WO1998003156A2 - Topically applied composition for hormone replacement therapy - Google Patents

Topically applied composition for hormone replacement therapy Download PDF

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Publication number
WO1998003156A2
WO1998003156A2 PCT/GB1997/001969 GB9701969W WO9803156A2 WO 1998003156 A2 WO1998003156 A2 WO 1998003156A2 GB 9701969 W GB9701969 W GB 9701969W WO 9803156 A2 WO9803156 A2 WO 9803156A2
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WO
WIPO (PCT)
Prior art keywords
preparation
oestrogen
progestogen
phase
content
Prior art date
Application number
PCT/GB1997/001969
Other languages
French (fr)
Other versions
WO1998003156A3 (en
Inventor
Peter Chadwick Somerville
Anthony E. Beezer
John Carlton Mitchell
Roy Anthony Lane
Original Assignee
Resource Medical Limited
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 Resource Medical Limited filed Critical Resource Medical Limited
Priority to AU36285/97A priority Critical patent/AU3628597A/en
Publication of WO1998003156A2 publication Critical patent/WO1998003156A2/en
Publication of WO1998003156A3 publication Critical patent/WO1998003156A3/en

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Classifications

    • 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
    • A61K31/569—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 substituted in position 17 alpha, e.g. ethisterone
    • 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
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • 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
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/14—Liposomes; Vesicles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/63—Steroids; 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin

