WO2004014397A1 - Creme analgesique contenant du salicylate disperse dans de l'huile de silicones et des micro-eponges pour une administration soutenue de revulsifs tels que le menthol - Google Patents

Creme analgesique contenant du salicylate disperse dans de l'huile de silicones et des micro-eponges pour une administration soutenue de revulsifs tels que le menthol Download PDF

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Publication number
WO2004014397A1
WO2004014397A1 PCT/TR2003/000060 TR0300060W WO2004014397A1 WO 2004014397 A1 WO2004014397 A1 WO 2004014397A1 TR 0300060 W TR0300060 W TR 0300060W WO 2004014397 A1 WO2004014397 A1 WO 2004014397A1
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WO
WIPO (PCT)
Prior art keywords
counter
salicylate
irritants
cream according
cream
Prior art date
Application number
PCT/TR2003/000060
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English (en)
Inventor
Koral Embil
Original Assignee
Edko Pazarlama Tanitim Ticaret Limited Sirketi
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 Edko Pazarlama Tanitim Ticaret Limited Sirketi filed Critical Edko Pazarlama Tanitim Ticaret Limited Sirketi
Priority to AU2003248618A priority Critical patent/AU2003248618A1/en
Publication of WO2004014397A1 publication Critical patent/WO2004014397A1/fr

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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
    • A61K9/0012—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A61K31/125—Camphor; Nuclear substituted derivatives thereof
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/606—Salicylic acid; Derivatives thereof having amino groups
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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]

