WO1996008255A1 - Dispositif pour l'administration transdermique du levonorgestrel - Google Patents

Dispositif pour l'administration transdermique du levonorgestrel Download PDF

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Publication number
WO1996008255A1
WO1996008255A1 PCT/US1995/012158 US9512158W WO9608255A1 WO 1996008255 A1 WO1996008255 A1 WO 1996008255A1 US 9512158 W US9512158 W US 9512158W WO 9608255 A1 WO9608255 A1 WO 9608255A1
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WIPO (PCT)
Prior art keywords
group
acrylate
copolymer
levonorgestrel
percent
Prior art date
Application number
PCT/US1995/012158
Other languages
English (en)
Inventor
Daniel C. Duan
Cheryl L. Moore
Jamieson C. Keister
Steven M. Wick
David J. Wirtanen
John R. Hart
Original Assignee
Minnesota Mining And Manufacturing Company
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 Minnesota Mining And Manufacturing Company filed Critical Minnesota Mining And Manufacturing Company
Priority to AU37236/95A priority Critical patent/AU3723695A/en
Publication of WO1996008255A1 publication Critical patent/WO1996008255A1/fr

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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
    • A61K31/575—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
    • 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

Definitions

  • This invention relates to transdermal drug
  • this invention relates to pharmaceutical formulations containing levonorgestrel.
  • Transdermal drug delivery devices are designed to deliver a therapeutically effective amount of drug across the skin of a patient.
  • Devices known to the art include reservoir type devices involving membranes that control the rate of drug release to the skin and devices involving a dispersion of the drug in a matrix such as a pressure sensitive adhesive.
  • the skin presents a substantial barrier to ingress of foreign substances into the body. It is therefore often desirable or necessary to incorporate certain materials that enhance the rate at which the drug passes through the skin.
  • the type of device, the transdermal flux rate that is suitable, and the suitable formulation components are dependent upon the particular drug to be delivered.
  • Levonorgestrel is a progestational hormone (a progestogen, or progestin) .
  • progestogen or progestin
  • progestin progestogen
  • the present invention provides a transdermal delivery device comprising:
  • lower alkyl as used herein means straight chain or branched chain alkyl containing 1 to 4 carbon atoms.
  • the present invention provides transdermal drug delivery devices containing levonorgestrel.
  • the levonorgestrel is present in a transdermal delivery device of the invention in a therapeutically effective amount, i.e., an amount effective to bring about a desired therapeutic result in the treatment of a condition.
  • therapeutically effective amount varies according to the condition being treated (e.g., osteoporosis, symptoms of menopause), any drugs being coadministered with levonorgestrel, desired duration of treatment, the surface area of the skin over which the device is to be placed, and other components of the transdermal
  • levonorgestrel is present in a device of the invention in an amount of about 0.05 to about 5 percent
  • the matrix is substantially free of solid undissolved levonorgestrel.
  • the copolymer utilized in the practice of the invention should be substantially chemically inert to levonorgestrel.
  • the inherent viscosity of the copolymer is such as to ultimately provide a suitable pressure sensitive skin adhesive when used in a device of the invention.
  • the copolymer has an inherent viscosity in the range 0.2 dl/g to about 2 dl/g, more preferably in the range 0.3 dl/g to about 1.4 dl/g.
  • Suitable copolymers for use in a matrix layer preferably comprise about 40 to 90 percent by weight, more preferably 50 to 70 percent by weight, based on the total weight of all monomers in the copolymer, of one or more A monomers selected from the group
  • alkyl acrylates containing 4 to 10 carbon atoms in the alkyl group consisting of alkyl acrylates containing 4 to 10 carbon atoms in the alkyl group and alkyl methacrylates containing 4 to 10 carbon atoms in the alkyl group.
