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WO2004000361A1 - Compositions pharmaceutiques metastables - Google Patents

Compositions pharmaceutiques metastables Download PDF

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Publication number
WO2004000361A1
WO2004000361A1 PCT/AU2003/000785 AU0300785W WO2004000361A1 WO 2004000361 A1 WO2004000361 A1 WO 2004000361A1 AU 0300785 W AU0300785 W AU 0300785W WO 2004000361 A1 WO2004000361 A1 WO 2004000361A1
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Prior art keywords
pharmaceutical composition
composition according
active agent
volatile solvent
physiologically active
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PCT/AU2003/000785
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English (en)
Inventor
Nina Frances Wilkins
Kathryn Traci-Jane Klose
Timothy Matthias Morgan
Barry Leonard Reed
Barrie Charles Finnin
Original Assignee
Acrux Dds Pty Ltd
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Publication date
Application filed by Acrux Dds Pty Ltd filed Critical Acrux Dds Pty Ltd
Priority to AU2003240299A priority Critical patent/AU2003240299B2/en
Priority to JP2004514438A priority patent/JP2005534670A/ja
Priority to EP03729714A priority patent/EP1531867A4/fr
Priority to NZ537436A priority patent/NZ537436A/en
Priority to EA200500083A priority patent/EA012648B1/ru
Priority to BR0312003-1A priority patent/BR0312003A/pt
Priority to CA002490057A priority patent/CA2490057A1/fr
Publication of WO2004000361A1 publication Critical patent/WO2004000361A1/fr
Priority to US11/019,542 priority patent/US20050181032A1/en

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    • 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
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • 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
    • 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
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
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    • 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
    • A61K9/7015—Drug-containing film-forming compositions, e.g. spray-on
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    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
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    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones

Definitions

  • the present invention relates to compositions for the transdermal delivery of physiologically active agents, to uses of those compositions, and to methods for the transdermal delivery of physiologically active agents.
  • transdermal drug delivery has received increased attention because it not only provides a relatively simple dosage regime but it also provides a relatively slow and controlled route for release of a physiologically active agent into the systemic circulation.
  • transdermal drug delivery is complicated by the fact that the skin behaves as a natural barrier and therefore transport of agents through the skin is a complex mechanism.
  • the skin consists of two principle parts, a relatively thin outermost layer (the 'epidermis') and a thicker inner region (the 'dermis').
  • the outermost layer of the epidermis (the 'stratum corneum') consists of flattened dead cells which are filled with keratin.
  • the region between the flattened dead cells of the stratum corneum is filled with lipids which form lamellar phases that are responsible for the natural barrier properties of the skin.
  • the agent For effective transdermal delivery of a physiologically active agent that is applied to the surface of the skin ('topical application'), the agent must be partitioned firstly from the vehicle into the stratum corneum, it must typically then be diffused within the stratum corneum before being partitioned from the stratum corneum to the viable epidermis and dermis and then into the bloodstream.
  • the physiologically active agent to be present as a saturated solution or mass.
  • physiologically active agents are commonly formulated with incorporation of one or more drug penetration enhancers.
  • aqueous ethanol is commonly used as a vehicle in formulations for topical application and it is known that ethanol can act as a penetration enhancer that can increase the flux of an active agent across the skin due to a solvent drag effect (Berner et al., 1989, J. Pharm. Sci, 78(5), 402-406.
  • Penetration enhancers are known to cause skin irritation in some individuals.
  • ethanol is unlikely to act as a penetration enhancer since, due to the small quantity applied to the skin, the ethanol acts as an intermediary solvent which spreads the drug and enhancer over the skin. Since the drying time of the compositions in question is less than 2 minutes, and in vitro weight loss measurements have previously confirmed that the ethanol evaporates off pig skin with a surface temperature of 32 °C within 1 minute all that remains is the drug. The short exposure time, less than 2 minutes, of ethanol or similar lipid extracting solvents to the skin is unlikely to alter the barrier function of the skin (Abrams et al., 1993, J. Invest. Dermatol, 101 , 609-613).
  • U.S. Patent Number 6444234 combines particular solvents and solute modifiers with skin stabilisers in a transdermal delivery system to form a true solution and thus minimizing irritation to the skin.
  • US Patent Number 6299900 describes the non-occlusive delivery of a physiologically active agent across the skin however, this composition relies on a penetration enhancer to achieve an increased flux.
  • Compositions formulated without the use of a penetration enhancer are generally not effective enough to deliver significant amounts of the physiological active through the skin.
  • Compositions containing alcohol and acetone vehicles have been used for topical delivery of antibiotics, as seen in U.S. Patent Number 6017912, which describes the use of fluoroquinolone in the topical treatment of skin infections and inflammatory conditions.
  • such compositions have inherently low permeabilities of the physiological active.
  • the physiological active In order to overcome the low permeability, the physiological active must have a maximised thermodynamic activity.
  • U.S. Patent Number 6528094 the use of stable shaped particles is particularly well-suited to the fabrication of pharmaceutical formulations, particularly where sustained release and uniform bioavailability are desired. It has been shown that to achieve high permeation rates across the skin, the concentrations of the drug dissolved may need to be high such that it possesses a high tendency to crystallise. As a result transdermal patches are often thermodynamically unstable because the drug shows a tendency to recrystallise during storage (Xinghang et al., 1996, Int. J. Pharm., 142(1), 115-119 and Latsch et al., 2003, Eur. J. Pharm. & Biopharm., In Press, Corrected Proof).
  • the present invention arises from the inventor's studies of volatile sprays and aerosols and in particular from the realisation that, for finite dose formulations, appreciable enhancement of percutaneous absorption can be attained from the in situ formation of a metastable deposit within the skin using a volatile vehicle, such as a spray or aerosol.
  • the present invention arises, at least in part, from the realisation that an increase in the percutaneous absorption of the physiologically active agent may be achieved by the deliberate formation of a metastable drug in situ that has a lower melting point than would be otherwise achieved from the range of crystalline polymorph(s) routinely supplied by the commercial manufacturer. This reduction in melting point translates to an increase in the diffusion of the drug across the epidermis and dermis and into the bloodstream.