Definitions

  • This invention concerns pharmaceutical compositions in the form of creams for topical application to the skin in the treatment of pain, particularly for the relief of 5 post-exercise pains such as muscular sprains or strains.
  • Pain relief products of this kind often contain analgesics and counter-irritants or rubefacients as active ingredients.
  • Analgesics such as salicylates depress the cutaneous sensory pain receptors to diminish the symptoms, mostly through their 0 anti-inflammatory action and inhibition of prostaglandins.
  • Counter-irritants on the other hand relieve pain by stimulation of pain receptors to induce sensations of cold or warmth and provide a counter-stimulation to superficial or deep-seated pain, thus indirectly relieving or distracting from the pain.
  • the active ingredients are normally formulated in conventional emulsions to be immediately effective.
  • compositions of the invention a salicylate analgesic is included to provide immediate action and counter-irritants are included to provide both an immediate and extended counter-irritant action.
  • the compositions have the advantages of reducing skin irritation by the use of sustained release counter-irritants and a 0 longer lasting counter-irritant effect.
  • the compositions also have the advantage of enabling the user to increase the pain relieving effect when required, by rubbing the area to which the composition has been applied to release further quantities of counter-irritant.
  • the active ingredients are also formulated as water in silicone emulsions which are generally superior in terms of effectiveness as compared to 5 conventional oil-based emulsions.
  • the water in silicone emulsions used in the invention can for example give an increased cooling effect which compliments or works synergistically with counter-irritants such as menthol; they are less greasy than conventional water in oil emulsions; they optimise the sustained release of the counter-irritant; and they give a relatively low odour product.
  • the composition of the invention is thus a pain relief cream for topical application to the skin which includes a water phase containing one or more salicylate analgesics dispersed in a silicone oil phase containing one or more counter- irritants, and porous particles containing one or more counter-irritants for delayed or sustained release of those counter-irritants after application.
  • the salicylate present in the water phase should be suitable for topical application and may be a water-soluble salicylate such as triethylamino (TEA) or diethylamino (DEA) salicylate, but may also be a sparingly soluble salicylate such as aspirin.
  • TEA salicylate is preferred.
  • An oil soluble salicylate such as methyl salicylate may also be included in the oil phase.
  • the salicylate can generally be present in the compositions in an amount of 8-12% by weight (all percentages herein are by weight on the basis of the total composition).
  • the water phase may also include an additional water-soluble counter-irritant such as histamine, for example in the form of a salt, in an amount for example of 0.005- 0.02%. This provides an immediate counter-irritant effect where required in addition to the counter-irritant present in the oil phase.
  • an additional water-soluble counter-irritant such as histamine, for example in the form of a salt, in an amount for example of 0.005- 0.02%. This provides an immediate counter-irritant effect where required in addition to the counter-irritant present in the oil phase.
  • a penetration enhancer such as diethylene glycol monoethyl ether (ethoxidiglycol) may also be included in the water phase, for example in an amount of 1-3%.
  • Preservatives or bactericides such as a paraben( e.g.methyl or propyl paraben)or diazolidinyl urea may also be included, e.g. in an amount of 0.1-1.0%.
  • Additives may also be included in the water phase to stabilise the emulsion, in particular ionic stabilisers such as salts (e.g. magnesium sulphate or sodium chloride) in an amount of for example 1-5%.
  • the silicone oil which is the basis of the oil phase may be a polyalkylsiloxane or an emulsifying blend of silicone oils, or a mixture of these types.
  • the polyalkylsiloxane may be a polydimethyl-siloxane oil or mixtures thereof such as a dimethicone blend.
  • Organo-silicone compounds such as phenyl trimethicone, octyl trimethicone or dimethiconol may also be used, e.g. together with a polyalkylsiloxane.
  • any cosmetic or medical grade silicone oil with a viscosity of 100-1000 centistokes or blends thereof can be used.
  • Emulsifying blends of silicone oils can be used both as the main silicone oil and also to control the emulsification of the polyalkylsiloxane oil in the aqueous phase.
  • emulsifiers can be based on polydiorganosiloxane-polyoxyalkylene copolymers in which the organo group is methyl, ethyl, vinyl or phenyl and the alkylene group is ethylene or propylene.
  • copolymers which are usually formulated together with a volatile cyclic siloxane such as a cyclopolydimethylsiloxane, are described in US 4122029 and one example is DC 3225C (Dow Corning, cyclomethicone and dimethicone copolyol) .
  • DC 3225C Low Corning, cyclomethicone and dimethicone copolyol
  • Alternatives are SF 1328(GE Silicones, cyclomethicone and dimethicone copolyol) and Abil ® EM97 (Goldschmidt, cyclopentasiloxane and dimethicone copolyol).
  • the silicone oil generally acts to restrain the release of the counter-irritant from the microsponges and this has the advantage of prolonging the effect of the counter-irritant as compared to the use of a hydrocarbon oil.
  • the silicone oils are also less greasy than hydrocarbon oils and give a final product which has relatively low odour as compared to conventional pain relief creams.
  • An important feature of the invention is the use of a major amount of an emulsifying blend of silicone oils as compared to the relatively small amounts used for emulsification purposes. The reason for this is that the emulsifying blends contain a high proportion of volatile constituents which evaporate as the cream is rubbed onto the skin, and this creates a cooling effect which compliments the effect of the counter-irritants.
  • the total amount of silicone oil used may for example be 7-15% by weight, and is preferably a mixture of 6-14, e.g. 8-12% of an emulsifying blend with 1-5, e.g. 2-4% of a polyalkylsiloxane.
  • An organic hydrocarbon oil which is compatible with the silicone oil may also be included, for example hydrogenated polybutene. The latter is a very stable material and helps stabilise the emulsions, and can be used in amounts of 1-5%.
