WO1997009971A2 - Reservoirs a medicament superabsorbant et de grande capacite a utiliser dans des systemes d'administration transdermique de medicaments - Google Patents

Reservoirs a medicament superabsorbant et de grande capacite a utiliser dans des systemes d'administration transdermique de medicaments Download PDF

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Publication number
WO1997009971A2
WO1997009971A2 PCT/US1996/014784 US9614784W WO9709971A2 WO 1997009971 A2 WO1997009971 A2 WO 1997009971A2 US 9614784 W US9614784 W US 9614784W WO 9709971 A2 WO9709971 A2 WO 9709971A2
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WIPO (PCT)
Prior art keywords
drug
transdermal
superabsorbent material
reservoir
superabsorbent
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PCT/US1996/014784
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English (en)
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WO1997009971A3 (fr
Inventor
Tung-Fen Chen
Chia-Ming Chiang
Janan Jona
Priti Joshi
Asha Ramdas
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Cygnus, Inc.
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Application filed by Cygnus, Inc. filed Critical Cygnus, Inc.
Priority to AU72388/96A priority Critical patent/AU7238896A/en
Publication of WO1997009971A2 publication Critical patent/WO1997009971A2/fr
Publication of WO1997009971A3 publication Critical patent/WO1997009971A3/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
    • 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 generally to transdermal drug delivery, and more particularly relates to high capacity, superabsorbent drug reservoirs for incorporation into transdermal drug delivery systems.
  • the invention further relates to transdermal drug delivery systems containing the high capacity reservoirs, and to methods for manufacturing and using the new transdermal systems.
  • the delivery of drugs through the skin provides many advantages; primarily, such a means of delivery is a comfortable, convenient and noninvasive way of administering drugs.
  • the variable rates of absorption and metabolism encountered in oral treatment are avoided, and other inherent inconveniences — e.g., gastrointestinal irritation and the like — are eliminated as well.
  • Transdermal drug delivery also makes possible a high degree of control over blood concentrations of any particular drug.
  • Skin is a structurally complex, relatively thick membrane. Molecules moving from the environment into and through intact skin must first penetrate the stratum corneum. They must then penetrate the viable epidermis, the papillary dermis, and the capillary walls into the blood stream or lymph channels. To be so absorbed, molecules must overcome a different resistance to penetration in each type of tissue. Transport across the skin membrane is thus a complex phenomenon. However, it is the cells of the stratum corneum which present the primary barrier to absorption of topical compositions or transdermally administered drugs. The stratum corneum is a thin layer of dense, highly keratinized cells approximately 10-15 microns thick over most of the body.
  • the high capacity drug reservoirs useful in conjunction with the present methods and transdermal systems are comprised of superabsorbent materials, usually crosslinked polymers which are capable of absorbing far more than their own weight. Using such materials, the transdermal system as a whole contains a far greater quantity of drug than possible with conventional transdermal systems. This in turn enables delivery of greater quantities of drug, at higher fluxes.
  • the high capacity drug reservoirs may reduce or in some cases eliminate the need for permeation enhancers, which, as well known in the art, can cause irritation, sensitization, or other problems.
  • smaller transdermal patches may be made using such technology, i.e., patches that are at least as effective as prior patches in terms of overall drug release and drug flux, but are significantly reduced in terms of size.
  • the invention may be used to deliver a wide variety of drugs.
  • the present drug delivery systems may be used in the transdermal administration of 2-methyl-10-(4-methyl-l- piperazinyl) -4H-thieno[2, 3-b] [1,5]benzodiazepine, also known as "olanzapine.”
  • the drug is described in U.S. Patent No. 5,229,382 to Chakrabarti et al., issued July 20, 1993, and assigned to Lilly Industries Limited.
  • Olanzapine is an antagonist of dopamine at the D-l and D-2 receptors, and in addition has antimuscarinic anticholinergic properties and antagonist activity at 5HT-2 receptor sites and at noradrenergic ⁇ -receptors
  • the drug has relaxant, anxiolytic and anti-emetic properties, and, as explained in the
  • Chakrabarti et al. patent is useful in the treatment of psychosis, acute mania and mild anxiety states, and is particularly useful in the treatment of schizophrenia and schizophreniform illnesses.
