WO1999032096A1 - Nouvelles formulations d'administration transdermique d'asimadoline - Google Patents

Nouvelles formulations d'administration transdermique d'asimadoline Download PDF

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Publication number
WO1999032096A1
WO1999032096A1 PCT/US1998/026652 US9826652W WO9932096A1 WO 1999032096 A1 WO1999032096 A1 WO 1999032096A1 US 9826652 W US9826652 W US 9826652W WO 9932096 A1 WO9932096 A1 WO 9932096A1
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WIPO (PCT)
Prior art keywords
asimadoline
reservoir
permeation enhancer
therapeutically effective
weight
Prior art date
Application number
PCT/US1998/026652
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English (en)
Inventor
William Van Osdol
Tyler Watanabe
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 AU18283/99A priority Critical patent/AU1828399A/en
Publication of WO1999032096A1 publication Critical patent/WO1999032096A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • 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

Definitions

  • This invention relates to sustained release formulations for the safe and efficacious administration of asimadoline for, among other things, the treatment of chronic pain. More particularly, the invention relates to novel methods, compositions, and devices for transdermally administering asimadoline to a subject through a body surface or membrane over a sustained time period.
  • the transdermal route of administration appeared to offer many advantages, particularly with respect to agents that had short half lives and therefore required frequent, repeated dosing or were subject to a high degree of first-pass metabolism by the liver when orally administered.
  • the peaks and valleys in blood concentration resulting from frequent periodic doses of short half-life agents would be eliminated and replaced by substantially constant plasma concentration. This would not only improve individual compliance but also would eliminate the alternating periods of high side-effects and ineffective blood concentrations associated with period dosing.
  • Administering the agent through the skin directly into the blood stream would also eliminate first-pass metabolism of orally administered agents.
  • transdermal route of administration rather than being available to every short half-life agent of high potency and skin permeability, was found to be available only to those few agents that possess the proper combination of a host of characteristics, most of which are unpredictable, required to render the agent suitable for safe and effective transdermal administration.
  • the most significant of these characteristics are the following:
  • the permeability of the skin to the agent must be sufficiently high so that the agent can be administered at a therapeutically effective rate through an area of skin no greater than about 200 cm 2 and preferably no greater than 50 cm 2 .
  • the person-to-person variation in skin permeability at similar sites should also be considered.
  • U.S. Patent Nos. 4,568,343, 4,746,515, 4,863,738, 4,865,848, 4,888,354, 5,378,730, 5,641 ,504 and WO 95/09006, WO 95/01167, WO 96/37231 , and WO 96/40259 are related to various compositions and methods for enhancing permeation of drugs through the skin and are hereby incorporated in their entirety by reference.
  • the skin beneath the transdermal delivery device has the capability of creating a skin depot of drug by absorbing, adsorbing, or binding a certain amount of agent.
  • the amount of agent so bound must be supplied to the skin before the agent can be delivered into the blood stream at steady, therapeutically effective rates. If large amounts of the agent are bound in the skin, significant delays in the onset of therapeutic effect ("lag time") will be observed together with corresponding delays in termination of effect upon removal of the device. The potential also exists for toxic quantities of potent agents to be contained within the skin beneath the device.
  • Skin binding is not related to skin permeability. Agents that are highly permeable may also be highly bound causing a lag time sufficiently long as to render them unsuitable for their intended use.
  • Sensitization is an allergic reaction which is induced when an agent is first applied to the skin and is elicited upon continued exposure which may occur immediately or after a long period of seemingly harmless exposure.
  • the sensitization may be local, elicited by topical exposure, which manifests itself as contact dermatitis accompanied by blistering, itching, reddening and burning at the site of application.
  • the sensitization may be systemic, elicited by topical application but manifesting itself by more general allergic reactions at sites other than the site of application. Most seriously, the systemic sensitization may be elicited by oral or intravenous administration of the drug. If the latter occurs, the individual will be unable to take the drug by any route of administration.
  • the half-life of an agent is the time after administration that half of the amount administered has been eliminated from the body. Because blood concentrations of continuously administered agents will continue to increase for approximately five half-lives before steady-state constant blood concentrations are achieved, an agent must have a relatively short half-life to be suitable for continuous transdermal administration. The transdermal half-lives of most agents have not been determined. When half-lives of agents determined from intravenous administration are compared with half-lives determined from transdermal administration, the transdermal half-lives are generally longer but there can be wide variation in half-life between individuals based upon factors such as age, sex, health, and body type.