  • the counter-irritant present in the silicone oil phase is preferably menthol but may also be another counter-irritant such as a nicotinate, e.g. benzyl or methyl nicotinate, or camphor.
  • the free counter-irritant present in the oil phase provides an immediate effect and the preferred additive is menthol. Menthol may be used in amounts of for example 10-18%, preferably 16%, taking into account any menthol also present in porous particles contained in the composition.
  • the counter-irritant present in the porous particles included in the compositions may be menthol, camphor or a nicotinate, as in the oil phase.
  • Porous particles containing menthol are preferably used, together with particles containing a nicotinate such as methyl nicotinate in circumstances where a stronger counter- irritant effect is required.
  • the amount of menthol present in the particles may for example be in the range of 3-5%, and is indicated above the amount used should be calculated to provide a total menthol level of, preferably, 16%.
  • the amount of nicotinate present in the particles is relatively small, for example 0.02-0.06%.
  • porous particles for carrying the counter-irritants for delayed or sustained release, for example as described in WO 88/01164, WO89/10132, US 4 873 091, US 4690825 and EP 306236A. They may be composed of a wide range of materials and many synthetic organic polymers are suitable, as well as natural substances such as cellulose or gelatin. The choice Of material will depend in part on the intended means of delayed release, i.e. diffusion, compression, dissolving or melting.
  • the diameters of the particles will generally be in the range 1 to 1000 microns, preferably 5 to 100 microns, more preferably 10 to 25 microns.
  • the surface area of the particles will generally range from about 1 to 500 m 2 /g preferably 20 to 200 m 2 /g and the total pore volume is preferably in the range 0.3 to 4.0 cnrVg, more preferably 0.6 to 2.0 cm 3 /g.
  • the porous particles preferably primarily release the counter-irritants over a period of time by diffusion and also to some extent by the action of pressure during application to compress the particles. After the first application of the composition to the affected area, the use of gentle pressure, for example by rubbing, causes release of further quantities of the active ingredients.
  • the particles are preferably formed by cross-linking polymers such as polyolefins, including polyethylene, polystyrene, polydicyclopentadiene etc.; polyacrylate esters, e.g. optionally alkoxylated C M0 allyl, cycloalkyl, aryl or aralkyl esters of polyacrylic or polymethacrylic acids; polyvinyl esters e.g. polyvinyl acetate of polyvinyl laurate; polyvinyl ketones, e.g. polyvinylmethyl ketone; and polyvinyl ethers, e.g. polyvinylpropyl ether.
  • suitable materials are polystyrene cross-linked with e.g. divinylbenzene and polymethacrylates cross- linked for example with ethylene glycol dimethacrylate.
  • the particles may be loaded with ingredients by the methods described in US 690825 and US 5145675.
  • the formulation may also include other additives such as fragrances and antioxidants such as BHA (butylated hydroxy anisole), BHT (butylated hydroxy toluene), alkyl gallates such as propyl gallate, ortocopherols.
  • BHA butylated hydroxy anisole
  • BHT butylated hydroxy toluene
  • alkyl gallates such as propyl gallate, ortocopherols.
  • the creams of the invention may be used to relieve pain in a variety of conditions, including for example superficial or deep-seated sprains, strains and other sports injuries and post-exercise pain.
  • the cream is applied topically to the affected area and immediate relief is provided by the free salicylate and counter-irritant.
  • the porous particles also provide delayed release of the counter-irritant, and release of further counter-irritant can be stimulated by the user as required by rubbing the cream already present on the affected area.
  • compositions may be made by preparing the aqueous and oil phases and then mixing them together and then adding the porous particles, using methods generally known for the manufacture of creams.
  • a particularly suitable method includes the steps of preparing an aqueous solution of the water phase ingredients of the composition and mixing it with the oil phase mixture to form an emulsion, followed by the addition of ingredients such as fragrance, and finally the porous particles.
  • DC3225C is an emulsifying blend of cilicone oils (octamethyl cyclotetrasiloxane, decaraethyl cyclopentasiloxane and dimethyl,methylhydroxypropyl, ethoxylated, propoxylated siloxane and water).
  • MDS Mertrichloride Delivery System
  • Total menthol level target is 16% (total free and entrapped).
  • the oil phase ingredients were slowly mixed at 35°C to dissolve the menthol and the heating then stopped.
  • the water phase ingredients were mixed to form a solution and added very slowly over 15-20 minutes to the oil phase with vigorous propeller stirring to form a viscous emulsion. Stirring was continued and the fragrance was then added slowly and mixed in. Stirring was then stopped and finally the microsponges were mixed in slowly to give the cream product.
  • the cream product was produced by the same method as in Example 1.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Dermatology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une crème de soulagement de douleurs à appliquer au niveau topique sur la peau. Ladite crème comprend une phase aqueuse qui contient au moins un analgésique de salicylate dispersé dans une phase d'huile de silicones qui contient au moins un révulsif, et des particules poreuses qui renferment au moins un révulsif et permettent une libération retardée ou soutenue de ces révulsifs, après l'application. Cette composition permet de soulager la douleur immédiatement et dans la durée, elle n'engendre que peu d'irritations cutanées et elle produit un effet de refroidissement amélioré.
PCT/TR2003/000060 2002-08-07 2003-07-21 Creme analgesique contenant du salicylate disperse dans de l'huile de silicones et des micro-eponges pour une administration soutenue de revulsifs tels que le menthol WO2004014397A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003248618A AU2003248618A1 (en) 2002-08-07 2003-07-21 Analgetic cream comprising salicylate dispersed in silicone oil and microsponges for substained delivery of counter-irritants like menthol

