrhea consisting, for example, in administering new medicinal compositions and associations (synergistic combination of xanthines and.
  • such a treatment should be of the preventive type, allowing to intervene 2-3 days in advance with respect to the starting of the flow with the aim to avoid the manifestation of symptoms, of non invasive type and easy to be used by patients, should avoid scarcely practicable administration routes such as the intrauterine or intravaginal ones, and should be characterized by low side effects, in particular it should not have the gastro-damaging effects of orally taken NSAIDs.
  • Suitable topical systems are for example the matrix patches, both multilayers and monolayer, the hydrogel cataplasms, the hydrocolloidal plasters and in general the transdermal systems for the topical administration of NSAIDs known in the field, for example those described in the international patent application O02/02086 (Labtec Ges Fuer Technsammlung) or in the Italian patent application n. MI2001A002827, filed on December 28,
  • Preferably said systems have dimensions such as to cover a skin surface comprised between 50 and 150 cm 2 .
  • the NSAIDs usable, alone or in admixture, according to the present invention are generally all the NSAIDs, both as free acids and as salts and, more particular, arylpropionic or arylacetic NSAIDs, such as for example ibuprofen, ketoprofen, naproxen, flurbiprofen, fenoprofen, pranoprofen, indomethacin, diclofenac, sulindac, ibufenac, ketorolac and aclofenac, or salicylates such as for example salicylic acid and methyl salycilate, the oxicams, such as for example piroxicam, or the fenamates, such as for example flufenamic acid.
  • ketoprofen and diclofenac are particularly preferred.
  • the above NSAIDs are used in the transdermal systems as free acids or, alternatively, as organic or inorganic salts.
  • Preferred organic salts are those with basic aminoacids, such as for example lysine or arginine, while preferred inorganic salts are alkaline or earth-alkaline salts, more preferably sodium or potassium salts.
  • both the isolated optical isomers, preferably the active ones, and any admixture thereof are encompassed within the scope of the present invention.
  • transdermal topical systems usable in the- resent invention generally allow a constant release of the active drug during the 24 hours.
  • said systems comprise an amount of NS JDD up to about 1000 mg, preferably from 10 mg to 400 mg, more preferably from 10 mg to 200 mg, even more preferably from 30 mg to 150 mg per dosage unit.
  • the preferred range is from 30 mg to 200 mg, preferably from 30 mg to 110 mg for ketoprofen and from 50 mg to 150 mg, preferably from 120 mg to
  • a transdermal matrix patch comprising from 30 mg to 200 mg, preferably from 30 to 150 mg of ketoprofen or diclofenac is applied onto the lumbar or low abdomen region once a day, starting from 1-2 days before the expected onset menstrual flow, up to symptoms resolution for a rninimum duration of 3 days and for a maximum duration not exceeding 5 days.
  • Ketoprofen was used for the class of arylpropionic derivatives. Ibuprofen, naproxen and flurbiprofen pertain to this class too.
  • a ketoprofen matrix patch having a size of 90 cm 2 was used.
  • This patch is a matrix transdermal system, made by a polyester woven fabric on which a mass containing the active drug is distributed (solution of ketoprofen and adhesive - acrylate copolymer) and by a protective layer, as described for example in the already mentioned international patent application WO02/02086 (Labtec Ges Fuer Technologische).
  • Diclofenac was used for the class of arylacetic derivatives in a matrix patch of 140 cm 2 containing 140 mg of diclofenac sodium salt.
  • This matrix patch is made by a non-woven fabric on which a mass containing the active drug is distributed (suspension of sodium diclofenac in polyhydroxylated hydrogenated castor oil, an" aminoallcylmethacrylate - methacrylate copolymer, one or more cross-linking agents, and adhesive system and other optional excipients) and by a protective layer, such as the one described in the already mentioned patent application n. MI2001A002827.
  • the above-mentioned patches were evaluated in a "cross-over" pilot study on 6 volunteers that showed an anamnesis of primary dysmenorrhea for at least three preceding cycles.
  • D - diclofenac patch containing 140 mg of sodium diclofenac
  • Each patch was applied onto the region of low abdomen for the 3 days preceding the cycle and for the subsequent first 3 days of the flow, a patch every 24 hours.
  • Figure 1 shows the significant difference in the severity of the pain pointed out during the three days of the cycle between the control and the treatments with the two NSAIDs.