  • suitable alkyl acrylates and methacrylates are n-butyl, n-pentyl, n-hexyl, isoheptyl, n-nonyl, n- decyl, isohexyl, 2-ethyloctyl, isooctyl and 2- ethylhexyl acrylates and methacrylates.
  • Preferred alkyl acrylates include isooctyl acrylate, 2-ethylhexyl acrylate, butyl acrylate, and cyclohexyl acrylate.
  • the most preferred alkyl acrylate is isooctyl acrylate.
  • Preferred alkyl methacrylates include butyl
  • methacrylate cyclohexyl methacrylate, isobornyl methacrylate, and methyl methacrylate.
  • Exemplary B monomers include acrylic acid, methacrylic acid, maleic acid, a hydroxyalkyl acrylate containing 2 to 4 carbon atoms in the hydroxyalkyl group, a
  • alkoxyethyl acrylate containing 1 to 4 carbon atoms in the alkoxy group alkoxyethyl methacrylate containing 1 to 4 carbon atoms in the alkoxy group, 2- ethoxyethoxyethyl acrylate, furfuryl methacrylate, furfuryl acrylate, tetrahydrofurfuryl acrylate,
  • the preferred B monomers include hydroxyethyl acrylate, hydroxyethyl methacrylate, glyceryl acrylate, N,N-dimethyl acrylamide, 2-ethoxyethoxyethyl acrylate, 2-ethoxyethyl acrylate, tetrahydrofurfuryl acrylate, and acrylic acid.
  • Most preferred B monomers include hydroxyethyl acrylate and N,N-dimethyl acrylamide, and a combination thereof.
  • the matrix layer further comprises an adjuvant selected from the group consisting of C 8 -C 22 fatty acids such as isostearic acid, octanoic acid, and oleic acid, C 8 -C 22 fatty alcohols such as oleyl alcohol and lauryl alcohol, lower alkyl esters of C 8 -C 22 fatty acids such as ethyl oleate, isopropyl myristate, butyl stearate, and methyl laurate, di (lower) alkyl esters of C 6 -C 8 diacids such as diisopropyl adipate, monoglycerides of C 8 -C 22 fatty acids such as glyceryl monolaurate,
  • C 8 -C 22 fatty acids such as isostearic acid, octanoic acid, and oleic acid
  • C 8 -C 22 fatty alcohols such as oleyl alcohol and lauryl alcohol
  • tetrahydrofurfuryl alcohol polyethylene glycol ether, polyethylene glycol, propylene glycol, 2-(2- ethoxyethoxy) ethanol, N,N-dimethyldodecylamine-N-oxide, and a combination of any one or more of any of the foregoing.
  • Preferred adjuvants include glyceryl monolaurate, N, N-dimethyldodecylamine-N-oxide,
  • tetrahydrofurfuryl alcohol polyethylene glycol ether, propylene glycol, methyl laurate, and diisopropyl adipate.
  • the adjuvant is dissolved in the matrix layer and is present in an amount that enhances levonorgestrel penetration through the skin compared to a like device not containing the adjuvant when this phenomenon is measured using the skin penetration model described below.
  • Certain adjuvants affect aspects of performance of a transdermal device other than and in addition to drug penetration rate.
  • certain adjuvants are useful in softening or increasing the compliance value and/or lowering the glass
  • the adjuvants enumerated above are generally oily substances that function as plasticizers when incorporated in a copolymer. Such materials can affect adversely the performance of a copolymer, for example by softening it to the point of cohesive failure (where substantial residue is left on the skin upon removal of the device from the skin) or by separating from the continuous phase of the layer and forming an oily layer that reduces adhesion. Also, certain adjuvants can crystallize in the copolymer, resulting in unstable drug delivery rates.
  • adjuvant amounts in excess of 20% and less than about 50% by weight based on the total weight of the matrix layer have been found to be preferred in order to obtain optimal flux rates, and amounts in excess of 30% are more preferred.
  • adjuvants can be included in amounts of up to about 60% by weight based on the total weight of the matrix layer without
  • the macromonomer when used, is generally present in an amount of not more than about 30%, more preferably not more than 20%, even more preferably not more than about 15%, and most preferably not more than about 10%, by weight based on the total weight of all monomers in the copolymer.
  • the macromonomer can be a compound of the formula
  • X is a moiety comprising an ethylenically unsaturated group (e.g.,
