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WO1992020377A1 - Compositions ameliorant la penetration dans la peau a base de monolinoleate de glycerol - Google Patents

Compositions ameliorant la penetration dans la peau a base de monolinoleate de glycerol Download PDF

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Publication number
WO1992020377A1
WO1992020377A1 PCT/US1992/004255 US9204255W WO9220377A1 WO 1992020377 A1 WO1992020377 A1 WO 1992020377A1 US 9204255 W US9204255 W US 9204255W WO 9220377 A1 WO9220377 A1 WO 9220377A1
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WO
WIPO (PCT)
Prior art keywords
drug
skin
composition
permeation
gmlo
Prior art date
Application number
PCT/US1992/004255
Other languages
English (en)
Inventor
Eun Soo Lee
Diane E. Nedberge
Su Il Yum
Original Assignee
Alza Corporation
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 Alza Corporation filed Critical Alza Corporation
Priority to US08/162,026 priority Critical patent/US5641504A/en
Publication of WO1992020377A1 publication Critical patent/WO1992020377A1/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
    • A61K9/70—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1274—Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases or cochleates; Sponge phases
    • 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
    • A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches

Definitions

  • This invention relates to the transdermal delivery of drugs or other biologically active agents and more particularly to methods and compositions for enhancing the percutaneous absorption of drugs or other agents when incorporated in transdermal drug delivery systems or devices.
  • transdermal route of parenteral delivery of drugs provides many advantages, and transdermal systems for delivering a wide variety of drugs or other beneficial agents are described in U.S. Pat. Nos. 3,598,122, 3,598,123, 4,379,454, 4,286,592, 4,314,557 and 4,568,343, for example, all of which are incorporated herein by reference.
  • drugs which would appear to be ideal candidates for transdermal delivery are found to have such low permeability through intact skin that they cannot be delivered in therapeutically effective amounts from reasonably sized devices.
  • terapéuticaally effective rate and “therapeutically effective amount”, as used herein, refer to a rate or an amount of drug or other agent which provides a therapeutic effect or result.
  • therapeutically effective rate refers to a rate or an amount of drug or other agent which provides a therapeutic effect or result.
  • reasonable size refers to a device of a size with a base surface area (that area in contact with the skin site) that is from about 1 cm 2 to about 50 cm 2 , preferably from about 5 cm 2 to about 25 cm 2 . While devices of as large as 200 cm 2 can be considered to be of "conventional" size, such large sizes are not generally acceptable to people, as a practical matter.
  • glycerol monolinoleate is effective in enhancing the permeation of drugs through body surfaces and membranes generally, and through skin in particular.
  • glycerol monolinoleate is able to enhance the permeability of these drugs such that they can be delivered at therapeutically effective rates with reasonably sized transdermal delivery devices.
  • the present invention provides a composition of matter for application to a body surface or membrane to deliver at least one drug, in a therapeutically effective amount, by permeation through the body surface or membrane comprising a least one drug and a permeation-enhancing amount of glycerol monolinoleate.
  • the invention further provides a method for the transdermal coadministrat on of a therapeutically effective amount of a drug together with a skin permeation-enhancing amount of glycerol monolinoleate.
  • the system of the invention is a transdermal drug delivery device comprising a matrix adapted to be placed in drug- and permeation enhancer-transmitting relation with the skin or mucosa site.
  • the matrix contains sufficient amounts of glycerol monolinoleate and of a drug to continuously coadminister to the skin for a predetermined period of time the drug and the permeation enhancer to provide a therapeutic effect.
  • the device is of a reasonable size useful for the application of the drug and the enhancer to a human body.
  • the invention is further directed to a composition of matter which optionally includes, in addition to the drug and GMLO, one or more additional permeation enhancing compounds and to a method for the transdermal administration of such a composition.
  • FIG. 1 is a cross-sectional view of one embodiment of a transdermal therapeutic drug delivery device which may be used in accordance with the present invention.
  • FIG. 2 is a cross-sectional view of another embodiment of a transdermal therapeutic drug delivery device which may be used in accordance with the present invention.
  • FIG. 3 is a cross-sectional view of yet another embodiment of a transdermal therapeutic drug delivery device which may be used in accordance with this invention.
  • glycerol monolinoleate can be used to effectively enhance the permeability of select drugs through body surfaces and particularly through the skin. Specifically, it has been found that GMLO enhances the permeability such that therapeutically effective amounts of a drug can be delivered from reasonably sized devices at therapeutically effective rates.
  • drug and “agent” are used interchangeably and are intended to have their broadest interpretation as to any therapeutically active substance which is delivered to a living organism to produce a desired, usually beneficial, effect.
