+

WO1997040792A1 - Administration transdermique d'hormones steroidiennes au moyen de diethanolamides d'acides gras c12-c18 utilises comme activateurs de l'infiltration - Google Patents

Administration transdermique d'hormones steroidiennes au moyen de diethanolamides d'acides gras c12-c18 utilises comme activateurs de l'infiltration Download PDF

Info

Publication number
WO1997040792A1
WO1997040792A1 PCT/US1997/007104 US9707104W WO9740792A1 WO 1997040792 A1 WO1997040792 A1 WO 1997040792A1 US 9707104 W US9707104 W US 9707104W WO 9740792 A1 WO9740792 A1 WO 9740792A1
Authority
WO
WIPO (PCT)
Prior art keywords
matrix
skin
steroid hormone
testosterone
enhancer
Prior art date
Application number
PCT/US1997/007104
Other languages
English (en)
Inventor
Venkateshwaran Srinivasan
Charles D. Ebert
Original Assignee
Theratech, Inc.
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 Theratech, Inc. filed Critical Theratech, Inc.
Priority to AU27463/97A priority Critical patent/AU2746397A/en
Publication of WO1997040792A1 publication Critical patent/WO1997040792A1/fr

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
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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

Definitions

  • the present invention is in the field of transdermal/transmucosal drug delivery. More particularly it concerns the use of dialkanolamides of fatty acids to enhance the transdermal administration of steroid hormones from a pressure sensitive adhesive matrix.
  • Steroid hormones such as progestins, estrogens, and androgens have poor skin permeability. Therefore, in order to administer steroids transdermally or transmucosally at therapeutically effective rates through a reasonably sized area of skin or mucosa, it is necessary to use permeation enhancers in combination with the steroid.
  • U.S. Patent Nos. 5,164,190 and 5,152,997 describe the use of a combination of subsaturation concentration and permeation enhancers to increase the flux of steroid drugs across skin.
  • the exemplified enhancers include glycerol dioleate, glycerol monooleate, methyl laurate, oleic acid, and ethanol.
  • U.S. Patent Nos. 4,906,169 and 5,023,084 describe laminated composites for coadministering an estrogen and progestin transdermally.
  • the estrogen is contained in a polymer layer and the progestin is contained in an underlying adhesive layer.
  • Polyacrylic, polyisobutylene and silicone adhesives are mentioned.
  • These patents also teach that a permeation enhancer can be included in the adhesive.
  • "Saturated and unsaturated fatty acids and their esters, alcohols, monoglycerides, acetate, diethanolamides and N,N- dimethylamides . . .” are mentioned as enhancers.
  • N-Decyl alcohol and capric acid are taught as preferred enhancers.
  • 4,818,540 and 5,296,230 also describe laminated composites for administering estrogens or progestins transdermally.
  • the steroid is contained in a polymer layer.
  • An adhesive layer underlies the polymer layer for affixing the composite to the skin.
  • the patent teaches that the adhesive layer may contain permeation enhancers. The same enhancers that are taught in the ' 169 and '084 patents discussed above are also described in these patents.
  • U.S. Patent No. 5,314,694 discloses transdermal delivery devices but not a matrix type as disclosed herein where the drug and permeation enhancer is dissolved or dispersed in an adhesive which also serves to also affix the patch to the skin.
  • the devices disclosed in U.S. Patent No. 5,314,694 are typical reservoir type patches containing the drug and/or enhancer in a reservoir and a separate adhesive layer affixes the reservoir is referred to the skin.
  • the disclosure does not teach that a diethanolamide of a C[ 2 -C ]8 fatty acid is uniquely effective in enhancing the permeability of steroid hormones in a pressure sensitive adhesive matrix.
  • PCT Publication WO 94/21262 describes the use of diethanolamides of fatty acids as permeation enhancers in combination with alprazolam. The diethanolamide and alprazolam are formulated in a nonadhesive polymeric reservoir.