  • R 2 is a hydrogen atom or a lower alkyl group
  • R 3 is a lower alkyl group
  • n is an integer from 20 to 500 and each R 4 is a monovalent radical selected from the group consisting of
  • Suitable macromonomers include polymethylmethacrylate,
  • styrene/acrylonitrile and polystyrene macromonomers.
  • Polymethylmethacrylate macromonomers are preferred.
  • Exemplary macromonomers include those having a general formula selected from the group consisting of
  • R 7 is a hydrogen atom or a lower alkyl group
  • R 8 is hydrogen or methyl
  • R 2 , R 3 , and R 4 are as defined above.
  • ELVACITE 1010 a polymethylmethacrylate macromonomer having an inherent viscosity of 0.070-0.080, a T g of 105°C, a GPC weight average molecular weight of 7,000- 10,000, a GPC number average molecular weight of 2,500- 4,000, and a polydispersity of 2.5-3.0
  • ELVACITE 1020 a polymethylmethacrylate macromonomer having an inherent viscosity of 0.085-0.10, a T g of 105°C, a GPC weight average molecular weight of 12,000-15,000, a GPC number average molecular weight of 4,600-6,000, and a polydispersity of 2.5-3.0).
  • the amount and structure of the comonomers in the copolymer, the inherent viscosity of the copolymer, and the amount and structure of the adjuvant are selected such that the device has a compliance value (measured according to the test method set forth in detail below) of 1 x 10 -5 to 5 x 10 -4 cm 2 /dyne. Compliance values outside this range sometimes are obtained from materials that are suitable. However, those matrices having substantially lower compliance values will generally be relatively stiff and have less than optimal adhesion to skin.
  • Those having substantially higher compliance values will generally have less than optimal cold flow and might leave substantial residual matrix when removed from the skin. Also, a matrix that is intended to function as a pressure sensitive skin adhesive
  • compositions can be readily selected for a given set of desired properties
  • B monomers have been found to increase the amount of levonorgestrel and decrease the amount of oily adjuvant that can be dissolved in a matrix layer. Further, a strongly hydrogen bonding copolymer will be a relatively less compliant material. Therefore if B monomers such as acrylic acid or acrylamide are used a lesser amount of macromonomer (or none at all) will be required in order to lower compliance sufficiently to avoid cohesive failure.
  • Macromonomers also decrease compliance. Therefore a given target compliance value can often be achieved using a lower inherent viscosity A/B copolymer
  • a relatively high compliance pressure sensitive skin adhesive layer involving a macromonomer will generally have better adhesive properties than an A/B copolymer having the same compliance value.
  • Increasing macromonomer content generally increases the amount of adjuvant that can be loaded into a pressure sensitive skin adhesive without cohesive failure.
  • Increasing inherent viscosity will also tend to allow higher adjuvant loading without cohesive failure.
  • a change that would increase inherent viscosity of a copolymer (such as increased molecular weight through selection of polymerization conditions and/or solvent ratios) will generally decrease compliance.
  • stabilizers and reinforcers e.g., colloidal silicon dioxide
  • colloidal silicon dioxide can be incorporated into the matrix if necessary or desirable.
  • a transdermal delivery device of the invention also comprises a backing.
  • the backing is flexible such that the device conforms to the skin.
  • Suitable backing materials include conventional flexible backing
  • materials used for pressure sensitive tapes such as polyethylene, particularly low density polyethylene, linear low density polyethylene, high density
  • polyethylene polyethylene, polyester polyethylene terephthalate, randomly oriented nylon fibers, polypropylene,
  • ethylene-vinyl acetate copolymer polyurethane, rayon and the like.
  • the backing should be substantially inert to the ingredients of the matrix layer.