Definitions

  • This invention relates to products for the hormonal treatment of menopausal (including perimenopausal and post- menopausal) disorders in women.
  • hormone replacement therapy involves the administration of a progestogen in conjunction with an oestrogen, according to a specific regimen.
  • Two particular types of product are in widespread use for the administration of hormone replacement therapy, namely products for oral administration and transdermal patches.
  • Products for oral administration normally take the form of, for example, pills, capsules or tablets, and these are usually available in the form of packages containing a specific number of unit dosages of each hormone.
  • a blister-pack containing progestogen-containing tablets and oestrogen-containing tablets, the package indicating the daily dose of each such tablet.
  • Transdermal patches contain therapeutically- effective amounts of progestogen and oestrogen, and supply the hormones through the skin into the blood stream in a controlled release manner.
  • a product for hormone replacement therapy is provided in the form of a topically- applied cosmetic.
  • the invention provides a topically- administrable cosmetic preparation comprising a therapeutically-effective amount of a liposome-encapsulated oestrogen and/or progestogen.
  • this preparation should be in the form of a paste, gel or cream, and supplied in unit dosage form, so that it may be applied to the skin in the same way as a cosmetic paste, gel or cream.
  • the preparation may be supplied in a gelatin-based capsule, the top of which may be removed to reveal the effective product.
  • the formulation may be supplied in a pump-dispenser, calibrated to deliver unit doses of the hormones.
  • the oestrogen is suitably 17-beta oestradiol or oestradiol valerate.
  • the progestogen is suitably medroxyprogesterone acetate, norethisterone, norethisterone acetate, L-norgestrel or progesterone.
  • the progestogen is L-norgestrel.
  • the products of the invention may be made by solubilising the hormones into a suitable liposome, preferably one which is surface-modified by PEGylation, in which the hormones are stabilised, and then mixing the liposome with cream—or gel- forming ingredients.
  • suitable further ingredients for incorporation in the product of the invention include emollients, for example alpha-hydroxy acids, vitamin D3 (for improved skin turgor, texture and firmness) , refined borage oil (e.g. Crossential GLA 25) , non ionic emulsifying wax (e.g. Polawax GP 200) , synthetic beeswax (e.g. Syncrowax BB4), fatty acid esters (e.g.
  • a unit dose of the product of the invention may be supplied in the form of a 0.5 to 1 gram cream or gel containing the therapeutically-effective amount of hormones. As mentioned above, such unit dosage amount may be contained in a soft gelatine capsule, for example in the form of a teardrop having a twist-off top. 28 such capsules will constitute a month's supply.
  • a pump-dispenser containing from 14 to 28 grams of cream may be calibrated so as to meter 0.5 to 1 gram charges for administration each day.
  • oestradiol is therapeutically active in the present invention at applied concentrations of around 1.0 to 3.0 x IO '4 moldm '3 (25 to 75 ⁇ g per mL liposome solution) .
  • L-Norgestrel is effective at concentrations of between 1.0 to 4.0 x IO "4 moldm '3 , corresponding to 5 to 20 ⁇ g per L liposome solution.
  • Each dosage unit of the product of the invention suitably comprises 0.5g or lg of topically-applied cosmetic containing from 25 to 75 ⁇ g, e.g. 50 ⁇ g of oestrogen and, when present, from 5 to 20 ⁇ g, e.g. 12.5 ⁇ g, of progestogen.
  • the product contains such an amount of liposome-encapsulated hormone as will provide these amounts of hormone.
  • the selected hormones are solubilised in liposomes prepared from: 1.
  • DPPC Dipalmitoylphosphatidylcholine
  • lipid of choice is DPPC .
  • the solubilisation is effected by conventional methods essentially involving dissolution of the selected phospholipid and the hormones in an appropriate solvent (for example alcohol, chloroform) followed by solvent removal under vacuum and subsequent addition of water (buffer) at temperatures above the phase transition temperature of the lipid (approximately 323K; for example, the phase transition temperature of DPPC is around 314K) and agitation.
  • an appropriate solvent for example alcohol, chloroform
  • water buffer
  • This procedure results in the production of hormones solubilised in multilamellar vesicles.
  • the suspension density of the liposomal preparation will be appropriate for the eventual formulation in a unit dose/metered dose presentation.
  • Cosmetic base cream formulations appropriate for delivery in soft gelatine capsules/pump delivery devices, which contain for example appropriate mixtures of grades of polyethylene glycols (molar mass range from ca 400 to 6000) , suitable stabilisers such as poloxamers (ABA block copolymers with a wide range of polyethylene to polypropylene ratios and of wide ranging total molar masses these materials exhibit a significant variation in hydrophobic/hydrophilic properties) , surfactants (for example sodium dodecyl sulphate) and salts may be utilised to support the liposomes.