  • the present inventor's have found that some combinations of physiologically active agent and volatile solvent form a metastable solid in situ when they are applied topically.
  • the present invention provides a composition including: - one or more physiologically active agents; and - a volatile pharmaceutically acceptable solvent wherein the physiologically active agent forms a metastable deposit upon evaporation of the volatile solvent.
  • the lower melting point metastable deposit arises, at least in part, from either a metastable pseudopolymorph such as an alcohol solvate, a metastable polymorph, a metastable amorphous solid, or a mixture of these.
  • the reduction in melting point (at atmospheric pressure) provided by the metastable deposit will be in the range of from 1 to 50 e C and preferably from 2 to 30 Q C.
  • the metastable deposit is readily partitioned into the skin upon evaporation of the volatile solvent and rapidly diffuses across the stratum corneum.
  • the formation of the higher melting point crystalline deposits in the skin leads to a higher propensity toward skin irritation and a decrease in percutaneous absorption efficiency (due to the need for greater energy to dissolve the crystal prior to diffusional transport).
  • the metastable deposit also has excellent skin feel and touch when in some instances it may be desirable to rub the metastable deposit into the skin of a human.
  • the composition of the invention is essentially free of penetration enhancers.
  • Penetration enhancers have the effect of increasing skin permeability by reversibly damaging or altering the physiochemical nature of the stratum corneum to reduce its diffusion resistance.
  • Penetration enhancers are generally lipophilic, non-volatile compounds with a molecular weight greater than 100 and a vapour pressure below 10mm Hg at atmospheric pressure and normal skin temperature of 32 S C.
  • the composition of the invention may also provide lower irritancy than some other delivery systems such as benzyl alcohol sprays, because the irritating penetration enhancer is removed.
  • the composition of the present invention may avoid problems with crystallisation and/or supersaturation that are encountered with storage of existing type transdermal patches because the pharmaceutical compositions of this invention exist as stable, single phase solutions and hence have no crystalline nature (or polymorphic memory) during their pharmaceutical shelf life.
  • Another advantage of the present invention is the rapid partitioning into the skin from these in-situ forming metastable compositions which means the skin can act as a natural crystalline inhibitor for the physiologically active agent, further improving the stability of the metastable deposit within the skin.
  • the present invention also provides a method of delivering a metastable drug formulation to a host, the method including the steps of applying a topical spray composition containing one or more physiologically active agents, and a volatile pharmaceutically acceptable solvent to the skin of the host so that the volatile solvent evaporates to form a metastable deposit containing the active agent.
  • the present invention further provides a composition for spray application to the skin of a subject for transdermal administration of a physiologically active agent, the composition comprising: (i) a physiologically active agent;
  • a propellant preferably a fluoro hydrocarbon
  • composition when applied to the skin as a spray forms a metastable deposit in the skin of the subject.
  • the invention also provides a spray device for transdermal administration of a physiologically active agent comprising a chamber for maintaining the composition under pressure, a mixture contained within the chamber comprising the physiologically active agent, a pharmaceutically acceptable solvent which is volatile when applied to skin and a propellant which is preferably maintained at least partially in liquid form under pressure within the chamber and valve means for providing delivery of the mixture and wherein the mixture provides a metastable deposit of physiologically active agent on the skin.
  • the propellant is preferably a hydrofluorocarbon such as HFC-134a or HFC-227. HFC-134a is the most preferred propellant.
  • the hydrofluorocarbon propellant is preferably from 15 to 50% by volume of the total pharmaceutical composition and more preferably from 20 to 40% by volume of the total composition.
  • the invention further provides the use of an active agent for manufacture of a medicament for treatment or prophylaxis disease in a subject wherein the composition includes a physiologically active agent and a volatile carrier and is topically applied to the skin of the subject for transdermal administration wherein the volatile solvent evaporates to form a metastable deposit containing the active agent.
  • metastable composition avoids the disadvantage of spray nozzle blockage seen with existing film-forming sprays or aerosols.
  • the invention also provides a composition as described above contained in a chamber wherein the propellent is HFC-134a.
  • the volatile solvent and active will preferably provide a single phase solution of the active.
  • amorphous means substantially non-crystalline. It will be appreciated that, unless specified otherwise, the term amorphous includes within its scope a phase that does display some crystallinity.