  • the adhesive copolymers described above for use in a device of the invention can be prepared by methods well known to those skilled in the art and described, for example, in U.S. Patent RE 24,906 (Ulrich) and U.S. Pat. No. 4,732,808 (Krampe at al.).
  • Transdermal delivery devices of the invention are preferably prepared by combining the copolymer, any desired adjuvants, and the levonorgestrel with an organic solvent (e.g., ethyl acetate, methanol, acetone, 2-butanone, ethanol, isopropyl alcohol, toluene, alkanes, and mixtures thereof) to afford a coating formulation.
  • an organic solvent e.g., ethyl acetate, methanol, acetone, 2-butanone, ethanol, isopropyl alcohol, toluene, alkanes, and mixtures thereof.
  • the total solids content of the coating formulation is preferably in a range of about 15 to 40 percent by weight, and more preferably in the range of about 20 to 35 percent by weight, based on the total weight of the coating formulation.
  • the coating formulation is combined and shaken at high speed until a homogeneous formulation is obtained, then allowed to stand to dissipate air bubbles.
  • the resulting coating formulation is knife coated onto a suitable release liner to provide a predetermined uniform thickness of the coating
  • Suitable release liners include
  • conventional release liners comprising a known sheet material such as a polyester web, a polyethylene web, or a polystyrene web, or a polyethylene-coated paper, coated with a suitable fluoropolymer or silicone based coating.
  • the coated release liner is dried and then laminated onto a backing material using conventional methods.
  • Devices of the invention involving a matrix that is not a skin adhesive can be adhered to the skin using conventional means such as a peripheral ring of adhesive surrounding the matrix.
  • transdermal delivery devices of the invention can be made in the form of an article such as a tape, a patch, a sheet, a dressing or any other form known to those skilled in the art.
  • the device will be in the form of a patch of a size suitable to deliver a preselected amount of levonorgestrel through the skin.
  • the device will have a surface area of about 1 cm 2 to about 40 cm 2 .
  • a device of the invention can be used to treat any condition capable of treatment with levonorgestrel.
  • the device can be placed on the skin and allowed to remain for a time sufficient to achieve or maintain the intended therapeutic effect.
  • the time that constitutes a sufficient time can be selected by those skilled in the art with consideration of the flux rate of the device of the invention and upon the condition being treated.
  • the portion of the cell below the mounted skin is completely filled with receptor fluid (30% N-methyl-2- pyrrolidone in water) such that the receptor fluid is in contact with the skin.
  • the receptor fluid is stirred using a magnetic stirrer (not illustrated).
  • the sampling port is covered except when in use.
  • the cell is then placed in a constant temperature (32 ⁇ 2°C) and humidity (50 ⁇ 10% relative humidity) chamber.
  • the receptor fluid is stirred by means of a magnetic stirrer throughout the experiment to assure a uniform sample and a reduced diffusion barrier on the dermal side of the skin.
  • the entire volume of receptor fluid is withdrawn at specified time intervals (6, 12, 24, 48 and 72 hours) and immediately replaced with fresh fluid.
  • the withdrawn fluid is filtered through a 0.45 ⁇ M filter.
  • a 1 mL portion of filtrate is then analyzed for levonorgestrel using high performance liquid chromatography (Column: 15 cm X 4.6 mm I.D.
  • test sample is centered on the stationary plate of a shear-creep rheometer with the long axis of the test sample centered on the short axis of the plate.
  • the small, non-stationary plate of the shear-creep rheometer is centered over the first sample on the stationary plate such that the hook is facing up and toward the front of the rheometer.
  • the second test sample is centered on the upper surface of the small, non- stationary plate matching the axial orientation of the first test sample.
  • the large, non-stationary plate is placed over the second test sample and the entire assembly is clamped into place.
  • the end of the small, non-stationary plate that is opposite the end with the hook is connected to a chart recorder.