  • Constant blood levels may not produce the desired therapeutic effects. For example, a therapeutic effect may only be observed at peak blood concentration obtained from bolus dosing but the peak blood or plasma concentration cannot be maintained because of side effects associated therewith. Also, continuous administration of many agents produces tolerance that may require either some agent-free interval or continually increasing and therefore potentially hazardous doses of the agent.
  • Potency Although a certain degree of potency is required for transdermally administered agent to be effective, it is also possible for an agent to be too potent. As potency increases, lower blood concentrations are required and much smaller quantities are administered. Because of normal inter-individual variations and skin permeability, it may not be possible to precisely control whether a individual is receiving 1 mg/hr or 2 mg/hr, for example. For a highly potent agent, a 1 mg/hr administration may be totally ineffective and a 2 mg/hr rate fatal. Thus, the therapeutic index of an agent, which is the ratio of toxic blood concentration to the therapeutic blood concentration, becomes extremely significant. A highly potent agent should also have a relatively wide therapeutic window in order to be suitable for transdermal administration.
  • the present invention is directed to the transdermal administration of asimadoline, N-[(aS)- ⁇ -[[(3S)-3-Hydroxy-1-pyrrolidinyl]methyl]benzyl]-N- methyl-2,2-diphenylacetamide, a peripheral ⁇ -opioid receptor agonist for the treatment of chronic pain.
  • the drug is synthesized directly as the hydrochloride salt which has a molecular weight of 451 gm/mole and a melting point of 222 - 224° C.
  • the preparation of asimadoline is described in US Patent No. 5,532,266, which is herein incorporated in its entirety by reference.
  • asimadoline is administered orally b.i.d. or intravenously at a daily dose of about 1-10 mg.
  • Transdermal administration of asimadoline significantly enhances patient compliance by alleviating the discomfort of needles, cumbersome I.V. apparatii, and the administration of twice-a-day oral dosages by providing a convenient dosage form for once or twice weekly application.
  • Other benefits discussed above associated with the transdermal administration of asimadoline are also provided, such as sustained blood levels and the elimination of side effects associated with oral administration. DESCRIPTION OF TERMS
  • asimadoline intends not only the basic form of asimadoline but also pharmaceutically acceptable salt forms of asimadoline, the R or S enantiomers of asimadoline, either individually or as a racemic mixture, and to mixtures thereof.
  • the term "asimadoline therapy” intends all medical conditions for which asimadoline is or will be indicated, including, without limitation, for the treatment of chronic pain.
  • the term “individual” intends a living mammal and includes, without limitation, humans and other primates, livestock and sports animals such as cattle, pigs and horses, and pets such as cats and dogs.
  • the term "monoglyceride” refers to a monoglyceride or mixture of monoglycerides of C 8 - C 20 fatty acids and includes, without limitation, glycerol monolaurate (GML), glycerol monooleate (GMO), glycerol monocaprate (GMC), glycerol monocaprylate (GMCL), and glycerol monolinoleate (GMLO).
  • GML glycerol monolaurate
  • GMO glycerol monooleate
  • GMC glycerol monocaprate
  • GMCL glycerol monocaprylate
  • GMLO glycerol monolinoleate
  • permeation enhancement intends an increase in the permeability of skin to asimadoline in the presence of a permeation enhancer as compared to permeability of skin to asimadoline in the absence of a permeation enhancer.
  • permeation enhancer intends an agent or a mixture of agents which acts to increase the permeability of the skin to asimadoline.
  • permeation-enhancing amount intends an amount of a permeation enhancer which provides permeation enhancement throughout a substantial portion of the administration period.
  • predetermined area of skin intends a defined area of intact unbroken skin or mucosal tissue. That area will usually be in the range of about 5 cm 2 to about 100 cm 2 .
  • salt intends, but is not limited to, pharmaceutically acceptable organic or inorganic salts. Typical inorganic salts include hydrogen halides such as hydrochlorides, carbonates, phosphates, sulfates, hydrogen sulfates, hydrobromides, nitrates, and sulfides.
  • Organic salts includes, but are not limited to, acid addition salts including salts of monocarboxylic and polycarboxylic acids such as acetic acid, malic acid, maleic acid, propionic acid, succinic acid, fumaric acid, citric acid, benzoic acid, cinnamic acid, tartaric acid, and the like.
  • sustained time period or “administration period” intends at least about 8 hours and will typically intend a period in the range of about one to about seven days.
  • the term "therapeutically effective amount” intends the dose of asimadoline and/or its active metabolites that provides asimadoline therapy, in the case of adult and juvenile humans, the optimum dosage range is the equivalent of the oral dose of about 1-10 mg asimadoline per day.