  • suitable stabilisers such as poloxamers (ABA block copolymers with a wide range of polyethylene to polypropylene ratios and of wide ranging total molar masses these materials exhibit a significant variation in hydrophobic/hydrophilic properties)
  • surfactants for example sodium dodecyl sulphate
  • salts may be utilised to support the liposomes.
  • the preparation of the formulated material will be performed at temperatures which are determined by the phase transition temperature of the liposomes and which are sensitive to the importance of the kinetics of cooling from the selected blending temperature.
  • novel hormone replacement therapy presentation provided by the invention is easy and comfortable to apply, and may be applied in the same manner as any other cosmetic preparation. It clearly does not suffer from the same problems as transdermal patches, and it represents a reduction in side-effects in relation to orally-administered hormones. For example, the hormones when administered in the form of the present invention do not pass through the liver.
  • Example 1 Preparation of small unilamellar vesicles (SUVs) associated with hormone.
  • SUVs small unilamellar vesicles
  • An SUV vehicle for drug encapsulation offers the most suitable type of liposome system for the present application.
  • DPPC DPPC (62.5mg, 8.51xl0 "5 mol) was dissolved in pH7 phosphate buffer (25mL at 320K) to give a final DPPC concentration of 3.41X10 "3 moldm "3 .
  • This solution was vortexed (Fisons whirlimixer) for 120s, then the contents were transferred to a sonicator ampoule and cooled in a beaker of cold water (maintained at -320K) .
  • the contents were sonicated twice for 360s, leaving a 60s interval between sonications, at a power setting of >26 ⁇ (Soniprep 150) .
  • the solution was then filtered using a 0.2 ⁇ m cellulose Millipore filter. This procedure resulted in the formation of SUV liposomes of diameter 50nm ⁇ lOn ) that are stable for at least 12 hours.
  • a specific ratio of drug: liposome was achieved by weighing the required ratio of solid drug materials into a volumetric flask (25mL) along with the DPPC lipid (0.0625g). In order to ensure that the solids were mixed thoroughly, they were dissolved in chloroform ( ⁇ 2mL) , and the solvent was removed carefully and slowly in vacuo over a period of 12 hours. The procedure outlined above for production of SUV liposomes was then followed.
  • the above method prepares 25mL of drug/ liposome complex containing quantities or mixtures of drugs such that lmL solution contains sufficient drug quantities so as to be within the range required in the final formulation.
  • the high concentrations of hormone incorporated into the liposomes in the above method may be diluted to any concentration necessary for therapeutic efficacy.
  • higher concentrations of hormone may be incorporated, if required.
  • oestradiol for formulations containing oestradiol as the only additive, the following amounts of constituents may be used: 0.68mg oestradiol (1.0 x 10 "4 moldm '3 ); 62.5mg DPPC in 25mL buffer. This corresponds to a dose of 27.2 ⁇ g oestradiol in lmL liposome solution.
  • oestradiol 1.0 x IO "4 moldm “3 ); 0.78mg L- Norgestrel (1.0 x 10 "4 moldm “3 ); 62.5mg DPPC in 25mL buffer. This corresponds to a dose of 27.2 ⁇ g oestradiol, 31.2 ⁇ g L- Norgestrel in lmL liposome solution.
  • liposomal hormones may be generated in order to incorporate the full range of the desired delivered quantity of drug (25-75 ⁇ g for oestradiol; 5-20 ⁇ g for L-Norgestrel in lmL complex) . These may then be diluted accordingly.
  • the following amounts of hormones are preferably used in 62.5mg DPPC in 25mL buffer; oestradiol: 0.68-2.1 mg (1.0 - 4.0 x IO "4 moldm "3 ); L-Norgestrel: 0.13-0.39mg (1.0 - 3.0 x 10 "4 moldm '3 ); 62.5mg DPPC in 25mL buffer.
  • Example 2 Dispersion of the drug/ liposome complexes into cream formulations.
  • phase B Slowly add phase B to phase A at room temperature, while stirring thoroughly. Homogenise the emulsion. Prepare phase C and add the mixture of phase A and B, while stirring thoroughly. Homogenise. Phase D may then be added, as required.
  • phase B Slowly add phase B to phase A at room temperature, while stirring. Homogenise the emulsion and add phase C stirring thoroughly. Homogenise the emulsion and slowly add phase D. Mix the product for a short time.
  • phase A Heat phase A to 348K. Mix phase B to 348K and homogenise. Add phase B to phase A, stirring thoroughly. Homogenise, cool to 313K and slowly add phase C, stirring thoroughly.
  • Phosal 75 SA and NAT 8450 are obtainable from Nattermann Phospholipid, Germany;
  • Solulane C-24 and Glucam E-20 are obtainable from Americhol, Edison, New Jersey;
  • Silkpro is obtainable from Ikeda, Japan.