  • the first day of the cycle such a difference is already at its highest point, thus demonstrating a preventive effect elicited by the application of the
  • transdermal systems used in the present study were the following:
  • T 2 patch with a surface of 90 cm 2 (size: 8.2x11 cm), containing 100 mg of ketoprofene (name: Ketoprofen TDS 100 mg patch).
  • the volunteers were females from 18 to 40 years of age with a history of primary dysmenorrhea of at least 4 months duration, suffering from a moderate pain
  • the regimen of application of the patches or plasters in the lumbar or lower abdominal area was of 1 patch (plaster) a day, starting 1-2 days before the onset of the menstrual flow and following during menstruation up to symptoms resolution for a minimum duration of 3 days and for a maximum duration not exceeding 5 days.
  • the total duration of the treatment was of 4 months.
  • Two menstrual cycles with patient's usual medication used to treat dysmenorrhea symptoms mainly NSAIDs, but also analgesics and muscle- relaxants, by oral or rectal route, at need
  • the same patient's usual medication at need were taken as rescue medication during the treatment periods with NSAIDs patches or plasters.
  • the efficacy of the treatments was evaluated on 29 volunteers (per protocol population, PP) according to the following patient's parameters: pain intensity, intensity of symptoms, ability to perform activities of daily living, measured starting from 1-2 days before the expected onset of menstrual flow up to symptoms resolution; global efficacy judgment, medication ranking with respect to the usual therapy, amount and frequency of rescue medication.
  • the safety of the therapy was evaluated on 36 volunteers (intent to treat population, ITT) taking into consideration the adverse events occurrence, the global investigator's and patient's judgment on tolerability, clinical laboratory analyses, vital signs and physical examination.
  • Figure 4 shows the mean pain vs. time curve for the treated periods in comparison to control periods.
  • the analysis of primary end-point demonstrates that both diclofenac sodiu and ketoprofen patches were significantly superior to control therapy in reducing the menstrual pain.
  • Figure 5 relates to the total scoring (calculated as arithmetic sum) of the subjective evaluation of the other menstrual symptoms (pelvic pain, headache, nervousness, depression, nausea, vomiting, diarrhea, tachycardia, fatigue, dizziness, backache, myalgia, etc.) on all days of menstruation.
  • the statistical analysis found a significant improvement in symptoms scoring after both diclofenac sodium and ketoprofen treatment as compared to control.
  • diclofenac sodium and ketoprofen patches were significantly superior to control therapy.
  • Figure 6 discloses that the total rescue medication consumption significantly decreased during TI and T2 treatment periods as compared to control.
  • Tables I and II disclose a summary of the statistical results of primary and secondary end-points on the per-protocol population.
  • 100 mg patches administered once a day for 3-5 days as prevention treatments, are effective in lowering the intensity of dysmenorrhea pain and symptoms and in reducing consumption of other systemic medications.

Abstract

The use of transdermal administration systems of non-steroidal anti-inflammatory drugs (NSAIDs) in the prevention and treatment of painful symptoms associated with primary dysmenorrhea is described.

Description

USE OF TRANSDERMAL TOPICAL SYSTEMS FOR THE PREVENTION AND TREATMENT OF PRIMARY DYSMENORRHEA
The present invention relates to a new therapeutic use of transdermal topical systems comprising at least a non-steroidal anti-inflammatory drug and, more particularly, it relates to the use of said systems in the prevention and treatment of painful symptoms associated with primary dysmenorrhea. Dysmenorrhea is clinically defined as "painful menstruation". In its essential or primary form, that is the one not depending on a specific pathological reason, it is believed to involve, at least for some period of life, about 50% of women in their fertile age.
It is estimated that about 10% of women are indisposed for 1-3 days per month, which consequently results in not attendance at school or at work. Primary dysmenorrhea is associated with an increased production and release of prostaglandins at uterine level, with a subsequent increase in the muscular tone and in the contractions of miometrium, vessel spasm of the circulatory bed of the uterus that can result into ischemic pain, spasms and painful cramps, localized at the lower abdomen. The pain often irradiates to the groin, to the higher part of thighs and to the back. Other associated symptoms can be: nausea, vomiting, diarrhea and headache.