  • this includes therapeutic agents in all of the major therapeutic areas, including, but not limited to, anti-infectives such as antibiotics and antiviral agents, analgesics and analgesic combinations, anorexics, antiarthritics, antiasth atic agents, anticonvulsants, antidepressants, antidiabetic agents, antidiarrheals, antihistamines, steroidal anti-inflammatory agents, nonsteroidal anti-inflammatory agents, anti-migraine preparations, anti-motion sickness preparations, antinauseants, antineoplasties, antiparkinsonism drugs, antipruritics, antipsychotics, antipyretics, antispas odics including gastrointestinal and urinary, anticholinergics, sympathomimetrics, xanthine derivatives, cardiovascular preparations including calcium channel blockers, beta-blockers, anti-arrhyth ics, antihypertensives, diuretics, vasodilators including general, coronary, peripheral and cerebral, central
  • Representative drugs which may be delivered according to the present invention include, by way of illustration but are not limited to, tetracaine, lidocaine, ketoprofen, piroxicam, propranolol, indomethacin, naproxen, nisoldipine, nifedipine, nicardipine, nitrendipine, diclofenac, scopolamine, isosorbide dinitrate, nitroglycerin, estradiol, clonidine, cortisone, theophylline, phenylephrine, terbutaline, ephedrine, narcodine, quinidine, estradiol diacetate, pilocarpine, furosemide, tetracycline, insulin, chlorpheniramine, sulfathiazides, morphinone, morphine, dihydrocodeine, dihydromorphine, oxycodone, hydrocodone, codeine, norcodeine, hydro
  • Steroid drugs which may be delivered according to the present invention include, but are not limited to, estrogens and estrogen esters, such as the natural 170-estradiol (or, estradiol) and estrone and the semi-synthetic estrogen derivatives such as the esters of natural estrogen, such as estradiol-17/S-enanthate, estradiol-17 / 6- valerate, estradiol-3-benzoate, estradiol-17J-undecenoate, estradiol- 16,17-hemisuccinate or estradiol-17J-cypionate, and the 17-alkylated estrogens, such as ethinyl estradiol, ethinyl estradiol-3- isopropylsulphonate, quinestrol, estranol or methyl estradiol; progestogens and progestogen esters, such as progesterone, levonorgestrel , norethisterone, gestodene and ST-1435; androgen
  • Administration of the drug according to the invention comprises administering the drug at a therapeutically effective rate to an area of a body surface or membrane and simultaneously administering glycerol monolinoleate to the area of the body surface or membrane at rates which are sufficient to substantially increase the permeability of the area to the drug formulation.
  • GMLO and the drug to be delivered are placed in drug- and GMLO-transmitting relationship to the appropriate body surface, preferably in a carrier therefor, and maintained in place for the desired period of time.
  • the drug and GMLO are typically dispersed within a physiologically compatible matrix or carrier which may be applied directly to the body surface or skin as an ointment, gel, cream, suppository or sublingual or buccal tablet, for example, but are more preferably administered from a transdermal therapeutic delivery device as more fully described below.
  • GMLO is a known compound for use as an ingredient in cosmetics or as a food additive. Its use as a permeation enhancer for enhancing the permeation of a drug or other agent through the skin has not been previously known.
  • GMLO has a low toxicity and is colorless and odorless. Additionally, it does not produce irritation, even on prolonged exposure and under occlusion, and it does not sensitize the skin on repeated exposure.
  • GMLO has a permeation-enhancing effect on the transport of drugs through body surface tissues generally, in addition to the skin.
  • skin is one of the most effective body barriers to the permeation of foreign substances, the effect of GMLO on skin permeation makes it extremely useful in transdermal delivery.
  • the following description of embodiments of the invention is therefore directed primarily to improving systemic delivery of these drugs. It may be desirable in certain instances or with certain drugs to include one or two permeation enhancers in addition to the GMLO. Thus, in certain embodiments of the present invention, a second permeation enhancer is included together with the drug and GMLO.
  • This second enhancer may be selected from those compounds that have a permeation-enhancing effect with the drug and are compatible with the drug and with GMLO.
  • the second permeation enhancer is methyl laurate and/or a lower C. ⁇ alkanol, preferably ethanol. While it is known in the art to combine permeation enhancers, this invention utilizes a novel combination of ethanol and/or GMLO. The combined effect produces a significant and surprising improvement over use of either GMLO or ethanol alone.
  • FIG. 1 One embodiment of a transdermal delivery device of the present invention is illustrated in FIG. 1.
  • device 1 is comprised of a drug- and glycerol monolinoleate-containing reservoir ("drug reservoir") 2 which is preferably in the form of a matrix containing the drug and the enhancer dispersed therein.
  • drug reservoir 2 also includes this second enhancer.
  • An impermeable backing layer 3 is provided adjacent one surface of drug reservoir 2.
  • Adhesive overlay 4 maintains the device 1 on the skin and may be fabricated together with, or provided separately from, the remaining elements of the device. With certain formulations, the adhesive overlay 4 may be preferable to an in-line contact adhesive, such as adhesive layer 28 as shown in FIG. 3.
  • Impermeable backing layer 3 is preferably slightly larger than drug reservoir 2, and in this manner prevents the materials in drug reservoir 2 from adversely interacting with the adhesive in overlay 4.