  • the term "therapeutically effective rate” intends a delivery rate of asimadoline and/or its active metabolites effective to achieve therapeutic blood or plasma levels in an individual during the administration period and is typically within the range of about 10 - 550 ⁇ g/hr, preferably about 40 - 450 ⁇ g/hr.
  • therapeutic blood or plasma level intends the level of asimadoline and/or its active metabolites in blood or plasma that achieves a therapeutic effect for the desired asimadoline therapy.
  • transdermal intends both percutaneous and transmucosal administration, i.e., passage of asimadoline through intact unbroken skin or mucosal tissue into the systemic circulation.
  • compositions and methods for the transdermal delivery of asimadoline and/or its active metabolites, and delivery systems for effecting the same which are suitable for the transdermal administration of asimadoline and/or its active metabolites continuously through a body surface or membrane at a therapeutically effective rate in order to achieve and maintain therapeutic blood or plasma levels in an individual.
  • Another aspect of this invention is to improve patient compliance of patients in need of asimadoline therapy by providing compositions, devices, and methods for the transdermal administration of asimadoline at a therapeutically effective rate.
  • the invention comprises the following aspects, either alone or in combination:
  • a composition of matter for the transdermal administration of asimadoline comprising an amount of asimadoline in a carrier effective to permit sustained release of asimadoline at a therapeutically effective rate during an administration period of at least 12 hours in order to administer a therapeutically effective amount of asimadoline in order to achieve and maintain therapeutic blood or plasma levels throughout a substantial portion of the administration period.
  • a device for the transdermal administration of asimadoline at a therapeutically effective rate comprising:
  • (c) means for maintaining the reservoir in asimadoline transmitting relation with a body surface or membrane, wherein a therapeutically effective amount of asimadoline is delivered at a therapeutically effective rate during an administration period of at least 12 hours in order to achieve and maintain therapeutic blood or plasma levels throughout a substantial portion of the administration period.
  • compositions and devices may further comprise a pharmaceutically acceptable salt of asimadoline, a permeation enhancing amount of a permeation enhancer such as a monoglyceride and a cosolvent selected from the group consisting of C 10 - C 20 fatty acid esters, caproyl lactylic acid, lauroyl lactylic acid, dimethyl lauramide, dodecyl acetate, lauryl lactate, isopropyl myristate, ethyl palmitate, and methyl laurate.
  • a pharmaceutically acceptable salt of asimadoline such as a monoglyceride
  • a cosolvent selected from the group consisting of C 10 - C 20 fatty acid esters, caproyl lactylic acid, lauroyl lactylic acid, dimethyl lauramide, dodecyl acetate, lauryl lactate, isopropyl myristate, ethyl palmitate, and methyl laurate.
  • the invention is directed to a method for treating an individual suffering from chronic pain comprising transdermally administering asimadoline to the individual wherein a therapeutically effective amount of asimadoline is delivered at a therapeutically effective rate during an administration period of at least 12 hours in order to achieve and maintain therapeutic blood or plasma levels of asimadoline throughout a substantial portion of the administration period.
  • Figure 1 is a cross-section through a schematic perspective view of one embodiment of a transdermal therapeutic system according to this invention.
  • Figure 2 is a cross-section view through another embodiment of this invention prior to application to the skin.
  • Figure 3 is a cross-section view through another embodiment of this invention prior to application to the skin.
  • Figure 4 is a cross-section view through another embodiment of this invention prior to application to the skin.
  • Figure 5 depicts the release rate of asimadoline from polymer matrix formulations containing various permeation enhancers.
  • Figure 6 depicts the time-averaged in vitro flux of asimadoline from polymer matrix formulations containing various permeation enhancers through human cadaver epidermis over 96 hours.
  • Figures 7A and 7B depict the asimadoline flux through different human cadaver epidermis as a function of time.
  • asimadoline can be safely and efficaciously administered by a sustained release formulation. More specifically, it has been found that asimadoline can be safely and efficaciously administered transdermally at a therapeutically effective rate to provide, among other things, treatment for chronic pain, preferably when coadministered with a suitable permeation enhancer.
  • the present invention provides novel compositions, devices, and methods for asimadoline therapy with improved patient compliance to an individual in need of such therapy.
  • a preferred embodiment is directed to the transdermal administration of asimadoline hydrochloride as the inventors have found that asimadoline hydrochloride may be transdermally administered at therapeutically effective rates.
  • Other salts which provide the necessary flux and irritation levels can be determined in accordance with the principles of the teachings of this invention.
  • Therapeutic blood or plasma levels can be obtained from administration rates in the range of 10 - 550 ⁇ g/hr, preferably about 40 - 450 mg/hr.
  • Representative in vitro skin fluxes of asimadoline hydrochloride through human skin are in the range of about 0.2 - 10 mg/cm 2 hr, depending on the drug form, permeation enhancer, and if an in-line adhesive is present.