  • U.S. Patent No. 5,252,334 teaches away from the use of permeation enhancers for the transdermal delivery of steroids. Even though various enhancers have been used previously to increase the rate at which steroids permeate through skin, there is still a need to find enhancers that permit even higher rates to be achieved. Better enhancers may allow the steroids, particularly testosterone, to be formulated in simple single matrix patches of relatively small size. This will enable less expensive patches that are more cosmetically acceptable.
  • one aspect of the invention is a method of enhancing the transdermal administration of a steroid hormone from a pressure sensitive adhesive matrix comprising coadministering a diethanolamide of a C 12 -C I g fatty acid from said matrix.
  • Another aspect of this invention is the use of a highly pure composition of lauramide DEA for enhancing the transdermal administration of a steroid hormone from a pressure sensitive adhesive matrix.
  • Another aspect of the invention is a matrix for administering a steroid hormone transdermally comprising a mixture of: a) a pressure sensitive adhesive; b) a steroid hormone; and c) a diethanolamide of a C 12 -C J 8 fatty acid.
  • transdermal patch for administering a steroid hormone comprising a laminated composite of: a) a backing layer; and b) a matrix layer adapted to be placed in diffusional contact with skin or mucosa comprising a mixture of:
  • transdermal intends percutaneous and transmucosal (e.g. transbuccal) administration, i.e., passage of steroid through unbroken skin or mucosa into circulation.
  • Structurally "steroids” are the class of compounds all related through the cyclic nuclei they contain, i.e., a partly or completely hydrogenated 17 H- cyclopentanophenanthrene nucleus, the general formula for which is given below:
  • Steroid hormones can be natural, synthetic or semi-synthetic and can be classified according to their biological function as:
  • Progestagens examples of which are (without limitation) progesterone, norethindrone acetate, norgestrel, levo-norgestrel, norethindrone, desogestrel, and gestodene.
  • Glucocorticoids examples of which are (without limitation) corticol, corticone, hydrocortisone, betamethasone, dexamethasone, prednisone, predisolone and triamcinolone.
  • Mineralocorticoids examples of which are (without limitation) aldosterone and desoxycorticosterone.
  • Estrogens examples of which are (without limitation) 17 ⁇ estradiol and ethynyl estradiol.
  • Androgens examples of which are (without limitation) testosterone, methyl testosterone, dihydrotestosterone and androsteinedione.
  • Cardiac glycosides examples of which are (without limitation) digoxin and digitoxin.
  • a combination of steroid hormones may be administered.
  • combination of an estrogen and a progestagen or an estrogen and an androgen e.g., estradiol and testosterone
  • an estrogen and an androgen e.g., estradiol and testosterone
  • a “therapeutically effective amount” of steroid intends an amount that provides the desired pharmacological result. These amounts are known by those skilled in the art. For instance, in the case of administering testosterone to males, the therapeutically effective amount will typically be about 1 to 10 mg/day.
  • permeation enhancement and “enhancement , ' are used interchangeably and describe an increase in the permeability of skin or mucosa to a steroid hormone. Permeation enhancement results in an increase in the flux of steroid through skin or mucosa. Skin flux may be measured in vitro using the procedure described in the examples, infra. A "skin/mucosa permeation enhancing amount" of diethanolamide of a
  • C 12 -C lg fatty acid is intended to mean an amount that results in steroid flux increase of at least about 15%, more usually 30% to 300% relative to steroid flux in the absence of an enhancer.
  • diffusional contact means that the matrix is either directly or indirectly in contact with the skin or mucosa in a manner in which there is a diffusional pathway by which the steroid(s) can migrate from the matrix to the skin or mucosa.
  • the adhesive component of this invention are referred to as "matrix patches" containing for example a hydrocarbon solvent-compatible polyacrylate or a hydrocarbon solvent compatible adhesive.
  • the adhesive reservoir or matrix can be a pressure-sensitive adhesive such as polyisobutylene, silicone, polyacrylate or other pressure sensitive adhesive acceptable for use as a matrix for a transdermal patch.