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2002/01966 2002-08-07
TR2002/01966A TR200201966A2 (tr) 2002-08-07 2002-08-07 Farmasötik terkip.

Publications (1)

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WO2004014397A1 true WO2004014397A1 (fr) 2004-02-19

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AU (1) AU2003248618A1 (fr)
TR (1) TR200201966A2 (fr)
WO (1) WO2004014397A1 (fr)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006127591A3 (fr) * 2005-05-23 2007-06-07 Nitromed Inc Sels renforçant l'oxyde nitrique organique de composes anti-inflammatoires non steroidiens, compositions et procedes d'utilisation
US9180091B2 (en) 2012-12-21 2015-11-10 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US9248136B2 (en) 2011-11-23 2016-02-02 Therapeuticsmd, Inc. Transdermal hormone replacement therapies
US9289382B2 (en) 2012-06-18 2016-03-22 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US9931349B2 (en) 2016-04-01 2018-04-03 Therapeuticsmd, Inc. Steroid hormone pharmaceutical composition
US10052386B2 (en) 2012-06-18 2018-08-21 Therapeuticsmd, Inc. Progesterone formulations
US10206932B2 (en) 2014-05-22 2019-02-19 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10258630B2 (en) 2014-10-22 2019-04-16 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10286077B2 (en) 2016-04-01 2019-05-14 Therapeuticsmd, Inc. Steroid hormone compositions in medium chain oils
US10328087B2 (en) 2015-07-23 2019-06-25 Therapeuticsmd, Inc. Formulations for solubilizing hormones
US10471072B2 (en) 2012-12-21 2019-11-12 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10471148B2 (en) 2012-06-18 2019-11-12 Therapeuticsmd, Inc. Progesterone formulations having a desirable PK profile
US10537581B2 (en) 2012-12-21 2020-01-21 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10675288B2 (en) 2011-11-23 2020-06-09 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10806740B2 (en) 2012-06-18 2020-10-20 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US11246875B2 (en) 2012-12-21 2022-02-15 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11266661B2 (en) 2012-12-21 2022-03-08 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4892890A (en) * 1984-11-01 1990-01-09 G. D. Searle And Company External analgesic compositions
EP0486117A1 (fr) * 1990-06-28 1992-05-20 EDKO Trading and Representation Co., Ltd Formulation pharmaceutique multiphasique
US5824334A (en) * 1989-09-05 1998-10-20 University Of Utah Research Foundation Tobacco substitute
WO1999032084A1 (fr) * 1997-12-22 1999-07-01 Edko Trading And Representation Company Limited Compositions de traitement d'affections cutanees et anorectales
US5962441A (en) * 1991-11-25 1999-10-05 Richardson-Vicks Inc. Use of salicylic acid for regulating skin wrinkles and/or skin atrophy

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4892890A (en) * 1984-11-01 1990-01-09 G. D. Searle And Company External analgesic compositions
US5824334A (en) * 1989-09-05 1998-10-20 University Of Utah Research Foundation Tobacco substitute
EP0486117A1 (fr) * 1990-06-28 1992-05-20 EDKO Trading and Representation Co., Ltd Formulation pharmaceutique multiphasique
US5962441A (en) * 1991-11-25 1999-10-05 Richardson-Vicks Inc. Use of salicylic acid for regulating skin wrinkles and/or skin atrophy
WO1999032084A1 (fr) * 1997-12-22 1999-07-01 Edko Trading And Representation Company Limited Compositions de traitement d'affections cutanees et anorectales