  • the range of desired and achievable cumulative release of asimadoline, arriving through the skin at a limited area is equivalent to the oral dosage of 1 - 10 mg per 24 hours.
  • the system is easily adapted to provide a cumulative release of asimadoline over a 24 hour period of less than 10 mg if necessary. Additionally, the system is easily adapted for shorter or longer duration treatments.
  • asimadoline is placed in asimadoline transmitting relationship to an appropriate body surface, preferably in a pharmaceutically acceptable carrier thereof, and maintained in place for the desired administration period.
  • the asimadoline and permeation enhancer are typically dispersed within a physiologically compatible matrix or carrier, as more fully described below, which may be applied directly to the body as an ointment, gel, cream, suppository or sublingual or buccal tablet.
  • a physiologically compatible matrix or carrier as more fully described below, which may be applied directly to the body as an ointment, gel, cream, suppository or sublingual or buccal tablet.
  • a physiologically compatible matrix or carrier as more fully described below, which may be applied directly to the body as an ointment, gel, cream, suppository or sublingual or buccal tablet.
  • compositions can also contain other permeation enhancers, stabilizers, dyes, diluents, pigments, vehicles, inert fillers, anti-irritants, excipients, gelling agents, vasoconstrictors, vasodilators, and other components of topical compositions as are known to the art.
  • asimadoline would be administered from a transdermal delivery device as more fully described below. Examples of suitable transdermal delivery devices are illustrated in Figs. 1 - 4. In the figures, the same reference numbers are used throughout the different figures to designate the same or similar components. The figures are not drawn to scale.
  • a preferred embodiment of a transdermal therapeutic system comprises transdermal delivery device 10 comprising a reservoir 12, preferably in the form of a matrix containing asimadoline, and a permeation enhancer dispersed therein.
  • Reservoir 12 is sandwiched between a backing 14 and an in-line contact adhesive layer 16.
  • the device 10 adheres to the surface of the skin 18 by means of the adhesive layer 16.
  • the adhesive layer 16 may optionally contain the permeation enhancer and/or asimadoline.
  • a removable release liner (not shown in FIG. 1) is normally provided along the exposed surface of adhesive layer 16 and is removed prior to application of device 10 to the skin 18.
  • a rate-controlling membrane (not shown) may be present between the reservoir 12 and the adhesive layer 16.
  • a non-rate controlling tie layer membrane as disclosed in US Patent No. 5,635,203, incorporated herein in its entirety by reference, may be present between the reservoir 12 and adhesive 16 in any of the embodiments depicted in figures 1- 4.
  • FIG. 1 Although the preferred embodiments of this invention utilize an in-line adhesive as is shown in Figure 1 , other means for maintaining the system on the skin can be employed. Such means include a peripheral ring of adhesive outside the path of the drug from the system to the skin or the use of other fastening means such as buckles, belts, and elastic arm bands.
  • reservoir 12 may be in the form of a matrix containing asimadoline and permeation enhancer dispersed within a suitable adhesive, preferably a pressure sensitive adhesive.
  • pressure sensitive adhesives include, but are not limited to, polysiloxanes, polyacrylates, polyurethanes, acrylic adhesives including cross linked or non-crosslinked acrylic copolymers, vinyl acetate adhesives, ethylene vinylacetate copolymers, and natural or synthetic rubbers including polybutadienes, polyisoprenes, and polyisobutylene adhesives, and mixtures and graft copolymers thereof.
  • the matrix formulations according to this embodiment comprise the adhesive containing asimadoline and permeation enhancer, if present, laminated to a backing on one surface and to a release liner on the other.
  • the matrix or carrier may also contain dyes, pigments, inert fillers, anti-irritants, excipients and other conventional components of pharmaceutical products or transdermal devices known to the art.
  • the matrix may also be provided with hydrophilic water absorbing polymers known in the art such as polyvinyl alcohol and polyvinyl pyrrolidone individually or in combination. Other suitable water soluble and water absorbing polymers are known in the art, such as those disclosed in U.S. Patent No.
  • transdermal therapeutic device 20 may be attached to the skin or mucosa of a patient by means of an adhesive overlay 22.
  • Device 20 is comprised of reservoir 12 preferably in the form of a matrix containing asimadoline and a permeation enhancer dispersed therein.
  • a backing layer 14 is provided adjacent to one surface of reservoir 12.
  • Adhesive overlay 22 maintains the device 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 22 may be preferable to the in-line contact adhesive 16 as shown in FIG. 1.