  • the adhesive component of the matrix is preferably a hydrocarbon solvent-compatible polyacrylate, particularly a copolymer of 2-ethylhexyl acrylate and one or more other monomers such as vinyl acetate, acrylic acid, N-vinyl-2-pyrrolidone, 2-hydroxyethyl acrylate, butylacrylate, octylacrylate, styrene, methyl methacrylate, methacrylic acid, maleic acid, acrylamide and N-methylol acrylamide.
  • Embodiments of such adhesives are available commercially from a number of sources, e.g.
  • the diethanolamides that are employed as permeation enhancers in the invention are diethanolamides of C ] 2 -C ] g fatty acids.
  • the fatty acid may be saturated or unsaturated and preferably has an even number of carbon atoms.
  • Examples that are useful in the invention are the diethanolamides of lauric, tridecylic, myristic, pentadecylic, palmitic, stearic, palmitoleic, oleic and linoleic acids. A mixture of such diethanolamides may be used. Lauramide diethanol ("lauramide
  • the diethanolamide component of the matrix will typically constitute 0.5% to 50% of the matrix, preferably 2.5% to 15%. Percentage of the components of the matrix are expressed on a dry weight basis. It has been found that commercially available lauramide DEA have verying degrees of purity. Substantially pure compositions of lauramide DEA are preferred. As used herein, “substantially pure” is defined as having a greater than about 75% lauramide DEA in the composition wherein "%" refers to area percent as determined by HPLC according to Example 9, infra.. More preferred is a composition containing greater than about 85% lauramide DEA and most preferred is greater than about 90% lauramide DEA.
  • the steroid will normally constitute 0.1% to 30%, preferably 0.5% to 10% of the matrix.
  • the matrix may be formulated by mixing the adhesive (which is typically obtained in solution), steroid(s), and diethanolamide in the appropriate proportions, casting the solution onto a substrate (e.g., a backing or release liner layer) and drying the cast layer of solution to drive off the solvent.
  • the backing layer will typically comprise an occlusive polymer layer, combination of polymer layers, or combination of polymeric and metallic layers. Backing materials are well known in the transdermal patch art.
  • the transdermal patches of this invention will also include a release liner layer.
  • Release liner materials are also well known in the transdermal patch art.
  • Pressure sensitive polyacrylate adhesive matrix systems containing steroids and in some cases additional components were prepared from acrylate copolymer solutions in organic solvents as follows. First, the solid content of the adhesive solution was determined by placing a known weight of solution in a weighed aluminum dish and evaporating the solvents overnight in a 70°C convection oven. The solid adhesive content of the solution was calculated by dividing the adhesive solid weight after drying by the total solution weight. Second, a weighed quantity of adhesive solution was added to a glass bottle and the solid adhesive weight was calculated from the known solid fraction of the given adhesive solution. Steroid compounds and enhancers were weighed and mixed with the adhesive solution in the quantities necessary to achieve the desired dry matrix composition. The solution containing the adhesive copolymer and other components was mixed (usually overnight).
  • the diffusion cell was placed in a temperature controlled circulating water bath calibrated to maintain the surface temperature of the skin at 32 °C.
  • the receiver compartment was constantly stirred by a magnetic stir-bar in the receiver compartment agitated by a magnetic stirring module placed under the water bath. At predetermined sampling intervals (usually 6, 12, and 24 hours), the entire contents of the receiver compartment were collected for drug quantitation and the receiver compartment was filled with fresh receiver solution, taking care to eliminate any air bubbles at the skin/solution interface.
  • C t ( ⁇ g/cm 3 ) is the concentration of the receiver compartment at sample time t (h)
  • V is the volume of the receiver compartment of the diffusion cell (6.3 cm 3 )
  • A is the diffusional area of the cell (0.64 cm 2 ).