Abstract

A product for use in hormone replacement therapy is applied in the form of a topically-applied cosmetic. This may take the form for example of a cream, paste or gel containing a therapeutically-effective amount of the hormone, and may be contained in dosage unit-containing capsules or a pump dispenser. Especially suitable products contain liposome-encapsulated oestrogen and/or progestogen.

Description

TOPICALLY APPLIED COMPOSITION FOR HORMONE REPLACEMENT THERAPY
This invention relates to products for the hormonal treatment of menopausal (including perimenopausal and post- menopausal) disorders in women.
The advantages of hormone replacement therapy are widely recognised, and many different products are available for the treatment. Broadly speaking the treatment involves the administration of a progestogen in conjunction with an oestrogen, according to a specific regimen. Two particular types of product are in widespread use for the administration of hormone replacement therapy, namely products for oral administration and transdermal patches. Products for oral administration normally take the form of, for example, pills, capsules or tablets, and these are usually available in the form of packages containing a specific number of unit dosages of each hormone. For example, there is known a blister-pack containing progestogen-containing tablets and oestrogen-containing tablets, the package indicating the daily dose of each such tablet. Transdermal patches contain therapeutically- effective amounts of progestogen and oestrogen, and supply the hormones through the skin into the blood stream in a controlled release manner.
Although both the oral and transdermal products are widely and successfully used, both of them can give rise to undesirable side-effects. For example, orally-administered hormones must pass through the liver before entering the blood stream, and may be modified therein. Transdermal patches can pose physical problems, may be uncomfortable and even provoke irritation. It is the object of the present invention to provide an entirely new form of product for hormone replacement therapy, which is neither an oral product nor a patch, and which does not suffer from the problems associated with these known formulations. In accordance with the invention a product for hormone replacement therapy is provided in the form of a topically- applied cosmetic.
More particularly, the invention provides a topically- administrable cosmetic preparation comprising a therapeutically-effective amount of a liposome-encapsulated oestrogen and/or progestogen.
It is preferred that this preparation should be in the form of a paste, gel or cream, and supplied in unit dosage form, so that it may be applied to the skin in the same way as a cosmetic paste, gel or cream. Thus, the preparation may be supplied in a gelatin-based capsule, the top of which may be removed to reveal the effective product. Alternatively the formulation may be supplied in a pump-dispenser, calibrated to deliver unit doses of the hormones.
The oestrogen is suitably 17-beta oestradiol or oestradiol valerate.
The progestogen is suitably medroxyprogesterone acetate, norethisterone, norethisterone acetate, L-norgestrel or progesterone. Preferably, the progestogen is L-norgestrel.
The products of the invention may be made by solubilising the hormones into a suitable liposome, preferably one which is surface-modified by PEGylation, in which the hormones are stabilised, and then mixing the liposome with cream—or gel- forming ingredients. Suitable further ingredients for incorporation in the product of the invention include emollients, for example alpha-hydroxy acids, vitamin D3 (for improved skin turgor, texture and firmness) , refined borage oil (e.g. Crossential GLA 25) , non ionic emulsifying wax (e.g. Polawax GP 200) , synthetic beeswax (e.g. Syncrowax BB4), fatty acid esters (e.g. Crodamol) , Carbopol 941, triethanolamine, propylene glycol, perfumes, preservatives and/or antioxidants, as desired and appropriate. A unit dose of the product of the invention may be supplied in the form of a 0.5 to 1 gram cream or gel containing the therapeutically-effective amount of hormones. As mentioned above, such unit dosage amount may be contained in a soft gelatine capsule, for example in the form of a teardrop having a twist-off top. 28 such capsules will constitute a month's supply. A pump-dispenser containing from 14 to 28 grams of cream may be calibrated so as to meter 0.5 to 1 gram charges for administration each day.
Therapeutically-effective amounts of hormones vary for different oestrogens and progestogens, as is apparent in the art. For example, oestradiol is therapeutically active in the present invention at applied concentrations of around 1.0 to 3.0 x IO'4 moldm'3 (25 to 75μg per mL liposome solution) . L-Norgestrel is effective at concentrations of between 1.0 to 4.0 x IO"4 moldm'3, corresponding to 5 to 20μg per L liposome solution.
Each dosage unit of the product of the invention suitably comprises 0.5g or lg of topically-applied cosmetic containing from 25 to 75μg, e.g. 50μg of oestrogen and, when present, from 5 to 20μg, e.g. 12.5μg, of progestogen. The product contains such an amount of liposome-encapsulated hormone as will provide these amounts of hormone.
Suitably, the selected hormones are solubilised in liposomes prepared from: 1. DPPC (Dipalmitoylphosphatidylcholine)
2. phosphatidyl choline
3. egg lecithin
4. other phospholipids selected for their appropriate physical and chemical properties. The lipid of choice is DPPC .
The solubilisation is effected by conventional methods essentially involving dissolution of the selected phospholipid and the hormones in an appropriate solvent (for example alcohol, chloroform) followed by solvent removal under vacuum and subsequent addition of water (buffer) at temperatures above the phase transition temperature of the lipid (approximately 323K; for example, the phase transition temperature of DPPC is around 314K) and agitation. This procedure results in the production of hormones solubilised in multilamellar vesicles. The suspension density of the liposomal preparation will be appropriate for the eventual formulation in a unit dose/metered dose presentation.
Cosmetic base cream formulations, appropriate for delivery in soft gelatine capsules/pump delivery devices, which contain for example appropriate mixtures of grades of polyethylene glycols (molar mass range from ca 400 to 6000) , suitable stabilisers such as poloxamers (ABA block copolymers with a wide range of polyethylene to polypropylene ratios and of wide ranging total molar masses these materials exhibit a significant variation in hydrophobic/hydrophilic properties) , surfactants (for example sodium dodecyl sulphate) and salts may be utilised to support the liposomes.