  • a string is connected to the hook of the small, non-stationary plate and extended over the front pulley of the
  • A is the area of one face of the test sample
  • h is the thickness of the adhesive mass (i.e., two times the thickness of the matrix on the tested sample)
  • X is the displacement
  • f is the force due to the mass attached to the string.
  • Adhesive Copolymers used in the examples that follow were prepared generally according to the methods described below.
  • Isooctyl acrylate 141.0 g
  • N,N- dimethylacrylamide 35.25 g
  • hydroxyethyl acrylate 35.25 g
  • ELVACITETM 1010 polymethylmethacrylate macromonomer 23.50 g, ICI
  • ethyl acetate 251.75 g
  • isopropanol 13.25 g
  • 2,2'-azobis(2,4- dimethylpentanenitrile) (0.47 g, VAZOTM 52, duPont
  • polymethylmethacrylate macromonomer (23.5 g), ethyl acetate (251.75 g), isopropanol (13.25 g) and VAZO 52 (0.47 g) were charged into a one liter bottle.
  • the mixture was deoxygenated by purging with nitrogen
  • polymethylmethacrylate macromonomer (25.0 g), ethyl acetate (261.25 g), isopropanol (13.75 g) and VAZO 52 (0.5 g) were charged into a one liter bottle.
  • the mixture was deoxygenated by purging with nitrogen
  • Dried adhesive is prepared by knife coating a 25 to 50 percent solids solution of the adhesive copolymer at a thickness of 15 to 25 mil (380 to 635 ⁇ M) onto a release liner.
  • the adhesive coated release liner is oven dried (e.g. 4 min at 110°F (43°C), 2 minutes at 185°F (85°C), and 10 minutes at 300°F
  • the dried adhesive copolymer is stripped off the release liner and stored in a glass container.
  • DDAO N,N-dimethyldodecylamine-N-oxide
  • diethylene glycol monoethyl ether diisopropyl adipate
  • glyceryl monolaurate isopropyl myristate
  • lauryl glycol methyl laurate
  • propylene glycol and
  • IOA isooctyl acrylate, hydroxyethyl acrylate, dimethylacrylamide and
  • Adhesive (7.5348 g of 55/40/5 isooctyl
  • levonorgestrel 0.0509 g
  • diethylene glycol monoethyl ether i.e., 2- (2-ethoxy ethoxy) ethanol (2.0088 g
  • the resulting formulation was knife coated at a thickness of 20 mil (508 ⁇ m) onto a release liner (Daubert 164Z 5 mil (127 ⁇ M) PESTER).
  • the coated release liner was oven dried for 4 minutes at 110°F (43°C), for 2 minutes at 185°F (85°C) and for 2 minutes at 225°F (107°C).
  • the resulting adhesive coating contained 59.0 percent 55/40/5 isooctyl acrylate/hydroxyethyl
  • Example 2 Using the general method of Example 1, a series of transdermal delivery devices in which the amount and type of skin penetration enhancer were varied was prepared. In all instances the adhesive used was
  • Example 2 Using the general method of Example 1, a series of transdermal delivery devices in which the amount and type of skin penetration enhancer were varied was prepared. In all instances the adhesive used was
  • the formulations were coated at 16 mil (406 ⁇ M) wet thickness, and the coated release liners were oven dried for 4 minutes at 125°F (52°C), for 2 minutes at 185°F (85°C) and for 2 minutes at 225°F (107°C).
  • Levonorgestrel was present at 1.0 percent, except in Example 36, where it was present at 1.1 percent.
  • the weight percent and identity of the skin penetration enhancer (s), the steady state flux, and the compliance values are shown in Table 3 below. Examples 39 - 44
  • Example 2 Using the general method of Example 1, a series of transdermal delivery devices in which the amount and type of skin penetration enhancer were varied was prepared. In all instances the adhesive used was
  • formulations were coated at 16 mil (406 ⁇ M) and the coated release liners were oven dried for 4 minutes at 125°F (52°C), for 2 minutes at 185°F (85°C) and for 2 minutes at 225°F (107°C).
  • the weight percent and identity of the skin penetration enhancer (s), the steady state flux, and the compliance values are shown in Table 4 below.
  • Example 2 Using the general method of Example 1, a series of transdermal delivery devices in which the amount and type of skin penetration enhancer were varied was prepared. In all instances the adhesive used was