  • physiologically active agent and volatile solvent of the present invention is limited functionally to those that together form a metastable deposit with a melting point lower than that seen from the range of crystalline polymorph(s) routinely supplied by the commercial manufacturer or obtained from crystallisation from methanol or chloroform.
  • active agent is relatively non-volatile relative to the volatile solvent so that upon application of the composition to the skin of the host, only the volatile solvent evaporates at physiological temperatures.
  • the physiologically active agent may selected from a range of potent, lipophilc, physiologically active agents with a molecular weight less than 600 Daltons and a melting point less than 200°C with the list including apomorphine, fentanyl, ropinirole, rivastigmine, buspirone, rizatriptan, anticholinergics such as oxybutynin, tolterodine and darifenacin, testosterone, MENT (7-methyl-19-testosterone), ethyinyl estradiol, or an pharmaceutically acceptable salt or derivative of any one of the aforementioned.
  • physiologically active agent may selected from a range of potent, lipophilc, physiologically active agents with a molecular weight less than 600 Daltons and a melting point less than 200°C with the list including apomorphine, fentanyl, ropinirole, rivastigmine, buspirone, rizatriptan, anticholinergics such as oxybutynin
  • the drug and solvent generally have the ability to intimately mix, such that the solvent will interact with the crystal face of the drug. Therefore, the drug will typically have a saturated solubility in the solvent of greater than or equal to 0.05% w/w, more preferably greater than or equal to 0.1% w/w.
  • the volatile solvent has a vapour pressure is above 35mm Hg at atmospheric pressure and normal skin temperature of 32°C.
  • the volatile solvent will preferably comprise a lower alcohol. More preferably the volatile solvent will comprise at least 60% by weight of the total volatile solvent component of lower alcohol.
  • the volatile solvent component will consist essentially of one or more lower alcohols.
  • the preferred lower alcohols are ethanol, isopropanol and mixture thereof.
  • the composition is a topical spray composition that contains the physiologically active agent and the volatile solvent and the method includes the step of spraying the composition onto the skin of the host to form the metastable deposit containing the physiologically active substance.
  • the metastable deposit is preferably formed in the epidermis of the host.
  • Figure 1 shows a plot of the cumulative amount of drug penetrating across the skin from the metastable composition compared to a saturated solution of drug.
  • Figure 2 gives an example of base DSC profiles before and after evaporation from ethanol.
  • Figure 3 shows a plot of the melting point of each model drug, before and after evaporation from a volatile solvent after a time period of 24 hours.
  • Figure 4 shows a plot of the diffusion profile for fentanyl through human epidermis, after evaporation from ethanol and isopropyl alcohol.
  • a benefit of the present invention is that the composition is stable, which means that it is not prone to supersaturation or crystallisation during its pharmaceutical shelf life. This may be contrasted with transdermal patches in which crystallisation of the active agent has presented a problem in the past.
  • the composition of the present invention can be held in a primary container during the shelf life without encountering shelf-life problems of the prior art transdermal patches.
  • composition of the present invention may contain from about 0.1% to about 10% of the physiologically active agent, and from about 85% to about 99.8% of the volatile solvent.
  • the vehicle may have additional pharmaceutical excipients, for example gelling agents, such as CARBOPOL and cellulose derivatives.
  • gelling agents such as CARBOPOL and cellulose derivatives.
  • the formation of a metastable deposit of drug within the stratum corneum can be expected to increase the penetration of a drug across the skin relative to a saturated solution of a drug or a simple dispersion of the solid drug on the surface of the skin as shown in figure 1 (levels not detected).
  • the active agents chosen represent a diverse range of physicochemical properties as shown in the following table:
  • the pans were maintained at ambient temperature and 33% relative humidity for 24 hours. After this time the pans were covered and hermetically sealed. DSC was then performed under a stream of nitrogen and at 10 Q C/minute and within a temperature range that depended on the drug.
  • the choice of solvent used in a composition can be selected on the basis of the desired transdermal delivery profile as measured by percutaneous penetration
  • Ethanol Acetone or lPA or Chloroform 60-90 : 10-40; or a mixture thereof.
  • Fentanyl diffusion profile through human epidermis, demonstrates a change in delivery profile which is solvent dependent (Figure 5).
  • fentanyl After evaporation from ethanol, fentanyl showed a sigmoidal, first order diffusion profile indicating that the initial burst across the skin is limited.
  • fentanyl shows a zero order release rate profile. Therefore, the leaving tendency may be modified to suit the desired delivery rate by altering the volatile solvent vehicle.