The preparation of the formulated material will be performed at temperatures which are determined by the phase transition temperature of the liposomes and which are sensitive to the importance of the kinetics of cooling from the selected blending temperature.
The novel hormone replacement therapy presentation provided by the invention is easy and comfortable to apply, and may be applied in the same manner as any other cosmetic preparation. It clearly does not suffer from the same problems as transdermal patches, and it represents a reduction in side-effects in relation to orally-administered hormones. For example, the hormones when administered in the form of the present invention do not pass through the liver. Various aspects and embodiments of the present invention will now be described in more detail by way of example. It will be appreciated that modification of detail may be made without departing from the scope of the invention.
Example 1: Preparation of small unilamellar vesicles (SUVs) associated with hormone.
Preparation of SUVs
An SUV vehicle for drug encapsulation offers the most suitable type of liposome system for the present application.
DPPC (62.5mg, 8.51xl0"5 mol) was dissolved in pH7 phosphate buffer (25mL at 320K) to give a final DPPC concentration of 3.41X10"3 moldm"3. This solution was vortexed (Fisons whirlimixer) for 120s, then the contents were transferred to a sonicator ampoule and cooled in a beaker of cold water (maintained at -320K) . The contents were sonicated twice for 360s, leaving a 60s interval between sonications, at a power setting of >26μ (Soniprep 150) . The solution was then filtered using a 0.2μm cellulose Millipore filter. This procedure resulted in the formation of SUV liposomes of diameter 50nm ±lOn ) that are stable for at least 12 hours.
Inclusion of Hormone
A specific ratio of drug: liposome was achieved by weighing the required ratio of solid drug materials into a volumetric flask (25mL) along with the DPPC lipid (0.0625g). In order to ensure that the solids were mixed thoroughly, they were dissolved in chloroform (~2mL) , and the solvent was removed carefully and slowly in vacuo over a period of 12 hours. The procedure outlined above for production of SUV liposomes was then followed.
The above method prepares 25mL of drug/ liposome complex containing quantities or mixtures of drugs such that lmL solution contains sufficient drug quantities so as to be within the range required in the final formulation. However, it will be apparent that the high concentrations of hormone incorporated into the liposomes in the above method may be diluted to any concentration necessary for therapeutic efficacy. Furthermore, higher concentrations of hormone may be incorporated, if required.
For formulations containing oestradiol as the only additive, the following amounts of constituents may be used: 0.68mg oestradiol (1.0 x 10"4 moldm'3); 62.5mg DPPC in 25mL buffer. This corresponds to a dose of 27.2μg oestradiol in lmL liposome solution.
For formulations containing both oestradiol and L- Norgestrel, the following amounts of constituents may be used: 0.68mg oestradiol (1.0 x IO"4 moldm"3); 0.78mg L- Norgestrel (1.0 x 10"4 moldm"3); 62.5mg DPPC in 25mL buffer. This corresponds to a dose of 27.2μg oestradiol, 31.2μg L- Norgestrel in lmL liposome solution.
Higher concentrations of liposomal hormones may be generated in order to incorporate the full range of the desired delivered quantity of drug (25-75μg for oestradiol; 5-20μg for L-Norgestrel in lmL complex) . These may then be diluted accordingly. In these formulations, the following amounts of hormones are preferably used in 62.5mg DPPC in 25mL buffer; oestradiol: 0.68-2.1 mg (1.0 - 4.0 x IO"4 moldm"3); L-Norgestrel: 0.13-0.39mg (1.0 - 3.0 x 10"4 moldm'3); 62.5mg DPPC in 25mL buffer.
Example 2: Dispersion of the drug/ liposome complexes into cream formulations.
Four cream formulations, Formulae A to D, are set out below that are particularly suitable for use according to the present invention. Other formulations will be well known to those of skill in the art. Once the liposomes have been generated, high centrif gation is used to reduce the drug/ liposome complex from 25mL to 0.25g. This complex can then be added to 0.25g or 0.75g cosmetic base, dependent upon whether the final preparation is desired to be 0.5g or l.Og.
Formula A %w/w
Phase A
Phosal 75 SA (a) 2.00
Safflower oil 10.00
Tocopheryl acetate 0.20
Retinyl palmitate 0.20
Phase B
Water 45.90
Urea 2.00
Phase C
Water to 100.00
Sodium carbomer 1.00
Propylene glycol 3.50
Phase D
Preservatives, perfumes qs
Slowly add phase B to phase A at room temperature, while stirring thoroughly. Homogenise the emulsion. Prepare phase C and add the mixture of phase A and B, while stirring thoroughly. Homogenise. Phase D may then be added, as required.
Formula B %w/w
Phase A
NAT 8450 (a) 2.00
Safflower oil 10.00 Tocopheryl acetate 0.20 Retinyl palmitate 0.20
Phase B Water to 100.00
Phase C
Water to 10.00
Sodium carbomer 1.00
Phase D
Preservatives, perfumes qs
Slowly add phase B to phase A at room temperature, while stirring. Homogenise the emulsion and add phase C stirring thoroughly. Homogenise the emulsion and slowly add phase D. Mix the product for a short time.
Formula C %w/w
Phase A Stearic acid 5.00 Squalene 5.00
Solulane C-24 (b) 1.00 Cetyl alcohol 1.00
Myristyl myristate 2.00 Silicon Fluid 350cs 1.00 Propyl paraben 0.10
Phase B
Silkpro (c) 2.00 Glucam E-20 (b) 5.00 Triethanolamine 1.00 Water 76.80 Methyl paraben 0.10
Mix phase A and heat to 358K. Mix phase B and heat to 358K and add to phase A, while stirring. Continue mixing and cool to 303K .
Formula D %w/w
Phase A
Propylene glycol dicaprylate 8.00 Caprylic/capric triglyceride 5.00 Glyceryl stearate 5.00
Cyclomethicone 5.00 Safflower oil 4.00
Stearic acid 3.50
Cetearyl alcohol 3.00
Lanolin alcohol 1.50
Phase B
Water to 100.00
Phosal 75 SA (a) 3.00
Propylene glycol 5.00
Triethanolamine qs
Phase C
Preservatives, perfume qs
Heat phase A to 348K. Mix phase B to 348K and homogenise. Add phase B to phase A, stirring thoroughly. Homogenise, cool to 313K and slowly add phase C, stirring thoroughly.
(a) Phosal 75 SA and NAT 8450 are obtainable from Nattermann Phospholipid, Germany; (b) Solulane C-24 and Glucam E-20 are obtainable from Americhol, Edison, New Jersey; (c) Silkpro is obtainable from Ikeda, Japan.