  • a strippable or removable liner 5 is also provided with device 1 and is removed just prior to application of device 1 to the skin.
  • FIG. 2 illustrates another embodiment of the invention, device 10, shown in place upon the skin 17.
  • the transdermal therapeutic delivery device 10 comprises a multilaminate drug formulation/enhancer reservoir 11 having at least two zones 12 and 14.
  • Zone 12 consists of a drug reservoir substantially as described with respect to FIG. 1.
  • Zone 14 comprises a GMLO reservoir which is preferably made from substantially the same matrix as is used to form zone 12.
  • Zone 14 comprises GMLO dispersed throughout and is substantially free of any undissolved drug.
  • a second permeation enhancer may optionally be included in zone 14 as well.
  • a rate-controlling membrane 13 for controlling the release rate of the GMLO and, optionally, any second enhancer from zone 14 to zone 12 is placed between the two zones.
  • a rate-controlling membrane (not shown) for controlling the release rate of the enhancer from zone 12 to the skin may also optionally be utilized and would be present between the skin 17 and zone 12.
  • the rate-controlling membrane may be fabricated from permeable, semipermeable or microporous materials which are known in the art to control the rate of agents into and out of delivery devices and having a permeability to the permeation enhancer lower than that of zone 12.
  • Suitable materials include, but are not limited to, polyethylene, polyvinyl acetate and ethylene vinyl acetate copolymers.
  • An advantage of the device described in FIG. 2 is that the drug-loaded zone 12 is concentrated at the skin surface rather than throughout the entire mass of the reservoir 11. This functions to reduce the amount of drug in the device while maintaining an adequate supply of GMLO permeation enhancer.
  • an impermeable backing 15 and an adhesive overlay 16 Superimposed over the drug formulation/enhancer reservoir 11 of device 10 is an impermeable backing 15 and an adhesive overlay 16 as described above with respect to FIG. 1.
  • a strippable liner (not shown) would preferably be provided on the device prior to use as described with respect to FIG. 1 and removed prior to application of the device 10 to the skin 17.
  • the carrier or matrix material has sufficient viscosity to maintain its shape without oozing or flowing. If, however, the matrix or carrier is a low- viscosity flowable material, the composition can be fully enclosed in a pouch or pocket formed between the impermeable backing and a permeable or microporous skin-contacting membrane, as known to the art from U.S. Pat. No. 4,379,454 (noted above), for example.
  • transdermal delivery device 20 comprises a drug reservoir 22 containing together the drug and the GMLO permeation enhancer.
  • a second permeation enhancer may also be included in drug reservoir 22.
  • Reservoir 22 is preferably in the form of a matrix containing the drug and the enhancer dispersed therein. Reservoir 22 is sandwiched between a backing layer 24, which is impermeable to both the drug and the GMLO, and an in-line contact adhesive layer 28.
  • the drug reservoir 22 is formed of a material, such as a rubbery polymer, that is sufficiently viscous to maintain its shape.
  • the device 20 adheres to the surface of the skin 17 by means of the contact adhesive layer 28.
  • the adhesive for layer 28 should be chosen so that it is compatible and does not interact with any of the drug or, in particular, the GMLO permeation enhancer.
  • the adhesive layer 28 may optionally contain enhancer and/or drug.
  • a strippable liner (not shown) is normally provided along the exposed surface of adhesive layer 28 and is removed prior to application of device 20 to the skin 17.
  • a rate-controlling membrane (not shown) is present and the drug reservoir 22 is sandwiched between backing layer 24 and the rate-controlling membrane, with adhesive layer 28 present on the skin-side of the rate-controlling membrane.
  • Various materials suited for the fabrication of the various layers of the transdermal devices of FIGS. 1, 2 or 3 are known in the art or are disclosed in the aforementioned transdermal device patents previously incorporated herein by reference.
  • the matrix making up the drug/GMLO permeation enhancer reservoir can be a gel or a polymer. Suitable materials should be compatible with the drug and GMLO and any other components in the system. Suitable matrix materials include, without limitation, natural and synthetic rubbers or other polymeric material, thickened mineral oil, or petroleum jelly, for example.
  • the matrix is preferably polymeric and is more preferably an anhydrous polymer.
  • a preferred embodiment according to this invention is fabricated from an ethylene vinyl acetate (EVA) copoly er, of the type described in U.S. Pat. No. 4,144,317, and is preferably selected from those EVAs having a vinyl acetate (VA) content in the range of about 9 to 60%, preferably about 28 to 60% VA.
  • EVA ethylene vinyl acetate
  • the matrix may also contain stabilizers, dyes, pigments, inert fillers, tackifiers, excipients and other conventional components of transdermal delivery devices as are known in the art.
  • the amounts of the drug that are present in the therapeutic device, and that are required to achieve a therapeutic effect depend on many factors, such as the minimum necessary dosage of the particular drug; the permeability of the matrix, of the adhesive layer and of the rate-controlling membrane, if present; and the period of time for which the device will be fixed to the skin. There is, in fact, no upper limit to the maximum amounts of drug present in the device.