  • Backing layer 14 is preferably slightly larger than reservoir 12, and in this manner prevents the materials in reservoir 12 from adversely interacting with the adhesive in overlay 22.
  • a rate-controlling membrane (not shown in FIG. 2) may be provided on the skin-proximal side of reservoir 12.
  • a removable release liner 24 is also provided with device 20 and is removed just prior to application of device 20 to the skin.
  • transdermal delivery device 30 comprises an asimadoline and permeation enhancer reservoir ("asimadoline reservoir") 12 substantially as described with respect to FIG. 1.
  • Permeation enhancer reservoir (“enhancer reservoir”) 26 comprises the permeation enhancer dispersed throughout and contains asimadoline at or below saturation, when in equilibrium with the asimadoline reservoir 12.
  • Enhancer reservoir 26 is preferably made from substantially the same matrix as is used to form asimadoline reservoir 12.
  • a rate-controlling membrane 28 for controlling the release rate of the permeation enhancer from enhancer reservoir 26 to asimadoline reservoir 12 is placed between the two reservoirs.
  • a rate- controlling membrane (not shown in FIG. 3) for controlling the release rate of the enhancer and/or asimadoline from asimadoline reservoir 12 to the skin may also optionally be utilized and would be present between adhesive layer 16 and reservoir 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 drug reservoir 12.
  • Suitable materials include, but are not limited to, polyethylene, polyvinyl acetate, ethylene n-butyl acetate and ethylene vinyl acetate copolymers.
  • the carrier or matrix material of the reservoirs has sufficient viscosity to maintain its shape without oozing or flowing. If, however, the matrix or carrier is a low-viscosity flowable material such as a liquid or a gel, the composition can be fully enclosed in a pouch or pocket, as known to the art from US Pat. No. 4,379,454 (noted above), for example, and as illustrated in FIG. 4.
  • Device 4 comprises a backing member 14 which serves as a protective cover for the device, imparts structural support, and substantially keeps components in device 40 from escaping the device.
  • Device 40 also includes reservoir 12, which contains the asimadoline and permeation enhancer and bears on its surface distant from backing member 14, a rate-controlling membrane 28 for controlling the release of asimadoline and/or permeation enhancer from device 40.
  • the outer edges of backing member 14 overlay the edges of reservoir 12 and are joined along the perimeter with the outer edges of the rate-controlling membrane 28 in a fluid-tight arrangement.
  • This sealed reservoir may be effected by pressure, fusion, adhesion, an adhesive applied to the edges, or other methods known in the art. In this manner, reservoir 12 is contained wholly between backing member 14 and rate-controlling membrane 28.
  • On the skin-proximal side of rate-controlling membrane 28 are an adhesive layer 16 and a removable liner 24 which would be removed prior to application of the device 40 to the skin.
  • reservoir 12 contains the permeation enhancer and contains asimadoline at or below saturation.
  • the asimadoline and an additional amount of permeation enhancer are present in adhesive layer 16, which acts as a separate reservoir.
  • Asimadoline can be administered to human skin or mucosa by direct application to the skin or mucosa in the form of an ointment, gel, cream or lotion, for example, but are preferably administered from a skin patch or other known transdermal delivery device which contains a saturated or unsaturated formulation of the asimadoline and enhancer.
  • the formulation may be aqueous or non-aqueous based.
  • the formulation should be designed to deliver the asimadoline and any anti-irritant and/or enhancer at the necessary fluxes.
  • Aqueous formulations typically comprise water or water/ethanol and about 1-5 wt% of a gelling agent, an example being a hydrophilic polymer such as hydroxyethylcellulose or hydroxypropylcellulose.
  • Typical non- aqueous gels are comprised of silicone fluid or mineral oil.
  • Mineral oil-based gels also typically contain 1-2 wt% of a gelling agent such as colloidal silicon dioxide.
  • a gelling agent such as colloidal silicon dioxide. The suitability of a particular gel depends upon the compatibility of its constituents with the asimadoline, anti-irritant, and the permeation enhancer in addition to any other components in the formulation.
  • the reservoir matrix should be compatible with asimadoline, the permeation enhancer, and any carrier therefor.
  • matrix refers to a well-mixed composite of ingredients.
  • the reservoir matrix is preferably a hydrophilic polymer, e.g., a hydrogel.
  • the reservoir matrix is preferably composed of a hydrophobic polymer.
  • Suitable polymeric matrices are well known in the transdermal drug delivery art, and examples are listed in the above-named patents previously incorporated herein by reference.
  • a typical laminated system would consist essentially of a polymeric membrane and/or matrix such as ethylene vinyl acetate (EVA) copolymers, such as those described in US Pat. No. 4,144,317, preferably having a vinyl acetate (VA) content in the range of from about 9% up to about 60% and more preferably about 9% to 40% VA.