Claims

1. A composition for hormone replacement therapy, in the form of a topically-applied cosmetic.
2. A topically-ad inistrable cosmetic preparation comprising a therapeutically-effective amount of liposome- encapsulated oestrogen.
3. A topically-administrable cosmetic preparation comprising a therapeutically-effective amount of liposome- bonded oestrogen and progestogen.
4. A preparation as claimed in any of claims 1 to 3 , in the form of paste, gel or cream.
5. A preparation as claimed in any of claims 1 to 4 , contained in an openable capsule or a pump-dispenser.
6. A preparation as claimed in any of claims 3 to 5 wherein the progestogen is L-Norgestrel, edroxyprogesterone acetate, norethisterone, norethisterone acetate or progesterone .
7. A preparation as claimed in any of claims 3 to 6 wherein the content of the progestogen is between 5μg and 20μg per dosage unit.
8. A preparation as claimed in claim 7 wherein the content of the progestogen is 12.5μg per dosage unit.
9. A preparation as claimed in any of claims 2 to 8 wherein the oestrogen is 17-beta oestradiol or oestradiol valerate.
10. A preparation as claimed in any of claims 2 to 9 wherein the content of the oestrogen is between 25μg and 75μg per dosage unit.
11. A preparation as claimed in claim 10 wherein the content of the oestrogen is 50μg per dosage unit.
12. A preparation as claimed in any of claims 3 to 6 wherein the content of the progestogen is between 5μg and 20μg and the content of the oestrogen is between 25μg and 75μg per dosage unit.
13. A preparation as claimed in any one of the preceding claims for use in hormone replacement therapy.
14. A preparation as claimed in any one of claims 1 to 12 for use in the manufacture of a medicament for the treatment of menopausal disorders in women.
15. A composition comprising a therapeutically-effective amount of liposome-bonded oestrogen and/or progestogen, for use in the manufacture of a medicament for the treatment of menopausal disorders in women.
16. A preparation substantially as hereinbefore described with reference to the specification.
PCT/GB1997/001969 1996-07-22 1997-07-22 Topically applied composition for hormone replacement therapy WO1998003156A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU36285/97A AU3628597A (en) 1996-07-22 1997-07-22 Topically applied composition for hormone replacement therapy