  • Testosterone is a naturally occurring steroid hormone which is administered transdermally for treatment of primary or secondary hypogonadism in males.
  • Pressure sensitive adhesive matrix systems containing testosterone and lauramide diethanol (DEA) as an enhancer were compared to systems using lauric acid, lauryl alcohol, glycolic acid, and esters of lauric acid. All matrix systems were prepared in a medical-grade acrylic adhesive (Duro-Tak 87-2516) according to the methods described above and contained 3% by weight testosterone and 10% by weight enhancer. The results of skin flux experiments using these matrix systems are summarized in Tables 1-3.
  • composition Duro-Tak 2516/Testosterone/Enhancer % (w/w)
  • fatty acid diethanolamide is unexpectedly superior at enhancing transdermal permeation of testosterone in a matrix system relative to ⁇ -hydroxy acids, fatty acids, fatty alcohols, fatty acid alkyl esters, fatty alcohol PCA esters, fatty acid monoglycerides, and fatty acid sorbitol esters— all of which are known in the art as transdermal permeation enhancers.
  • Testosterone flux from matrix systems and hydroalcoholic gel systems was evaluated using Lauramide DEA and the methyl ester of lauric acid as enhancers.
  • Hydroalcoholic solutions of 50 mg/ml testosterone in 50% by volume alcohol, USP (190 proof ethanol), 15% water, 30% glycerin, and 5% enhancer were prepared and mixed until the drug was fully dissolved.
  • the solution was then gelled with 3% (w/w) carbomer (Pemulen TR-2) which was neutralized with 0.2 N sodium hydroxide to a pH of 4 to 5.
  • the resulting gels were clear and visually homogeneous.
  • Skin flux experiments for the hydroalcoholic gels were similar to those conducted with the adhesive matrix systems with the following exceptions.
  • the epidermal membrane Prior to skin permeation experiments, the epidermal membrane was cut to an appropriate size and placed between the two halves of the diffusion cell with the stratum corneum facing the donor compartment.
  • the receiver compartment was filled with 0.02% (w/v) sodium azide in water, and the diffusion cell was placed in a circulating water bath calibrated to maintain the temperature of the skin surface at 32°C, and allowed to hydrate overnight. After hydration, the sodium azide solution in the receiver compartment was removed and replaced with an appropriate solution to maintain sink conditions for testosterone through the duration of the experiment (0.02% (w/v) sodium azide and 0.5% (w/v) Tween 40 in water).
  • Adhesive matrices containing 3% by weight testosterone and 10% by weight enhancer were prepared in Duro-Tak 87-2516 as described previously. Skin flux experiments using the matrix systems on the same skin sources as those shown in Table 5 were conducted and the results from these experiments are shown in Table 6.
  • Norethindrone acetate is a female progestin steroid hormone.
  • Adhesive matrix systems containing NEA and NEA with Lauramide DEA (Cyclomide® LE), sorbitan monolaurate (Arlacel® 20), or sorbitan monooleate (Arlacel® 80) as an enhancer were prepared as described above.
  • the matrix systems consisted of 10% by weight NEA and 0 or 15% of the enhancer in Duro-Tak 80-1 194 or Duro-Tak 80-1054. The results of in vitro skin flux experiments on these matrix systems are summarized in Table 7 and Table 8.
  • Estradiol is a naturally occurring female steroid hormone which is administered transdermally for female hormone replacement therapy
  • Adhesive matrix systems containing estradiol and estradiol with lauramide DEA (Cyclomide® LE), sorbitan monolaurate (Arlacel® 20), or sorbitan monooleate (Arlacel® 80) as an enhancer were prepared as described above
  • the matrix systems consisted of 4% by weight estradiol and 0 to 15% of the enhancer in a medical grade acrylic copolymer adhesive (Duro-Tak 80- 1194 or 80- 1070)
  • Tables 9-11 The results of in vitro skin flux experiments on these matrix systems are summarized in Tables 9-11.
  • Example 5 The effect of fatty acid diethanolamides differing in the fatty acid group were evaluated in matrix systems containing various steroids.
  • the fatty acid diethanolamides used as enhancers were lauramide DEA (Cyclomide ® DEA), stearamide DEA
  • Cocamide DEA is derived from coconut oil and contains palmitamide DEA.