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Abstract

La présente invention concerne une composition pharmaceutique pour administration transdermique. Cette composition contient un ou plusieurs agents physiologiquement actifs et un solvant volatil pharmaceutiquement acceptable, ledit agent physiologiquement actif formant un dépôt métastable lors de l'évaporation dudit solvant volatil.
PCT/AU2003/000785 2002-06-25 2003-06-24 Compositions pharmaceutiques metastables WO2004000361A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
AU2003240299A AU2003240299B2 (en) 2002-06-25 2003-06-24 Metastable pharmaceutical compositions
JP2004514438A JP2005534670A (ja) 2002-06-25 2003-06-24 準安定性医薬組成物
EP03729714A EP1531867A4 (fr) 2002-06-25 2003-06-24 Compositions pharmaceutiques metastables
NZ537436A NZ537436A (en) 2002-06-25 2003-06-24 Metastable pharmaceutical compositions
EA200500083A EA012648B1 (ru) 2002-06-25 2003-06-24 Фармацевтическая композиция для чрескожной доставки активного агента (варианты)
BR0312003-1A BR0312003A (pt) 2002-06-25 2003-06-24 Composições farmacêuticas metaestáveis para distribuição transdérmica e seus usos
CA002490057A CA2490057A1 (fr) 2002-06-25 2003-06-24 Compositions pharmaceutiques metastables
US11/019,542 US20050181032A1 (en) 2002-06-25 2004-12-23 Metastable pharmaceutical compositions

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AUPS3173 2002-06-25
AUPS3173A AUPS317302A0 (en) 2002-06-25 2002-06-25 Metastable pharmaceutical compositions

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EP (1) EP1531867A4 (fr)
JP (2) JP2005534670A (fr)
KR (1) KR20050120726A (fr)
AU (1) AUPS317302A0 (fr)
BR (1) BR0312003A (fr)
CA (1) CA2490057A1 (fr)
EA (1) EA012648B1 (fr)
NZ (1) NZ537436A (fr)
WO (1) WO2004000361A1 (fr)

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Publication number Priority date Publication date Assignee Title
CA2830519A1 (fr) * 2011-03-22 2012-09-27 The Population Council, Inc. Renegeration de myeline par des androgenes

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WO1997029735A1 (fr) * 1996-02-19 1997-08-21 Monash University Promoteurs de penetration dermique et systeme d'administration de medicaments comprenant ces promoteurs
WO1999020257A1 (fr) * 1997-10-16 1999-04-29 Macrochem Corporation Formulations de medicaments destines au traitement hormonal substitutif pour application cutanee locale
WO2000045795A2 (fr) * 1999-02-05 2000-08-10 Cipla Limited Sprays topiques
WO2002017927A1 (fr) * 2000-08-30 2002-03-07 Unimed Pharmaceuticals, Inc. Methode pour traiter la dyserection et augmenter la libido chez l'homme
WO2002017967A1 (fr) * 2000-08-30 2002-03-07 Unimed Pharmaceuticals, Inc. Procede pour augmenter la concentration de testosterone et de steroides apparentes chez la femme

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EP0581587A2 (fr) * 1992-07-31 1994-02-02 Tanabe Seiyaku Co., Ltd. Base pour l'administration percutanée
WO1997029735A1 (fr) * 1996-02-19 1997-08-21 Monash University Promoteurs de penetration dermique et systeme d'administration de medicaments comprenant ces promoteurs
WO1999020257A1 (fr) * 1997-10-16 1999-04-29 Macrochem Corporation Formulations de medicaments destines au traitement hormonal substitutif pour application cutanee locale
WO2000045795A2 (fr) * 1999-02-05 2000-08-10 Cipla Limited Sprays topiques
WO2002017927A1 (fr) * 2000-08-30 2002-03-07 Unimed Pharmaceuticals, Inc. Methode pour traiter la dyserection et augmenter la libido chez l'homme
WO2002017967A1 (fr) * 2000-08-30 2002-03-07 Unimed Pharmaceuticals, Inc. Procede pour augmenter la concentration de testosterone et de steroides apparentes chez la femme

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EA200500083A1 (ru) 2005-08-25
JP2010248250A (ja) 2010-11-04
CA2490057A1 (fr) 2003-12-31
EP1531867A4 (fr) 2011-03-23
AUPS317302A0 (en) 2002-07-18
NZ537436A (en) 2007-01-26
BR0312003A (pt) 2005-03-22
EP1531867A1 (fr) 2005-05-25
EA012648B1 (ru) 2009-12-30
JP2005534670A (ja) 2005-11-17
KR20050120726A (ko) 2005-12-23

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