  • the minimum amount of each drug is determined by the requirement that sufficient quantities of drug must be present in the device to maintain the desired rate of release over the given period of application.
  • the drug is generally dispersed through the matrix at a concentration in excess of saturation, i.e. at unit activity. The amount of excess is determined by the intended useful life of the system. However, the drug may be present at initial levels below saturation without departing from this invention.
  • the concentration in the matrix is generally in an amount below saturation, as the flux of the estrogen through human epidermis has been found to be proportional to the concentration of estrogen in the drug reservoir.
  • the glycerol monolinoleate is dispersed throughout the matrix, preferably at a concentration sufficient to provide permeation- enhancing concentrations of enhancer in the reservoir throughout the anticipated administration period.
  • a second permeation enhancer such as ethanol and/or methyllaurate, is also dispersed throughout the matrix, preferably at a concentration sufficient to provide permeation-enhancing concentrations of enhancer in the drug reservoir throughout the anticipated administration period.
  • the drug is delivered through the skin or other body surface at a therapeutically effective rate (that is, a rate that provides an effective therapeutic result) and the GMLO is delivered at a permeation-enhancing rate (that is, a rate that provides increased permeability of the application site to the drug) for a predetermined time period.
  • a therapeutically effective rate that is, a rate that provides an effective therapeutic result
  • a permeation-enhancing rate that is, a rate that provides increased permeability of the application site to the drug
  • a preferred embodiment of the present invention is a monolith such as that illustrated in FIG. 3 (either with or without a rate- controlling membrane) wherein reservoir 22 comprises, by weight, 50- 90% polymer (preferably EVA), 0.01-20% drug, and 1-70% GMLO.
  • the in-line adhesive layer 28 contains an adhesive which is compatible with the permeation enhancer.
  • a monolith such as that in FIG. 3 includes reservoir 22 comprising, by weight, 30-90% polymer (preferably EVA), 0.01-20% drug, 1-70% GMLO and 1-45% ethanol and/or 1-45% methyl laurate.
  • the devices of this invention can be designed to effectively deliver a drug for an extended time period of up to 7 days or longer. Seven days is generally the maximum time limit for application of a single device because the skin site is adversely affected by a period of occlusion greater than 7 days. Where it is desired to have drug delivery for greater than 7 days (such as, for example, when a hormone is being applied for a contraceptive effect), when one device has been in place on the skin for its effective time period, it is replaced with a fresh device, preferably on a different skin site.
  • the transdermal therapeutic devices of the present invention are prepared in a manner known in the art, such as by those procedures, for example, described in the transdermal device patents listed previously herein.
  • the drug to be tested at the appropriate concentration, the GMLO, at the appropriate concentration, and EVA 40% VA ("EVA 40") were dissolved in methylene chloride.
  • the solution was poured onto an FCD/polyester release liner to evaporate.
  • the dried material was then pressed to 4-5 mil (ca. 0.1 mm) thickness between two sheets of FCD/polyester release liner at 75°C.
  • the resulting film was heat- laminated to an impermeable backing (Medpar® or Scotchpak®, for example), and discs or squares were punched or die-cut from the laminate.
  • an in-line adhesive was included as a part of the device, the drug matrix/impermeable backing laminate was laminated to an adhesive.
  • each final laminate with adhesive was equilibrated for at least 5 days to allow the enhancer and the drug to partition into the contact adhesive.
  • the edges of the devices with in-line adhesive were masked with polyester tape so that the drug reservoir edges were not exposed to the epidermis or solutions when they were tested.
  • Discs (of a size larger than the device to be tested) were cut from the epidermis, and the discs were kept at 4°C in a hydrated state until they were used.
  • the release liner of the device was removed and the drug-releasing surface was placed against the stratum corneum side of a disc of epidermis which had been blotted dry just prior to use.
  • the excess epidermis was wrapped around the device so that none of the device edge was exposed to the receptor solution.
  • the device covered with epidermis was attached to the flat side of the Teflon holder of a release rate rod using nylon netting and nickel wire.
  • the rods were reciprocated in a fixed volume of receptor solution (distilled water). The entire receptor solution was changed at each sampling time. The temperature of the receptor solution in the water bath was maintained at 35 ⁇ C.
  • the GMLO used was Myverol® 1892K (Eastman Chemical Products; glycerol monolinoleate content of 68% and a total monoesters content of 90%).
  • the adhesive was 3M acrylate transfer adhesive MSP 32589 (an acrylate adhesive with 2-5% acid functionality).
  • the devices contained 2 wt% estradiol and 30 wt% Myverol 1892K GMLO in an EVA 40 matrix.
  • the resulting average flux over 74 hours was 0.15 -ig/cm 2 ⁇ hr (average of the two donors), in comparison to a control without GMLO which had an average flux of 0.02 /tg/cm 2 -hr.