Cited By (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006127591A3 (fr) * 2005-05-23 2007-06-07 Nitromed Inc Sels renforçant l'oxyde nitrique organique de composes anti-inflammatoires non steroidiens, compositions et procedes d'utilisation
US10675288B2 (en) 2011-11-23 2020-06-09 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US9248136B2 (en) 2011-11-23 2016-02-02 Therapeuticsmd, Inc. Transdermal hormone replacement therapies
US11103516B2 (en) 2011-11-23 2021-08-31 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US11793819B2 (en) 2011-11-23 2023-10-24 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US11529360B2 (en) 2012-06-18 2022-12-20 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10639375B2 (en) 2012-06-18 2020-05-05 Therapeuticsmd, Inc. Progesterone formulations
US11166963B2 (en) 2012-06-18 2021-11-09 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10052386B2 (en) 2012-06-18 2018-08-21 Therapeuticsmd, Inc. Progesterone formulations
US11110099B2 (en) 2012-06-18 2021-09-07 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US9289382B2 (en) 2012-06-18 2016-03-22 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11033626B2 (en) 2012-06-18 2021-06-15 Therapeuticsmd, Inc. Progesterone formulations having a desirable pk profile
US10471148B2 (en) 2012-06-18 2019-11-12 Therapeuticsmd, Inc. Progesterone formulations having a desirable PK profile
US10806740B2 (en) 2012-06-18 2020-10-20 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US11865179B2 (en) 2012-06-18 2024-01-09 Therapeuticsmd, Inc. Progesterone formulations having a desirable PK profile
US11123283B2 (en) 2012-12-21 2021-09-21 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US11266661B2 (en) 2012-12-21 2022-03-08 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US9180091B2 (en) 2012-12-21 2015-11-10 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US10537581B2 (en) 2012-12-21 2020-01-21 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10806697B2 (en) 2012-12-21 2020-10-20 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11622933B2 (en) 2012-12-21 2023-04-11 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US10835487B2 (en) 2012-12-21 2020-11-17 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10888516B2 (en) 2012-12-21 2021-01-12 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US11497709B2 (en) 2012-12-21 2022-11-15 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10471072B2 (en) 2012-12-21 2019-11-12 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11065197B2 (en) 2012-12-21 2021-07-20 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US11351182B2 (en) 2012-12-21 2022-06-07 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11304959B2 (en) 2012-12-21 2022-04-19 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10568891B2 (en) 2012-12-21 2020-02-25 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11116717B2 (en) 2012-12-21 2021-09-14 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US11246875B2 (en) 2012-12-21 2022-02-15 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11241445B2 (en) 2012-12-21 2022-02-08 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11103513B2 (en) 2014-05-22 2021-08-31 TherapeuticsMD Natural combination hormone replacement formulations and therapies
US10206932B2 (en) 2014-05-22 2019-02-19 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10258630B2 (en) 2014-10-22 2019-04-16 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10398708B2 (en) 2014-10-22 2019-09-03 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10668082B2 (en) 2014-10-22 2020-06-02 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10328087B2 (en) 2015-07-23 2019-06-25 Therapeuticsmd, Inc. Formulations for solubilizing hormones
US10912783B2 (en) 2015-07-23 2021-02-09 Therapeuticsmd, Inc. Formulations for solubilizing hormones
US10286077B2 (en) 2016-04-01 2019-05-14 Therapeuticsmd, Inc. Steroid hormone compositions in medium chain oils
US10532059B2 (en) 2016-04-01 2020-01-14 Therapeuticsmd, Inc. Steroid hormone pharmaceutical composition
US9931349B2 (en) 2016-04-01 2018-04-03 Therapeuticsmd, Inc. Steroid hormone pharmaceutical composition

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AU2003248618A1 (en) 2004-02-25
TR200201966A2 (tr) 2004-02-23

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