  • Example 2 Using the general method of Example 1, a series of transdermal delivery devices in which the amount and type of skin penetration enhancer were varied was prepared. In all instances the adhesive used was
  • formulations were coated at 16 mil (406 ⁇ M) and the coated release liners were oven dried for 4 minutes at 125°F (52°C), for 2 minutes at 185°F (85°C) and for 2 minutes at 200°F (93°C).
  • the weight percent and identity of the skin penetration enhancer(s) and the steady state flux are shown in Table 6 below.
  • Example 2 Using the general method of Example 1, a series of transdermal delivery devices in which the amount and type of skin penetration enhancer were varied was prepared. In all instances the adhesive used was
  • Example 2 Using the general method of Example 1, a series of transdermal delivery devices in which the amount and type of skin penetration enhancer were varied was prepared. In all instances the adhesive used was
  • Example 2 Using the general method of Example 1, a series of transdermal delivery devices in which the amount and type of skin penetration enhancer were varied was prepared. In all instances the adhesive used was
  • Example 2 Using the general method of Example 1, a series of transdermal delivery devices in which the amount and type of skin penetration enhancer were varied was prepared. In all instances the adhesive used was
  • acetate/isopropanol were combined in a glass vial.
  • the vial was capped then shaken overnight on a platform shaker.
  • the resulting formulation was allowed to stand to dissipate bubbles and then coated at a thickness of 16 mil (406 ⁇ m) onto a release liner (5 mil (127 ⁇ M) Daubert silicone release liner).
  • the coated release liner was oven dried for 4 minutes at 110°F (43 °C), for 2 minutes at 185°F (85°C) and for 2 minutes at 200°F
  • the resulting adhesive coating contained 54.8 percent 50/40/10 IOA/DMACM/PMMAMac copolymer, 1.4 percent levonorgestrel, 20.8 percent methyl laurate, 2.4 percent glyceryl monolaurate, 1.4 percent dimethyl- dodecylamine-N-oxide and 19.3 percent tetraglycol.
  • the coated liner was then laminated onto a 2 mil (50.8 ⁇ m) polypropylene backing. The laminate was die cut into 2 cm 2 patches. Penetration through human cadaver skin was determined using the test method described above. The steady state flux was 0 ⁇ g/cm 2 /hour. The compliance was 13.23 x 10 -5 cm 2 /dynes.
  • Example 81 Using the general method of Example 81, a series of transdermal delivery devices in which the amount and type of skin penetration enhancer were varied was prepared. In all instances the adhesive used was
  • levonorgestrel was present at 1.5 percent. The weight percent and identity of the skin penetration
  • Example 81 Using the general method of Example 81, a series of transdermal delivery devices in which the amount and type of skin penetration enhancer were varied was prepared. In all instances the adhesive used was
  • the resulting formulation was knife coated at a wet thickness of 16 mil (406 ⁇ M) onto a silicone coated polyester (5 mil, 127 ⁇ M) film.
  • the coated release liner was oven dried at 127°F (53 °C) for 30 minutes.
  • the resulting adhesive coating contained 1.5 percent levonorgestrel, 15.0 percent propylene glycol, 25.0 percent methyl laurate, 2.5 percent glyceryl
  • the coated liner was allowed to cool for 10 minutes then it was laminated to the corona treated side of a 2 mil (51 ⁇ M) polypropylene film.
  • the compliance was measured using the test method described above and found to be 6.57 x 10 -5 cm 2 /dynes. Skin penetration through human cadaver skin was measured using the test method described above; the steady state flux was found to be 0.40 ⁇ g/cm 2 /hr.
  • the carboy was tightly capped then placed on a roller/shaker for 19 hours.
  • the carboy was allowed to stand until all entrapped air bubbles had dissipated.
  • the resulting formulation was knife coated at a wet thickness of 13 mil (330 ⁇ M) onto a silicone coated polyester (5 mil, 127 ⁇ M) film.
  • the coated release liner was oven dried at 127°F (53°C) for 75 minutes.
  • the coated sheet materials were stored at 4°C then examined with a microscope after 1 week and 2 weeks of storage. The formulations and the results of the microscopic examinations are shown in Table 14.