  • the devices contained 20 wt% atenolol base and 30 wt% Myverol 1892K GMLO in an EVA 40 matrix.
  • the adhesive on those devices with adhesive was polyisobutylene-LMMS/polyvinylpyrrolidone L10 (80/20). Control devices were also tested for comparison. The resulting average flux over 53 hours is presented in Table II below.
  • the in vitro transdermal flux of progesterone, from a device as in FIG. 3 without an in-line adhesive, was determined for epidermis from one human cadaver (n 2), following the procedures of Example 1.
  • the devices contained 20 wt% progesterone and 45 wt% Myverol 1892K GMLO in an EVA 40 matrix.
  • the resulting average flux for 24-48 hours was 2.5 ⁇ g/cm 2 -hr, whereas the average flux of the control (20 wt% progesterone in EVA 40, no GMLO) was ⁇ 0.01 /zg/cm 2 -hr.
  • the devices contained 30 wt% oxybutynin base and 25 wt% Myverol 1892K GMLO in an EVA 40 matrix.
  • the resulting average flux over 77 hours was 3.8 ⁇ g/cm 2 -hr, whereas the average flux of the control was 1.0 ⁇ g/cm 2 -hr.
  • the matrix was subsaturated with the permeation enhancer, whose saturation concentration is about 45 wt%.
  • the flux would be further enhanced by including a larger percentage of GMLO in the 5 matrix.
  • the transdermal permeation through human cadaver epidermis of a o composition of the present invention containing diclofenac (as the diethylammonium salt) was determined and was compared to a prior art diclofenac-containing topical gel, Voltarene ® Emulgel ® (1.16% diclofenac diethylammonium salt; Ciba-Geigy).
  • the 1.16% ammonium salt was equivalent to 1.0% doclofenac sodium salt or 0.93% s diclofenac acid.
  • composition A comprised 29.04 wt% Myverol 1892K GMLO, 43.59 wt% ethanol, 24.21 wt% water (as the carrier), 1.16 wt% diclofenac diethylammonium salt, and 2.0 wt% hydroxypropylcellulose (HPC; gelling agent).
  • HPC hydroxypropylcellulose
  • Composition A and the prior art compound were each placed on human cadaver epidermis and the amounts of drug permeated across the 5 epidermis at 35 * C in standard diffusion cells was measured over 48 hours.
  • the donor loading was 10 mg/1.13 cm 2 and in a second test, the donor loading was 50 mg/1.13 cm 2 of skin area. All applications were non-occluded.
  • the total diclofenac which permeated through 1.0 cm 2 of epidermis into a receptor solution was determined o over 48 hours and is presented in Table III below. TABLE III
  • Example 6 the transdermal permeation through human cadaver epidermis of two compositions of the present invention containing hydrocortisone was determined and was compared to a prior art hydrocortisone-containing topical gel, Dermolate ® (0.5% hydrocortisone; Schering Corporation).
  • composition A comprised 29.20 wt% Myverol 1892K GMLO, 43.88 wt% ethanol, 24.42 wt% water (as the carrier), 0.05 wt% hydrocortisone, and 2.0 wt% hydroxypropylcellulose (HPC; gelling agent).
  • Composition B of the invention comprised 61.44 wt% Myverol 1892K, 13.89 wt% ethanol, 23.97 wt% water, and 0.50 wt% hydrocortisone. Composition B formed a kind of ointment and did not need to be gelled.
  • the two compositions and Dermolate were tested for in vitro drug permeation through human cadaver skin, at 35°C.
  • the donor loading was 10 mg/1.13 cm 2 and in a second test, the donor loading was 50 mg/1.13 cm 2 of skin area. All applications were non-occluded.
  • the total hydrocortisone which permeated through 1.0 cm 2 of epidermis into a receptor solution was determined over 48 hours and is presented in Table IV below.
  • Example 6 the transdermal permeation through human cadaver epidermis of a composition of the present invention containing ketoprofen was determined and was compared to a prior art ketoprofen-containing topical ointment, Profenid ® gel (2.5% ketoprofen; Specia Rhone Poulenc).
  • the vehicle of the invention comprised 43.0 wt% ethanol (95%, USP), 28.7 wt% Myverol 1892K GMLO and 23.9 wt% water. Two wt% of hydroxypropylcellulose was added to the vehicle as a gelling agent, after which 2.5 wt% of ketoprofen was added to the vehicle. Following procedures as earlier described, the vehicle and Profenid were tested for drug permeation rate through human cadaver skin by using standard two-compartment horizontal permeation cells, at 35°C. The total ketoprofen which permeated through 1.0 cm 2 of epidermis over the first 24 hours was 0.45 mg/cm 2 , whereas the total of Profenid permeated was 0.23 mg/cm 2 .
  • the vehicle composition of the invention was comprised of 43.9 wt% ethanol (95%, USP), 29.3 wt% Myverol 1892K GMLO and 24.4 wt% water.