  • EVA ethylene vinyl acetate
  • Polyisobutylene/oil polymers containing from 4-25% high molecular weight polyisobutylene and 20-81% low molecular weight polyisobutylene with the balance being an oil such as mineral oil or polybutene may also be used as the matrix material.
  • the amount of asimadoline present in the therapeutic device and required to achieve an effective therapeutic result depends on many factors, such as the minimum necessary dosage of the asimadoline for the particular indication being treated; the solubility and permeability of the matrix, taking into account the presence of permeation enhancer, 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.
  • the minimum amount of asimadoline is determined by the requirement that sufficient quantities of asimadoline must be present in the device to maintain the desired rate of release over the given period of application.
  • the maximum amount for safety purposes is determined by the requirement that the quantity of asimadoline present cannot exceed a rate of release that reaches toxic levels.
  • the asimadoline may be present in the matrix or carrier at a concentration at or below saturation.
  • An excess amount of asimadoline above saturation may be included in the matrix or carrier, the amount of excess being a function of the desired length of the delivery period of the system.
  • Asimadoline may be present at a level below saturation without departing from this invention as long as it is continuously administered to the skin or mucosal site at a therapeutic rate and for a period of time sufficient to deliver a therapeutically effective amount of asimadoline that provides the desired therapeutic result.
  • the permeation enhancer useful in the present invention is selected from those compounds which are compatible with asimadoline and which provide enhanced skin permeation to the drug when it is administered together with the drug to the skin of a user. Additionally, the permeation enhancer must not adversely interact with the adhesive of the in-line contact adhesive layer if one is present.
  • permeation enhancers are disclosed in the patents cited above previously incorporated by reference and can be selected from, but are not limited to, fatty acids, monoglycerides of fatty acids such as glycerol monolaurate, glycerol monooleate or glycerol monolinoleate; lactate esters of fatty acids such as lauryl lactate, cetyl lactate, and myristyl lactate; acyl lactylates such as caproyl lactylic acid; lauramide diethanolamine (LDEA); esters of fatty acids having from about 10 to about 20 carbon atoms, including, but not limited to, lauryl acetate, isopropyl myristate, and ethyl palmitate; alkyl laurates such as methyl laurate; dimethyl lauramide; polyethylene glycol-4 lauryl ether (Laureth-4); polyethylene glycol monolaurate; and lower C,. 4 alcohols such as isopropanol and ethanol,
  • a preferred permeation enhancer according to this invention comprises a monoglyceride of a fatty acid together with a suitable cosolvent, including, but not limited to, esters of C 10 - C 20 fatty acids such as lauryl lactate, lauryl acetate, ethyl palmitate, and methyl laurate.
  • a suitable cosolvent including, but not limited to, esters of C 10 - C 20 fatty acids such as lauryl lactate, lauryl acetate, ethyl palmitate, and methyl laurate.
  • Lauryl acetate has been found to be particularly desirable as it is obtainable at a high degree of purity, thus providing a purer and better defined permeation enhancer and a system which is more readily characterized.
  • the permeation enhancer comprises glycerol monolaurate (GML) and lauryl acetate within the range of 1-25 wt% and 1-20 wt%, respectively, at a ratio of GML/lauryl acetate within the range of 0.5 - 5.0, preferably 1.0 - 3.5.
  • GML glycerol monolaurate
  • lauryl acetate within the range of 1-25 wt% and 1-20 wt%, respectively, at a ratio of GML/lauryl acetate within the range of 0.5 - 5.0, preferably 1.0 - 3.5.
  • a particularly preferred embodiment comprises 20 wt% GML and 12 wt% lauryl acetate.
  • the permeation-enhancing mixture is dispersed through the matrix or carrier, preferably at a concentration sufficient to provide permeation- enhancing amounts of enhancer in the reservoir throughout the anticipated administration period. Where there is an additional, separate permeation enhancer matrix layer as well, as in FIGS. 3 and 4, the permeation enhancer normally is present in the separate reservoir in excess of saturation.
  • an anti-irritant is dispersed throughout the matrix or carrier, preferably at a concentration sufficient to deliver anti-irritant to the skin in an amount effective to reduce skin irritation throughout the anticipated administration period.
  • the anti-irritant is preferably present in excess of saturation in order to ensure that the anti-irritant is continuously administered with the asimadoline and continues to be present as long as any asimadoline is present in the epidermis.
  • Suitable anti-irritants include, but are not limited to, methyl nicotinate as disclosed in US Patent No. 5,451 ,407, corticosteroids, and buffering agents including ascorbic acid and acetic acid. Such anti-irritants are known in the art as seen in the above cited patents previously incorporated by reference.