The preferred pharmacological therapy of the painful symptoms of primary dysmenorrhea is represented by the oral administration of non-steroidal anti- inflammatory drugs (NSAIDs) that, by inhibiting the synthesis of prostaglandins, reduce their local or systemic effects [Clinical Therap. (1990), 12, 398-409]. In order to better struggle the painful symptoms, physicians are particularly oriented towards NSAIDs having a good analgesic effect.
However the NSAIDs, just because of their anti-prostaglandin mechanism of action, result to be seriously damaging for the stomach, as they antagonize the prostaglandins of the gastric mucous membrane and reduce their protective effect. For this reason, in primary dysmenorrhea, the oral NSAIDs are only suitable for short periods of treatment and for the reduction of painful symptoms after they have appeared. In the literature several other methods for treating dysmenorrhea consisting, for example, in administering new medicinal compositions and associations (synergistic combination of xanthines and. iron compounds - US 2.601.285, of ibuprofen and hydrochlorothiazide - US 5.155.105 or complex admixtures - US 2.646.385), in alternative pharmacological classes (for example the amidoureas described in US 4.241.087), in new routes of admimstration of known drugs (for example the intrauterme- US 4.016.270 or intravaginal administration - US 6.197.327) or in new therapeutic approaches of local type (for example the electrical stimulation of specific points of the body as described in the US patent application n. US 2002/0002388 Al) are known. However no one among the described approaches shows all the requirements for an ideal treatment of the symptoms of the primary dysmenorrhea. In fact such a treatment should be of the preventive type, allowing to intervene 2-3 days in advance with respect to the starting of the flow with the aim to avoid the manifestation of symptoms, of non invasive type and easy to be used by patients, should avoid scarcely practicable administration routes such as the intrauterine or intravaginal ones, and should be characterized by low side effects, in particular it should not have the gastro-damaging effects of orally taken NSAIDs. We have now surprisingly found that it is possible to prevent the appearance of the painful symptoms of primary dysmenorrhea by applying onto the lower abdominal or lumbar zone a transdermal topical system containing at least a NSAED, at such a concentration and formulation to allow an almost constant transdermal efflux of the drug, preferably for the three days preceding the menstrual flow and then maintaining the control over said symptoms preferably by a once-a-day application of the system for the first three days of the flow. A considerable advantage of the present treatment over the conventional approach is the significant reduction in the consumption of oral and rectal medications such as NSAIDs, analgesics, muscle-relaxants (rescue medication) that makes the well known side effects associated with those traditional medications disappear or, at least, drastically diminish.
Suitable topical systems, according to the present invention, are for example the matrix patches, both multilayers and monolayer, the hydrogel cataplasms, the hydrocolloidal plasters and in general the transdermal systems for the topical administration of NSAIDs known in the field, for example those described in the international patent application O02/02086 (Labtec Ges Fuer Technologische) or in the Italian patent application n. MI2001A002827, filed on December 28,
2001, with the title "Sodium diclofenac adhesive transdermal formulations".
Preferably said systems have dimensions such as to cover a skin surface comprised between 50 and 150 cm2.
The NSAIDs usable, alone or in admixture, according to the present invention are generally all the NSAIDs, both as free acids and as salts and, more particular, arylpropionic or arylacetic NSAIDs, such as for example ibuprofen, ketoprofen, naproxen, flurbiprofen, fenoprofen, pranoprofen, indomethacin, diclofenac, sulindac, ibufenac, ketorolac and aclofenac, or salicylates such as for example salicylic acid and methyl salycilate, the oxicams, such as for example piroxicam, or the fenamates, such as for example flufenamic acid. In the present context ketoprofen and diclofenac are particularly preferred.
According to the present invention the above NSAIDs are used in the transdermal systems as free acids or, alternatively, as organic or inorganic salts. Preferred organic salts are those with basic aminoacids, such as for example lysine or arginine, while preferred inorganic salts are alkaline or earth-alkaline salts, more preferably sodium or potassium salts.
In addition, when the selected NSAID bears one or more chiral centers, both the isolated optical isomers, preferably the active ones, and any admixture thereof are encompassed within the scope of the present invention.
The transdermal topical systems usable in the- resent invention generally allow a constant release of the active drug during the 24 hours.
In general said systems comprise an amount of NS JDD up to about 1000 mg, preferably from 10 mg to 400 mg, more preferably from 10 mg to 200 mg, even more preferably from 30 mg to 150 mg per dosage unit.