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9615350.7 1996-07-22
GBGB9615350.7A GB9615350D0 (en) 1996-07-22 1996-07-22 Hormone replacement therapy

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WO1998003156A2 true WO1998003156A2 (en) 1998-01-29
WO1998003156A3 WO1998003156A3 (en) 1998-03-19

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PCT/GB1997/001969 WO1998003156A2 (en) 1996-07-22 1997-07-22 Topically applied composition for hormone replacement therapy

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AU (1) AU3628597A (en)
GB (1) GB9615350D0 (en)
WO (1) WO1998003156A2 (en)

Cited By (1)

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WO2004075901A2 (en) * 2003-02-25 2004-09-10 Mesko Charles A Compositon for increasing levels of hormones and a method for preparation of said composition

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US4315925A (en) * 1980-05-30 1982-02-16 University Of Kentucky Research Foundation Method of administering natural female sex hormones
US4485054A (en) * 1982-10-04 1984-11-27 Lipoderm Pharmaceuticals Limited Method of encapsulating biologically active materials in multilamellar lipid vesicles (MLV)
EP0177223A2 (en) * 1984-09-24 1986-04-09 Michael Mezei Pharmaceutical multi-phase composition
WO1987001938A1 (en) * 1985-09-27 1987-04-09 The Regents Of The University Of California Liposome transdermal drug delivery system
US4895719A (en) * 1985-05-22 1990-01-23 Liposome Technology, Inc. Method and apparatus for administering dehydrated liposomes by inhalation
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US4315925A (en) * 1980-05-30 1982-02-16 University Of Kentucky Research Foundation Method of administering natural female sex hormones
US4485054A (en) * 1982-10-04 1984-11-27 Lipoderm Pharmaceuticals Limited Method of encapsulating biologically active materials in multilamellar lipid vesicles (MLV)
EP0177223A2 (en) * 1984-09-24 1986-04-09 Michael Mezei Pharmaceutical multi-phase composition
US4895719A (en) * 1985-05-22 1990-01-23 Liposome Technology, Inc. Method and apparatus for administering dehydrated liposomes by inhalation
WO1987001938A1 (en) * 1985-09-27 1987-04-09 The Regents Of The University Of California Liposome transdermal drug delivery system
US4913905A (en) * 1987-04-02 1990-04-03 Ciba-Geigy Corporation Transdermal therapeutic systems for active ingredient combinations
US5498420A (en) * 1991-04-12 1996-03-12 Merz & Co. Gmbh & Co. Stable small particle liposome preparations, their production and use in topical cosmetic, and pharmaceutical compositions
DE19548332A1 (en) * 1995-12-22 1997-07-10 Rotta Res Bv hormone patches

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004075901A2 (en) * 2003-02-25 2004-09-10 Mesko Charles A Compositon for increasing levels of hormones and a method for preparation of said composition
WO2004075901A3 (en) * 2003-02-25 2004-12-16 Charles A Mesko Compositon for increasing levels of hormones and a method for preparation of said composition

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WO1998003156A3 (en) 1998-03-19
AU3628597A (en) 1998-02-10

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