  • a corticosteroid is used as the anti-irritant, it is preferably administered at a flux within the range of 0.1 - 5.0 ⁇ g/cm 2 hr.
  • Hydrocortisone is a preferred corticosteroid and is present in an amount of about 1 - 5 wt%. The total amount of hydrocortisone administered is not to exceed 5 mg / 24 hour in order to avoid possible systemic effects.
  • Hydrocortisone esters such as hydrocortisone acetate are also suitable. More potent corticosteroids may not require a permeation enhancer as hydrocortisone and hydrocortisone acetate do.
  • hydrocortisone or its esters such as hydrocortisone acetate is that they are approved for over-the-counter use.
  • This invention contemplates the use of any corticosteroid in addition to hydrocortisone and includes, without limitation, beclomethasone, betamethasone, benzoid, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasol butyrate, desonide, dexamethasone, fluocinonide, prednisolone, and triamcinolone, for example.
  • the asimadoline, anti-irritant, and/or permeation enhancer be administered from a rate-controlled transdermal delivery device.
  • Rate control can be obtained either through a rate-controlling membrane as described in US Patent No. 3,797,494 listed above, or through an adhesive or both as well as through other means known in the art.
  • a certain amount of asimadoline may bind reversibly to the skin, and it is accordingly preferred that the skin-contacting layer of the device include this amount of asimadoline as a loading dose.
  • the surface area of the device of this invention can vary from about 1- 200 cm 2 .
  • a typical device will have a surface area within the range of about 5-60 cm 2 , preferably about 20 cm 2 .
  • the devices of this invention can be designed to deliver asimadoline effectively for an extended time period of from several hours up to 7 days or longer. Seven days is generally the maximum time limit for application of a single device because the adverse effects of occlusion of a skin site increases with time and the normal cycle of sloughing and replacement of the skin cells occurs in about 7 days.
  • a device for the transdermal administration of asimadoline, at a therapeutically effective rate comprises: (a) a reservoir comprising:
  • a device for the transdermal administration of asimadoline, at a therapeutically effective rate comprises:
  • a reservoir comprising: (i) 1 - 50% by weight of a pharmaceutically acceptable salt of asimadoline, (ii) 5 - 50% by weight of a permeation enhancer, (iii) 30 - 90% by weight of a polymeric carrier;
  • a device for the transdermal administration of asimadoline, at a therapeutically effective rate comprises: (a) a reservoir comprising:
  • (c) means for maintaining the reservoir in asimadoline - transmitting relation with the skin.
  • the backing may be flexible or nonflexible and may be a breathable or occlusive material. Suitable materials include, without limitation, polyethylene, polyurethane, polyester, ethylene vinyl acetate, acrylonitrile, cellophane, cellulose acetate, cellulosics, ethylcellulose, ethylene vinyl alcohol, plasticized vinylacetate-vinylchloride copolymers, polyethylene terephthalate, nylons, rayon, polypropylene, polyvinyl alcohol, polyvinyl chloride, metalized polyester films, polyvinylidene chloride, polycarbonate, polystyrene, and aluminum foil.
  • the backing may be a multi-laminate film.
  • the means for maintaining the reservoir in drug and permeation enhancer transmitting relation with the skin is preferably a pressure sensitive adhesive including, but not limited to, polyisobutylene adhesives, silicone adhesives, and acrylate adhesives known in the art including copolymers and graft copolymers thereof.
  • a further embodiment of the invention is directed to including in the adhesive a small percentage, e.g., from about 1 to about 5 wt% of asimadoline to assure an appropriate initial release rate.
  • the aforementioned patents describe a wide variety of materials which can be used for fabricating various layers or components of the transdermal asimadoline delivery systems according to this invention.
  • This invention contemplates the use of other materials other than those specifically disclosed herein including those which may become hereafter known to the artist capable of performing the necessary functions.
  • the invention is also directed to a method of continuously administering asimadoline and/or norasimadoline to a patient at a therapeutically effective rate over an administration period in order to administer a therapeutically effective amount and achieve and maintain therapeutic blood or plasma levels in a patient.
  • a preferred embodiment of the present invention comprises a method of treating chronic pain.
  • asimadoline is delivered at a therapeutic rate within a range of about 10 - 550 ⁇ g/hr, preferably about 40 - 450 ⁇ g/hr from a reasonably sized transdermal delivery device having a surface area of less than about 60 cm 2 for the treatment period, usually about 12 hours to 5 days, preferably 48-60 hours.