  • the systems consisted of 4% by weight estradiol or 3% by weight testosterone and 0 to 15% of the enhancer in Duro-Tak 87-2516 or Duro-Tak 80-1194.
  • Tables 12 and 13 The results of in vitro skin flux experiments on these matrix systems are summarized in Tables 12 and 13.
  • Example 6 Transdermal flux enhancement of steroids using fatty acid diethanolamide was compared to flux enhancement using triethanolamine.
  • Adhesive matrices containing 3% by weight testosterone as a model steroid and 5% by weight lauramide DEA or triethanolamine were prepared in Duro-Tak 87-2516, and the results of in vitro skin flux experiments using these matrices are shown in Table 14. Table 14
  • Example 7 Transdermal flux enhancement of testosterone and estradiol from a matrix system was evaluated using fatty acid amides with differing amine components.
  • Adhesive matrices containing 3% by weight testosterone or 1.5% by weight estradiol were prepared in an acrylic copolymer adhesive (Duro-Tak 87-2516, or 80-1070).
  • the fatty acid amides tested were lauramide DEA (Alkamide® LE), cocamide MEA (Alkamide® CME), lauramide MEA (Alkamide® L-203), lauramide MIA (Alkamide® LIPA/C), lauric acid
  • Transdermal flux enhancement of non-steroidal compounds, oxybutynin and diclofenac, from a matrix system was evaluated using Lauramide DEA and several other known permeation enhancers.
  • Adhesive matrices containing oxybutinin or diclofenac were prepared in an acrylic copolymer adhesive (Seksui TSR).
  • the matrices contained 10% (w/w) of one of the following enhancers lauramide DEA (Alkamide ® LE), glycerol monolaurate , lauric acid methyl ester, or lauryl alcohol. Results from in vitro flux experiments on these matrix systems are summarized in Tables 18 and 19.
  • Oxybutynin permeation from the system containing Lauramide DEA is lower than the permeation from systems containing glycerol monolaurate, methyl laurate, or lauryl alcohol as enhancers.
  • Diclofenac permeation from the system containing lauramide DEA is similar to or lower than the permeation from systems containing glycerol monolaurate methyl laurate, or lauryl alcohol as enhancers. These results are further evidence that the unusual transdermal flux enhancement of alkanoic acid diethanolamides is specific to steroidal compounds.
  • compositions containing highly pure formulations of lauramide DEA unexpectedly enhances the transdermal flux of drugs, including steroids.
  • Table 20 lists the commercially available lauramide DEA formulations that were evaluated for purity.
  • Table 21 shows the results of HPLC analysis of the above noted commercially available lauramide DEA formulations.
  • the mobile phase of the column was a 40:60 (v:v) wate ⁇ acetonitrile solution.
  • Transdermal flux enhancement of testosterone from a matrix system was evaluated using lauramide DEA of low purity (Alkamide LE (Rhone-Poulenc)) and high purity (Prophan (Sanyo Kasei)).
  • Adhesive matrices containing 6% by weight testosterone and 7.5% lauramide DEA were prepared in an acrylic copolymer adhesive 86.5% (TSR Adhesive). Table 22 reports the results of invitro skin flux experiments on these matrices.
  • Testosterone permeation from the systems containing greater than 85% pure lauramide DEA is, in most instances, greater than permeation from systems containing less pure (i.e., less than 75%) lauramide DEA.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des timbres transdermiques de type matrice destinés à administrer des stéroïdes. Ces timbres comprennent une matrice d'une ou plusieurs hormones stéroïdiennes contenant un adhésif sensible à la pression et un diéthanolamide d'un acide gras C12-C18 utilisé comme activateur de l'infiltration. Ces diéthanolamides présentent des qualités surprenantes d'infiltration si on les compare aux activateurs connus utilisés dans ces timbres.
PCT/US1997/007104 1996-04-30 1997-04-29 Administration transdermique d'hormones steroidiennes au moyen de diethanolamides d'acides gras c12-c18 utilises comme activateurs de l'infiltration WO1997040792A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU27463/97A AU2746397A (en) 1996-04-30 1997-04-29 Transdermal administration of steroid hormones using diethanolamides of c12-c18 fatty acids as permeation enhancers