  • Piroxicam 0.52 wt% sodium piroxicam
  • 2.0 wt% of hydroxypropylcellulose as a gelling agent
  • the total piroxicam which permeated per 1.0 cm 2 of epidermis into an aqueous receptor solution over the first 24 hours was 0.6 .g/cm 2
  • the total Feldene permeated was ⁇ 0.02 .g/cm 2 .
  • the in vivo transdermal permeation through human skin of testosterone utilizing a composition of the present invention was determined as follows.
  • the composition comprised 26.4 wt% Myverol 1892K GMLO, 37.0 wt% ethanol, 24.6 wt% water, 10.0 wt% testosterone and 2.0 wt% HPC.
  • GMLO Myverol 1892K
  • ethanol 37.0 wt% ethanol
  • water 24.6 wt% water
  • testosterone 10.0 wt% testosterone
  • HPC 2.0 wt% HPC.
  • the resulting gel was placed into a 10cm 2 cup, and three of these systems were applied onto the chest of a healthy male and were taped in place. The systems were maintained on the chest for 8 hr. Blood was drawn prior to placement of the systems (to obtain a baseline) and then at 2 hr, 4 hr and 8 hr after placement, and the amount of testosterone and of dihydrotestosterone in the plasma was analyzed. At 0 hr, the testosterone level in the plasma was 429 ng/dL; after placement of the testosterone systems, the amount of testosterone rose significantly, to 725 ng/dL at 2 hr, to 958 ng/dL at 4 hr, and to 783 ng/dL at 8 hr. During this period, the plasma level of dihydrotestosterone did not change significantly, ranging between 56 and 96 ng/dL.
  • composition containing testosterone was prepared having the following composition: 35.4 wt% Myverol 1892K GMLO, 35.4 wt% methyl laurate, 17.7 wt% ethanol, 10.0 wt% testosterone, and 2.0 wt% HPC.
  • This composition was tested for in vivo delivery of testosterone, following the procedures of Example 10.
  • the composition gave increased blood plasma levels of testosterone over 8 hr — 370 ng/dL at 0 hr, 725 ng/dL at 2 hr, 901 ng/dL at 4 hr, and 665 ng/dL at 8 hr.
  • the dihydrotestosterone plasma level ranged between 54 and 93 ng/dL during this period.

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Abstract

La présente invention concerne des compositions et des systèmes pour l'administration transcutanée d'un médicament contenant du monolinoléate de glycérol en tant qu'agent améliorant la pénétration. Un exemple de système d'administration de l'invention est un système (20) ayant un réservoir de médicament (22) contenant, ensemble, le médicament à administrer et le monolinoléate de glycérol améliorant la pénétration. Le réservoir est pris en sandwich entre un couche de support (24) et une couche adhésive de contact en ligne (28).
PCT/US1992/004255 1988-06-09 1992-05-20 Compositions ameliorant la penetration dans la peau a base de monolinoleate de glycerol WO1992020377A1 (fr)

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US703,440 1991-05-20

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Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993023025A1 (fr) * 1992-05-13 1993-11-25 Alza Corporation Administration transdermique d'oxybutynine
FR2699406A1 (fr) * 1992-12-21 1994-06-24 Commissariat Energie Atomique Films à base de copolymères, leurs applications dans des systèmes transdermiques et leurs procédés de préparation.
WO1995009007A1 (fr) * 1993-09-29 1995-04-06 Alza Corporation Renforcateur de permeation de l'oxybutine a base de monoglyceride/lactate
US5532278A (en) * 1995-01-31 1996-07-02 Sepracor, Inc. Methods and compositions for treating urinary incontinence using optically pure (S)-oxybutynin
WO1996035427A1 (fr) * 1995-05-10 1996-11-14 Hexal Ag Systeme therapeutique transdermique pour administrer de la testorerone
DE19622902A1 (de) * 1995-06-07 1996-12-12 Alza Corp Zusammensetzung zur Steigerung der Permeation der Haut, welche Glycerinmonolaurat und Laurylacetat umfassen
US5677346A (en) * 1995-01-31 1997-10-14 Sepracor, Inc. Treating urinary incontinence using (S)-desethyloxybutynin
WO1998000118A3 (fr) * 1996-07-03 1998-03-05 Alza Corp Dispositifs d'administration de medicaments et procede de fabrication
US5736577A (en) * 1995-01-31 1998-04-07 Sepracor, Inc. Methods and compositions for treating urinary incontinence using optically pure (S)-oxybutynin
US5807573A (en) * 1994-06-15 1998-09-15 Gs Development Ab Lipid based composition containing diacylglycerol, phospholipid, polar liquid and biologically active material