In particular the preferred range is from 30 mg to 200 mg, preferably from 30 mg to 110 mg for ketoprofen and from 50 mg to 150 mg, preferably from 120 mg to
150 mg for diclofenac per dosage unit, respectively.
The optimal dose, whose evaluation is up to the skilled in the art, depends on several factors, such as for example the intrinsic activity of the NSAID used, the degree of tissue penetration of the molecule, the kind of patch (matrix, hydrogel etc.), the kind of formulation and excipients that condition the drug release kinetic. hi a preferred embodiment of the present invention a transdermal matrix patch comprising from 30 mg to 200 mg, preferably from 30 to 150 mg of ketoprofen or diclofenac is applied onto the lumbar or low abdomen region once a day, starting from 1-2 days before the expected onset menstrual flow, up to symptoms resolution for a rninimum duration of 3 days and for a maximum duration not exceeding 5 days.
With the aim to better illustrate the present invention, however without limiting it, the following examples are now given.
EXAMPLES EXAMPLE 1 : preliminary "cross-over" pilot study
Two transdermal topical systems (patches) containing NSAIDs representing two classes of anti-inflammatory drugs were used.
Ketoprofen was used for the class of arylpropionic derivatives. Ibuprofen, naproxen and flurbiprofen pertain to this class too.
A ketoprofen matrix patch having a size of 90 cm2 was used. This patch is a matrix transdermal system, made by a polyester woven fabric on which a mass containing the active drug is distributed (solution of ketoprofen and adhesive - acrylate copolymer) and by a protective layer, as described for example in the already mentioned international patent application WO02/02086 (Labtec Ges Fuer Technologische).
Diclofenac was used for the class of arylacetic derivatives in a matrix patch of 140 cm2 containing 140 mg of diclofenac sodium salt.
This matrix patch is made by a non-woven fabric on which a mass containing the active drug is distributed (suspension of sodium diclofenac in polyhydroxylated hydrogenated castor oil, an" aminoallcylmethacrylate - methacrylate copolymer, one or more cross-linking agents, and adhesive system and other optional excipients) and by a protective layer, such as the one described in the already mentioned patent application n. MI2001A002827. The above-mentioned patches were evaluated in a "cross-over" pilot study on 6 volunteers that showed an anamnesis of primary dysmenorrhea for at least three preceding cycles.
The following treatments were applied:
C - Control: placebo patch, identical to patch K, without active drug.
K - ketoprofen: patch containing 100 mg of ketoprofen
D - diclofenac: patch containing 140 mg of sodium diclofenac
Each patch was applied onto the region of low abdomen for the 3 days preceding the cycle and for the subsequent first 3 days of the flow, a patch every 24 hours.
Each volunteer received all the above treatments for three subsequent cycles, according to the following scheme:
Volunteer 1° Cycle 2° Cycle 3° Cycle
1 C K D
2 K D C
3 D C K
4 K C D
5 c D K
6 D K C
If necessary, the consumption of 500 mg paracetamol oral tablets for relieving the algic - spastic symptoms and headache was allowed.
Volunteers were required to limit to the minimum the consumption of paracetamol.
Daily for the three days of the flow (days 1-2-3) the volunteers felt the presence of pain, expressing the seriousness thereof with a score from 0 to 3, the appearance of nausea (yes/no) and headache (yes/no) and the eventual number of dosages of paracetamol taken (rescue medication).
The obtained results are summarized in the following figures 1 to 3.
Figure 1 shows the significant difference in the severity of the pain pointed out during the three days of the cycle between the control and the treatments with the two NSAIDs. The first day of the cycle such a difference is already at its highest point, thus demonstrating a preventive effect elicited by the application of the
NSAID patch for the 3 previous days.
The data in Figure 2 confirm the above, showing that there existed a very significant difference, evaluated by means of Kruskal-Wallis variance analysis for non-parametrical data, between the two NSAIDs treatments and the control treatment, on the pain total scor for the three days of the cycle.
Also the total consumption of doses of paracetamol, even if generally limited, resulted significantly reduced by the NSAIDs treatment (Figure 3).
The episodes of nausea, which totally were of 7 during the control period, were reduced at 2 during the period with ketoprofen and at 3 during that with diclofenac.
EXAMPLE 2: enlarged "cross-over" pilot study
This phase II clinical study was performed in order to evaluate the efficacy, the safety and tolerability of diclofenac plasters and ketoprofen patches in the prevention and control of the primary dysmenorrhea symptoms.