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Abstract

L'invention concerne un dispositif d'administration transdermique d'un médicament, faisant appel à un copolymère basé sur des acrylates ou des méthacrylates, un adjuvant pour améliorer la pénétration dans la peau et une quantité de lévonorgestrel suffisante pour être efficace.
PCT/US1995/012158 1994-09-14 1995-09-12 Dispositif pour l'administration transdermique du levonorgestrel WO1996008255A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU37236/95A AU3723695A (en) 1994-09-14 1995-09-12 Transdermal device for delivery of levonorgestrel

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US30615494A 1994-09-14 1994-09-14
US08/306,154 1994-09-14

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WO1996008255A1 true WO1996008255A1 (fr) 1996-03-21

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997003698A1 (fr) * 1995-07-22 1997-02-06 Grünenthal GmbH Emplatre liberant des hormones
WO1998002147A2 (fr) * 1996-07-11 1998-01-22 Schering Aktiengesellschaft Systemes therapeutiques transdermiques
DE19728516A1 (de) * 1997-07-04 1999-01-07 Sanol Arznei Schwarz Gmbh TTS zur Verabreichung von Levonorgestrel
EP1310257A2 (fr) * 1997-09-11 2003-05-14 HESCH, Rolf Dieter Combinaison hormonale contraceptive
EP1875905A2 (fr) 2003-04-28 2008-01-09 Bayer Schering Pharma Aktiengesellschaft Composition pharmaceutique sous la forme d'un hydrogel pour l'administration transdermique d'agents actifs

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990006736A1 (fr) * 1988-12-16 1990-06-28 Rutgers, The State University Of New Jersey Procede, systeme et unite de dosage transdermique d'oestrogene/progestine
EP0416842A1 (fr) * 1989-09-08 1991-03-13 Cygnus Therapeutic Systems Système de matrice solide pour l'administration transcutanée de médicaments
EP0587047A2 (fr) * 1992-09-07 1994-03-16 JENAPHARM GmbH Composition pharmaceutique contenant des gestagènes

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Publication number Priority date Publication date Assignee Title
WO1990006736A1 (fr) * 1988-12-16 1990-06-28 Rutgers, The State University Of New Jersey Procede, systeme et unite de dosage transdermique d'oestrogene/progestine
EP0416842A1 (fr) * 1989-09-08 1991-03-13 Cygnus Therapeutic Systems Système de matrice solide pour l'administration transcutanée de médicaments
EP0587047A2 (fr) * 1992-09-07 1994-03-16 JENAPHARM GmbH Composition pharmaceutique contenant des gestagènes

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997003698A1 (fr) * 1995-07-22 1997-02-06 Grünenthal GmbH Emplatre liberant des hormones
US5985311A (en) * 1995-07-22 1999-11-16 Labtec Gesellschaft Fuer Techologische Forschung Und Entwicklung Mbh Transdermal hormone patch
WO1998002147A2 (fr) * 1996-07-11 1998-01-22 Schering Aktiengesellschaft Systemes therapeutiques transdermiques
WO1998002147A3 (fr) * 1996-07-11 1998-03-12 Schering Ag Systemes therapeutiques transdermiques
DE19728516A1 (de) * 1997-07-04 1999-01-07 Sanol Arznei Schwarz Gmbh TTS zur Verabreichung von Levonorgestrel
DE19728516C2 (de) * 1997-07-04 1999-11-11 Sanol Arznei Schwarz Gmbh TTS zur Verabreichung von Levonorgestrel und gegebenenfalls Estradiol
EP1310257A2 (fr) * 1997-09-11 2003-05-14 HESCH, Rolf Dieter Combinaison hormonale contraceptive
EP1310257A3 (fr) * 1997-09-11 2003-07-16 HESCH, Rolf Dieter Combinaison hormonale contraceptive
EP1875905A2 (fr) 2003-04-28 2008-01-09 Bayer Schering Pharma Aktiengesellschaft Composition pharmaceutique sous la forme d'un hydrogel pour l'administration transdermique d'agents actifs

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