US5939426A (en) * 1997-02-28 1999-08-17 Sepracor Inc. Methods for treating urinary incontinence using descarboethoxyloratadine
US5962464A (en) * 1997-02-11 1999-10-05 Sepracor Inc. Methods and compositions for treating allergic asthma using descarboethoxyloratadine
US6007837A (en) * 1996-07-03 1999-12-28 Alza Corporation Drug delivery devices and process of manufacture
US6100274A (en) * 1999-07-07 2000-08-08 Schering Corporation 8-chloro-6,11-dihydro-11- ](4-piperidylidine)-5H-benzo[5,6]cyclohepta[1,2-bpyridine oral compositions
US6114346A (en) * 1999-10-22 2000-09-05 Schering Corporation Treating sleep disorders using desloratadine
US6174545B1 (en) 1997-07-01 2001-01-16 Alza Corporation Drug delivery devices and process of manufacture
US6432446B2 (en) 2000-02-03 2002-08-13 Bridge Pharma, Inc. Non-arrhythmogenic metabolite of oxybutynin
US6709676B2 (en) 1999-12-20 2004-03-23 Schering Corporation Extended release oral dosage composition
US6723337B1 (en) 1997-09-26 2004-04-20 Samyang Corporation Transdermal drug delivery system for anti-inflammatory analgesic agent comprising diclofenac diethylammonium salt, and the manufacturing method thereof
US6743441B2 (en) 2000-04-26 2004-06-01 Watson Pharmaceuticals, Inc. Compositions and methods for minimizing adverse drug experiences associated with oxybutynin therapy
KR100483913B1 (ko) * 1996-07-03 2005-09-02 알자 코포레이션 약물송달장치
US6979463B2 (en) 1999-12-20 2005-12-27 Schering Corporation Stable extended release oral dosage composition
US7029694B2 (en) 2000-04-26 2006-04-18 Watson Laboratories, Inc. Compositions and methods for transdermal oxybutynin therapy
US7141696B2 (en) 2003-05-23 2006-11-28 Bridge Pharma, Inc. Smooth muscle spasmolytic agents
US7179483B2 (en) 2000-04-26 2007-02-20 Watson Pharmaceuticals, Inc. Compositions and methods for transdermal oxybutynin therapy
US7211582B1 (en) 1994-12-30 2007-05-01 Sepracor Inc. Methods for treating urticaria using descarboethoxyloratadine
US7214683B1 (en) 1994-12-30 2007-05-08 Sepracor Inc. Compositions of descarboethoxyloratadine
US7405223B2 (en) 2000-02-03 2008-07-29 Schering Corporation Treating allergic and inflammatory conditions
US10610507B2 (en) 2012-11-13 2020-04-07 NeuRx Pharmaceuticals LLC Methods for the treatment of sialorrhea

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EP0103911A1 (fr) * 1982-06-30 1984-03-28 THE PROCTER & GAMBLE COMPANY Compositions pharmaceutiques topiques contenant un agent émollient
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Publication number Priority date Publication date Assignee Title
US5411740A (en) * 1992-05-13 1995-05-02 Alza Corporation Transdermal administration of oxybutynin
US5500222A (en) * 1992-05-13 1996-03-19 Alza Corporation Transdermal administration of oxybutynin
WO1993023025A1 (fr) * 1992-05-13 1993-11-25 Alza Corporation Administration transdermique d'oxybutynine
FR2699406A1 (fr) * 1992-12-21 1994-06-24 Commissariat Energie Atomique Films à base de copolymères, leurs applications dans des systèmes transdermiques et leurs procédés de préparation.
WO1994014425A1 (fr) * 1992-12-21 1994-07-07 Commissariat A L'energie Atomique Films a base de copolymeres, leurs applications dans des systemes transdermiques et leurs procedes de preparation
US5556635A (en) * 1992-12-21 1996-09-17 Spi-Bio Films based on copolymers, their applications in transdermal systems and their processes of preparation
US5686097A (en) * 1993-09-29 1997-11-11 Alza Corporation Monoglyceride/lactate ester permeation enhancer for codelivery of steroids
WO1995009007A1 (fr) * 1993-09-29 1995-04-06 Alza Corporation Renforcateur de permeation de l'oxybutine a base de monoglyceride/lactate
US5807573A (en) * 1994-06-15 1998-09-15 Gs Development Ab Lipid based composition containing diacylglycerol, phospholipid, polar liquid and biologically active material
US7214684B2 (en) 1994-12-30 2007-05-08 Sepracor Inc. Methods for the treatment of allergic rhinitis
US7214683B1 (en) 1994-12-30 2007-05-08 Sepracor Inc. Compositions of descarboethoxyloratadine
US7211582B1 (en) 1994-12-30 2007-05-01 Sepracor Inc. Methods for treating urticaria using descarboethoxyloratadine
US5677346A (en) * 1995-01-31 1997-10-14 Sepracor, Inc. Treating urinary incontinence using (S)-desethyloxybutynin
US5736577A (en) * 1995-01-31 1998-04-07 Sepracor, Inc. Methods and compositions for treating urinary incontinence using optically pure (S)-oxybutynin