  • the length of time of asimadoline presence and the total amount of asimadoline in the plasma can be changed following the teachings of this invention to provide different treatment regimens. Thus, they can be controlled by the amount of time during which exogenous asimadoline is delivered transdermally to an individual or animal and the rate at which it is administered.
  • Drug reservoirs were prepared by mixing asimadoline hydrochloride, ethylene vinylacetate (EVA)(USI Chemicals, Illinois) having a vinyl acetate content of 40%, and dodecyl acetate (DA) (Inoue Perfumery Mfg. Co. LTD, Tokyo, Japan), glycerol monolaurate (GML) (Danisco Ingredients), polyvinyl pyrrolidone (PVP) (XL-10, ISP Technologies, Inc., Calvert City, KY), dimethyl lauramide (DML) (Lancaster Synthesis, Inc., Lancaster, PA), and/or caproyl lactylic acid (CLA) (American Ingredient Co., Grand Viejo, CA) in the amounts set forth in Table 1. The resulting mix was then calendered to a 5 mil thickness between 2 release liners. The drug reservoir was then heat laminated to a Medpar® backing.
  • EVA ethylene vinylacetate
  • DA dodecyl acetate
  • GML glyce
  • the entire receptor solution was removed from the test tubes and replaced with an equal volume of fresh receptor solutions previously equilibrated at 35°C.
  • Transdermal systems set forth in Table 1 were prepared according to Example 1 and used to measure permeation through human cadaver skin. Circular pieces of heat stripped human epidermis were blotted dry just prior to use and the stratum corneum surface of the epidermis was applied to the asimadoline releasing side of the system. The edges of epidermis were then folded around the system so that none of the system edge was exposed to the receptor solution. Asimadoline permeation through the epidermis was then measured according to the procedure set forth in Example 1.
  • Figure 6 depicts the mean in vitro transdermal flux of asimadoline hydrochloride through human epidermis with various permeation enhancers.
  • Figures 7A and 7B depict the asimadoline flux through two skins tested as a function of time.

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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition de matière destinée à être appliquée sur une surface ou une membrane du corps afin d'administrer de l'asimadoline par pénétration à travers la surface ou la membrane du corps, la composition comprenant l'asimadoline à administrer, à une dose thérapeutique efficace, seule ou en combinaison avec un activateur ou un mélange de pénétration. L'invention concerne également des dispositifs d'apport de médicament et des procédés pour l'administration transdermique d'asimadoline.
PCT/US1998/026652 1997-12-22 1998-12-15 Nouvelles formulations d'administration transdermique d'asimadoline WO1999032096A1 (fr)

Priority Applications (1)

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AU18283/99A AU1828399A (en) 1997-12-22 1998-12-15 Novel formulations for the transdermal administration of asimadoline

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US6837697P 1997-12-22 1997-12-22
US60/068,376 1997-12-22

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3932390A1 (fr) 2020-07-02 2022-01-05 Dr. August Wolff GmbH & Co. KG Arzneimittel Formulation de gel topique contenant de l'asimadoline

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19531464A1 (de) * 1995-08-26 1997-02-27 Merck Patent Gmbh N-Methyl-N-[(1S-)-1-phenyl-2-((3S)-3-hydroxypyrrolidin 1-yl-)-ethyl]-2,2-diphenyl-acetamid
US5763445A (en) * 1996-03-08 1998-06-09 Adolor Corporation Kappa agonist compounds pharmaceutical formulations and method of prevention and treatment of pruritus therewith
WO1998026770A2 (fr) * 1996-12-16 1998-06-25 Alcon Laboratories, Inc. Utilisation locale d'agonistes opioïdes kappa dans le traitement de la douleur oculaire

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19531464A1 (de) * 1995-08-26 1997-02-27 Merck Patent Gmbh N-Methyl-N-[(1S-)-1-phenyl-2-((3S)-3-hydroxypyrrolidin 1-yl-)-ethyl]-2,2-diphenyl-acetamid
US5763445A (en) * 1996-03-08 1998-06-09 Adolor Corporation Kappa agonist compounds pharmaceutical formulations and method of prevention and treatment of pruritus therewith
WO1998026770A2 (fr) * 1996-12-16 1998-06-25 Alcon Laboratories, Inc. Utilisation locale d'agonistes opioïdes kappa dans le traitement de la douleur oculaire

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3932390A1 (fr) 2020-07-02 2022-01-05 Dr. August Wolff GmbH & Co. KG Arzneimittel Formulation de gel topique contenant de l'asimadoline
WO2022003168A1 (fr) 2020-07-02 2022-01-06 Dr. August Wolff Gmbh & Co. Kg Arzneimittel Formulation de gel topique contenant de l'asimadoline

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