The transdermal systems used in the present study were the following:
Ti: plaster with a surface of 140 cm2 (size: 10x14 cm), containing 140 mg of diclofenac sodium (name: Diclofenac sodium 140 mg plaster).
T2: patch with a surface of 90 cm2 (size: 8.2x11 cm), containing 100 mg of ketoprofene (name: Ketoprofen TDS 100 mg patch).
The volunteers were females from 18 to 40 years of age with a history of primary dysmenorrhea of at least 4 months duration, suffering from a moderate pain
(grade 2 on Andersch and Milsom's system, as described in Am. I. Obstet.
Gynecol. (1982); 144; 655-660).
They were administered with Diclofenac sodium 140 mg plaster (TI) and
Ketoprofen TDS 100 mg patch (T2) for two consecutive menstrual cycles each, in random order, preceded by two control menstrual cycles for a total of six menstrual cycles evaluated. The regimen of application of the patches or plasters in the lumbar or lower abdominal area was of 1 patch (plaster) a day, starting 1-2 days before the onset of the menstrual flow and following during menstruation up to symptoms resolution for a minimum duration of 3 days and for a maximum duration not exceeding 5 days. The total duration of the treatment was of 4 months. Two menstrual cycles with patient's usual medication used to treat dysmenorrhea symptoms (mainly NSAIDs, but also analgesics and muscle- relaxants, by oral or rectal route, at need), were taken as controls. The same patient's usual medication at need, were taken as rescue medication during the treatment periods with NSAIDs patches or plasters.
The efficacy of the treatments was evaluated on 29 volunteers (per protocol population, PP) according to the following patient's parameters: pain intensity, intensity of symptoms, ability to perform activities of daily living, measured starting from 1-2 days before the expected onset of menstrual flow up to symptoms resolution; global efficacy judgment, medication ranking with respect to the usual therapy, amount and frequency of rescue medication.
The safety of the therapy was evaluated on 36 volunteers (intent to treat population, ITT) taking into consideration the adverse events occurrence, the global investigator's and patient's judgment on tolerability, clinical laboratory analyses, vital signs and physical examination.
The statistical analysis of the collected data was performed according to Wilcoxon signed rank and ANOVA repeated measures/Tukey-Kramer multiple comparison tests for end-points expressed as total scoring, while following the Chi-squares test for end-points expressed as frequencies.
The results of the present study are summarized in Figures 4 to 6 and in tables I and ll.
In particular Figure 4 shows the mean pain vs. time curve for the treated periods in comparison to control periods. The analysis of primary end-point (total scoring of the subjective evaluation of the pain on day 1 of menstruation) demonstrates that both diclofenac sodiu and ketoprofen patches were significantly superior to control therapy in reducing the menstrual pain.
The statistical analysis of total scoring (calculated as arithmetic sum) of the subjective evaluation of pain on all days of menstruation showed the same efficacy of diclofenac sodium and ketoprofen patches over control therapy in reducing the menstrual pain of more than 25%.
Figure 5 relates to the total scoring (calculated as arithmetic sum) of the subjective evaluation of the other menstrual symptoms (pelvic pain, headache, nervousness, depression, nausea, vomiting, diarrhea, tachycardia, fatigue, dizziness, backache, myalgia, etc.) on all days of menstruation. The statistical analysis found a significant improvement in symptoms scoring after both diclofenac sodium and ketoprofen treatment as compared to control.
As far as the total scoring (calculated as arithmetic sum) of the subjective evaluation of the ability to perform activities of daily living on all days of menstruation is concerned, diclofenac sodium and ketoprofen patches were significantly superior to control therapy.
Figure 6 discloses that the total rescue medication consumption significantly decreased during TI and T2 treatment periods as compared to control.
Tables I and II disclose a summary of the statistical results of primary and secondary end-points on the per-protocol population.
In addition the adverse events registered, namely flu (2 subjects), diarrhea (1 subject), migraine (2 subjects), back pain (1 subject), cystitis (2 subjects), dental abscess (1 subject), insomnia (1 subject), sprain of the left ankle (1 subject), and head ache (1 subject) occurred outside the menstruation period, none of them having relationship with the drug under evaluation.