US5532278A (en) * 1995-01-31 1996-07-02 Sepracor, Inc. Methods and compositions for treating urinary incontinence using optically pure (S)-oxybutynin
WO1996035427A1 (fr) * 1995-05-10 1996-11-14 Hexal Ag Systeme therapeutique transdermique pour administrer de la testorerone
DE19622902C2 (de) * 1995-06-07 2001-05-23 Alza Corp Zusammensetzung zur Steigerung der Permeation der Haut, welche Glycerinmonolaurat und Laurylacetat umfassen
DE19622902A1 (de) * 1995-06-07 1996-12-12 Alza Corp Zusammensetzung zur Steigerung der Permeation der Haut, welche Glycerinmonolaurat und Laurylacetat umfassen
US6007837A (en) * 1996-07-03 1999-12-28 Alza Corporation Drug delivery devices and process of manufacture
WO1998000118A3 (fr) * 1996-07-03 1998-03-05 Alza Corp Dispositifs d'administration de medicaments et procede de fabrication
KR100483913B1 (ko) * 1996-07-03 2005-09-02 알자 코포레이션 약물송달장치
US6054463A (en) * 1997-02-11 2000-04-25 Sepracor Inc. Methods for treating dermatitis using descarboethoxyloratadine
US5962464A (en) * 1997-02-11 1999-10-05 Sepracor Inc. Methods and compositions for treating allergic asthma using descarboethoxyloratadine
US5939426A (en) * 1997-02-28 1999-08-17 Sepracor Inc. Methods for treating urinary incontinence using descarboethoxyloratadine
US6174545B1 (en) 1997-07-01 2001-01-16 Alza Corporation Drug delivery devices and process of manufacture
US6723337B1 (en) 1997-09-26 2004-04-20 Samyang Corporation Transdermal drug delivery system for anti-inflammatory analgesic agent comprising diclofenac diethylammonium salt, and the manufacturing method thereof
US6100274A (en) * 1999-07-07 2000-08-08 Schering Corporation 8-chloro-6,11-dihydro-11- ](4-piperidylidine)-5H-benzo[5,6]cyclohepta[1,2-bpyridine oral compositions
US6114346A (en) * 1999-10-22 2000-09-05 Schering Corporation Treating sleep disorders using desloratadine
US6265414B1 (en) 1999-10-22 2001-07-24 Schering Corporation Treating sleep disorders using desloratadine
US6709676B2 (en) 1999-12-20 2004-03-23 Schering Corporation Extended release oral dosage composition
US7820199B2 (en) 1999-12-20 2010-10-26 Schering Corporation Stable extended release oral dosage composition
US7618649B2 (en) 1999-12-20 2009-11-17 Schering Corporation Extended release oral dosage composition
US6979463B2 (en) 1999-12-20 2005-12-27 Schering Corporation Stable extended release oral dosage composition
US8187630B2 (en) 1999-12-20 2012-05-29 Schering-Plough Corporation Extended release oral dosage composition
US6432446B2 (en) 2000-02-03 2002-08-13 Bridge Pharma, Inc. Non-arrhythmogenic metabolite of oxybutynin
US7405223B2 (en) 2000-02-03 2008-07-29 Schering Corporation Treating allergic and inflammatory conditions
US7902208B2 (en) 2000-02-03 2011-03-08 Schering Corporation Treating allergic and inflammatory conditions
US7087241B2 (en) 2000-04-26 2006-08-08 Watson Laboratories, Inc. Compositions and methods for minimizing adverse drug experiences associated with oxybutynin therapy
US7179483B2 (en) 2000-04-26 2007-02-20 Watson Pharmaceuticals, Inc. Compositions and methods for transdermal oxybutynin therapy
US7081250B2 (en) 2000-04-26 2006-07-25 Watson Laboratories, Inc. Compositions and methods for minimizing adverse drug experiences associated with oxybutynin therapy
US7081252B2 (en) 2000-04-26 2006-07-25 Watson Laboratories, Inc. Compositions and methods for minimizing adverse drug experiences associated with oxybutynin therapy
US7081251B2 (en) 2000-04-26 2006-07-25 Watson Laboratories, Inc. Compositions and methods for minimizing adverse drug experiences associated with oxybutynin therapy
US7081249B2 (en) 2000-04-26 2006-07-25 Watson Laboratories, Inc. Compositions and methods for minimizing adverse drug experiences associated with oxybutynin therapy
US7029694B2 (en) 2000-04-26 2006-04-18 Watson Laboratories, Inc. Compositions and methods for transdermal oxybutynin therapy
US6743441B2 (en) 2000-04-26 2004-06-01 Watson Pharmaceuticals, Inc. Compositions and methods for minimizing adverse drug experiences associated with oxybutynin therapy
US7141696B2 (en) 2003-05-23 2006-11-28 Bridge Pharma, Inc. Smooth muscle spasmolytic agents
US10610507B2 (en) 2012-11-13 2020-04-07 NeuRx Pharmaceuticals LLC Methods for the treatment of sialorrhea

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AU2010392A (en) 1992-12-30
ZA923663B (en) 1993-01-27
MX9202350A (es) 1992-11-01
PT100502A (pt) 1993-08-31

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