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US64037196A 1996-04-30 1996-04-30
US08/640,371 1996-04-30

Publications (1)

Publication Number Publication Date
WO1997040792A1 true WO1997040792A1 (fr) 1997-11-06

Family

ID=24567978

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/007104 WO1997040792A1 (fr) 1996-04-30 1997-04-29 Administration transdermique d'hormones steroidiennes au moyen de diethanolamides d'acides gras c12-c18 utilises comme activateurs de l'infiltration

Country Status (3)

Country Link
AU (1) AU2746397A (fr)
WO (1) WO1997040792A1 (fr)
ZA (1) ZA973749B (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7242935B2 (en) 1998-02-13 2007-07-10 Qualcomm Incorporated Method and system for performing a handoff in a wireless communication system, such as a hard handoff
US7245597B2 (en) 1999-08-11 2007-07-17 Qualcomm Incorporated Method and system for performing handoff in wireless communication systems
WO2008154240A1 (fr) * 2007-06-06 2008-12-18 Biohealth Llc Composition pharmaceutique d'un nouveau système destiné à la libération de stéroïdes dans le vagin
US7664209B2 (en) 1998-05-21 2010-02-16 Qualcomm Incorporated Method and apparatus for coordinating transmission of short messages with hard handoff searches in a wireless communications system
US8964692B2 (en) 2008-11-10 2015-02-24 Qualcomm Incorporated Spectrum sensing of bluetooth using a sequence of energy detection measurements
US9125816B2 (en) 2000-08-30 2015-09-08 Besins Healthcare Inc. Pharmaceutical composition and method for treating hypogonadism

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4906475A (en) * 1988-02-16 1990-03-06 Paco Pharmaceutical Services Estradiol transdermal delivery system
US5252334A (en) * 1989-09-08 1993-10-12 Cygnus Therapeutic Systems Solid matrix system for transdermal drug delivery
US5314694A (en) * 1990-10-29 1994-05-24 Alza Corporation Transdermal formulations, methods and devices
US5362497A (en) * 1989-05-25 1994-11-08 Takeda Chemical Industries, Ltd. Transdermal therapeutic composition
US5460820A (en) * 1993-08-03 1995-10-24 Theratech, Inc. Methods for providing testosterone and optionally estrogen replacement therapy to women
US5554381A (en) * 1993-08-09 1996-09-10 Cygnus, Inc. Low flux matrix system for delivering potent drugs transdermally
US5560922A (en) * 1986-05-30 1996-10-01 Rutgers, The State University Of New Jersey Transdermal absorption dosage unit using a polyacrylate adhesive polymer and process

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5560922A (en) * 1986-05-30 1996-10-01 Rutgers, The State University Of New Jersey Transdermal absorption dosage unit using a polyacrylate adhesive polymer and process
US4906475A (en) * 1988-02-16 1990-03-06 Paco Pharmaceutical Services Estradiol transdermal delivery system
US5362497A (en) * 1989-05-25 1994-11-08 Takeda Chemical Industries, Ltd. Transdermal therapeutic composition
US5252334A (en) * 1989-09-08 1993-10-12 Cygnus Therapeutic Systems Solid matrix system for transdermal drug delivery
US5314694A (en) * 1990-10-29 1994-05-24 Alza Corporation Transdermal formulations, methods and devices
US5460820A (en) * 1993-08-03 1995-10-24 Theratech, Inc. Methods for providing testosterone and optionally estrogen replacement therapy to women
US5460820B1 (en) * 1993-08-03 1999-08-03 Theratech Inc Method for providing testosterone and optionally estrogen replacement therapy to women
US5554381A (en) * 1993-08-09 1996-09-10 Cygnus, Inc. Low flux matrix system for delivering potent drugs transdermally