In conclusion the above experimental data clearly show that both treatments were significantly superior to subject's usual therapy for dysmenorrhea and that the systemic tolerability of diclofenac sodium plasters and ketoprofen patches was very good. In particular both diclofenac sodium 140 mg plasters and ketoprofen
100 mg patches, administered once a day for 3-5 days as prevention treatments, are effective in lowering the intensity of dysmenorrhea pain and symptoms and in reducing consumption of other systemic medications.

Claims

1. Use of non-steroidal anti-inflammatory drugs (NSAIDs) for the manufacture of transdermal topical systems for the prevention and treatment of the symptoms of the primary dysmenorrhea.
2. Use according to claim 1 wherein said NSAIDs are selected among the classes of arylacetic acids, arylpropionic acids, salicylic acids, oxicams and fenamates.
3. Use according to claim 2 wherein said NSAIDs are selected among ibuprofen, ketoprofen, naproxen, flurbiprofen, fenoprofen, pranoprofen, diclofenac, sulindac, ibufenac, ketorolac, aclofenac, indomethacin, salicylic acid, methyl salicylate, piroxicam, and flufenamic acid, preferably between ketoprofen and diclofenac.
4. Use according to claims 1 to 3 wherein said NSAIDs are used in the form of free acids.
5. Use according to claims 1 to 3 wherein said NSAIDs are used in the form of organic or inorganic salts.
6. Use according to claim 5 wherein the organic salt is a basic ammoacid salt, preferably a lysine or arginine salt.
7. Use according to claim 5 wherein the inorganic salt is an alkaline or earth- alkaline salt, preferably a sodium or potassium salt.
8. Use according to claim 1 wherein said NSAIDs are chiral compounds, both in the foπn of isolated optical isomers and of any admixture thereof.
9. Use according to claim 1 wherein said transdermal topical system is a matrix patch, a hydrogel cataplasm or a hydrocolloidal plaster.
10. Use according to claim 1 wherein said transdermal topical system covers a cutaneous surface from 50 to 150 cm2'.
11. Use according to claim 1 wherein said NSAIDs are present in the transdermal topical system in amount up to 1000 mg per dosage unit.
12. Use according to claim 1 wherein said NSAIDs are present in the transdermal topical system in amount from 10 to 400 mg, preferably from 10 to 200 mg, even more preferably from 30 mg to 150 mg, per dosage unit.
13. Use according to clai 1 wherein said NSAID is ketoprofen in an amount from 30 mg to 200 mg, preferably from 30 mg to 110 mg, per dosage unit.
14. Use according to claim 1 wherein said NSAID is diclofenac in an amount from 50 mg to 150 mg, preferably from 120 mg to 150 mg, per dosage unit.
15. Use according to claim 1 characterized in that said topical system is applied onto the low abdominal zone.
16. Use according to claim 1 characterized in that said topical system is applied onto the lumbar zone.
17. Use according to claim 1 characterized in that said topical system is applied starting 1-2 days before the onset of the menstrual flow up to symptoms resolution, for a minimum duration of 3 days and for a maximum duration not exceeding 5 days.
18. Use according to claim 1 characterized in that said topical system is applied once a day.
PCT/IB2003/002048 2002-05-21 2003-05-15 Use of transdermal topical systems for the prevention and treatment of primary dysmenorrhea WO2003097021A2 (en)

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US20010038861A1 (en) * 1999-12-16 2001-11-08 Tsung-Min Hsu Transdermal administration of nonsteroidal anti-inflammatory drugs using hydroxide-releasing agents as permeation enhancers
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WO2002002086A1 (en) * 2000-07-05 2002-01-10 LABTEC Gesellschaft für technologische Forschung und Entwicklung mbH Dermal therapeutic system containing 2-(3-benzophenyl)-propionic acid or '0-(2,6-dichloranilino)-phenyl!-ethanoic acid
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2278947A1 (en) * 2008-05-21 2011-02-02 Teikoku Pharma USA, Inc. Treatment of dysmenorrhea via transdermal administration of nonsteroidal anti-inflammatory drugs
JP2011519870A (en) * 2008-05-21 2011-07-14 テイコク ファーマ ユーエスエー インコーポレーテッド Treatment of dysmenorrhea by transdermal administration of non-steroidal anti-inflammatory drugs
EP2278947A4 (en) * 2008-05-21 2013-11-06 Teikoku Pharma Usa Inc Treatment of dysmenorrhea via transdermal administration of nonsteroidal anti-inflammatory drugs

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