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7242935B2 (en) 1998-02-13 2007-07-10 Qualcomm Incorporated Method and system for performing a handoff in a wireless communication system, such as a hard handoff
US7603123B2 (en) 1998-02-13 2009-10-13 Qualcomm Incorporated Method and system for performing a handoff in a wireless communication system, such as a hard handoff
US8170558B2 (en) 1998-02-13 2012-05-01 Qualcomm Incorporated Method and system for performing a handoff in a wireless communication system, such as a hard handoff
US7664209B2 (en) 1998-05-21 2010-02-16 Qualcomm Incorporated Method and apparatus for coordinating transmission of short messages with hard handoff searches in a wireless communications system
US7245597B2 (en) 1999-08-11 2007-07-17 Qualcomm Incorporated Method and system for performing handoff in wireless communication systems
US8199716B2 (en) 1999-08-11 2012-06-12 Qualcomm Incorporated Method and system for performing handoff in wireless communication systems
US9125816B2 (en) 2000-08-30 2015-09-08 Besins Healthcare Inc. Pharmaceutical composition and method for treating hypogonadism
US9132089B2 (en) 2000-08-30 2015-09-15 Besins Healthcare Inc. Pharmaceutical composition and method for treating hypogonadism
WO2008154240A1 (fr) * 2007-06-06 2008-12-18 Biohealth Llc Composition pharmaceutique d'un nouveau système destiné à la libération de stéroïdes dans le vagin
US8964692B2 (en) 2008-11-10 2015-02-24 Qualcomm Incorporated Spectrum sensing of bluetooth using a sequence of energy detection measurements

Also Published As

Publication number Publication date
ZA973749B (en) 1998-04-01
AU2746397A (en) 1997-11-19

Similar Documents

Publication Publication Date Title
AU710760B2 (en) Drug delivery compositions for improved stability of steroids
TW537899B (en) Composition for the transdermal administration of steroid drugs
CA2259532C (fr) Matrice d'administration de medicament transdermique pour la coadministration d'estradiol et d'un autre steroide
US5460820A (en) Methods for providing testosterone and optionally estrogen replacement therapy to women
AU2007200426A1 (en) Transdermal delivery of lasofoxifene
IL176112A (en) Skin-containing preparation through the stomach containing gastodone and carrier, a medical system for the administration through the skin containing gastodon and a kit
WO2001091757A1 (fr) Preparation streroide du type a absorption percutanee pour usage externe
EP0773028A1 (fr) Preparation se pretant a une absorption percutanee
WO2005060540A2 (fr) Formulations a liberation prolongee de norethindrone et methodes associees a ces formulations
WO1997040792A1 (fr) Administration transdermique d'hormones steroidiennes au moyen de diethanolamides d'acides gras c12-c18 utilises comme activateurs de l'infiltration
TW200528073A (en) Transdermal delivery of hormones without the need of penetration enhancers
KR960013236B1 (ko) 에스트로겐/프로게스틴 경피 전달 장치 및 이를 포함하는 키트
CA2483834A1 (fr) Formulations de norethindrone a liberation prolongee et methodes associees
JPH04342531A (ja) 経皮吸収製剤
JPH07247217A (ja) 経皮吸収製剤
JPH04360828A (ja) 経皮吸収製剤

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH HU IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG US UZ VN YU AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
NENP Non-entry into the national phase

Ref country code: JP

Ref document number: 97539126

Format of ref document f/p: F

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: CA

122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载