  • olanzapine is administered orally or by injection. While the drug has been established as an effective antipsychotic agent, drug non- compliance is a serious problem, and is believed to account for approximately one-third of all short-stay hospital costs.
  • Transdermal administration of olanzapine or a pharmaceutically acceptable salt thereof significantly enhances patient compliance by providing an advanced delivery system useful for administering the drug over an approximately three- to seven-day period.
  • the present systems are also useful in the transdermal administration of steroid drugs, including androgenic agents.
  • Particular compounds of interest are testosterone and pharmaceutically acceptable esters and derivatives thereof.
  • Such agents are useful in a variety of applications, e.g. , in treating hypogonadism, hypopituitarism, Addison's disease, impotence, male infertility disorders, anemia, and in male hormone replacement therapy.
  • the invention also involves the transdermal administration of androgenic agents in combination with estrogens, in treating, for example, menopause, osteoporosis, or other conditions for which estrogen-androgen combination therapy is indicated. Transdermal delivery of androgens, alone or in combination with estrogenic agents, has been described. See, e . g .
  • the present invention is thus directed in part to high capacity, "superabsorbent" reservoirs useful in transdermal drug delivery systems, which, by virtue of the novel reservoirs, are able to deliver greater quantities of drug, at higher fluxes, than possible with conventional transdermal systems.
  • the superabsorbent reservoirs may also reduce or in some cases eliminate the need for permeation enhancers. For those drugs which do still require the presence of an enhancer to achieve high flux, the superabsorbent reservoir provides a means whereby augmented loading of both drug and enhancer may be achieved.
  • Transdermal drug delivery systems containing the novel reservoirs will generally be in the form of a laminated composite comprising: (a) a backing layer; (b) the drug reservoir; and (c) a means for affixing the composite to the skin, typically either an "in ⁇ line" contact adhesive in the form of a layer underlying the entire surface of the system, or a peripheral adhesive ring.
  • the backing layer serves as the upper surface of the system during use and is substantially impermeable to the drug.
  • a release liner is present to protect the basal surface of the system.
  • Additional materials and components may also be present. For example, in some cases, it may be preferable or necessary to incorporate a rate- controlling membrane into the transdermal system. One or more additional reservoir and/or adhesive layers may also be included. Also, during storage and prior to use, a release liner should be present to protect the basal surface of the system.
  • the invention is also directed to a method for preparing a transdermal drug delivery system having a superabsorbent drug reservoir, comprising: (a) providing a superabsorbent material in the form of a substantially planar layer to serve as the drug reservoir, the layer having first and second opposing surfaces; (b) absorbing drug formulation into the drug reservoir; (c) laminating to the first surface of the reservoir a backing layer that is substantially impermeable to the drug and which defines the upper surface of the system during use; and (d) laminating to the opposing second surface of the reservoir a pressure-sensitive, pharmaceutically acceptable adhesive layer comprised of a material that is permeable to the drug.
  • the invention further provides a method for transdermally administering a drug to a mammalian individual, comprising positioning topically on the individual a transdermal drug delivery system containing a high capacity drug reservoir of a superabsorbent material as provided herein.
  • the systems are useful, for example, in the transdermal administration of androgenic agents such as testosterone. Administration is conducted for a time period and at an administration rate effective to provide the necessary therapy, e.g., treatment of impotence, infertility disorders, or the like.
  • administration rate effective to provide the necessary therapy, e.g., treatment of impotence, infertility disorders, or the like.
  • transdermal patches on the order of 30 cnr or smaller may be used to deliver the selected androgenic agent, while still achieving a drug flux that is for all contemplated indications more than sufficient.
  • the androgenic agent patches are designed to be worn for 24-hour periods.
  • the systems are also useful in transdermally administering olanzapine or a pharmaceutically acceptable salt thereof, to treat an individual suffering from or susceptible to psychosis, acute mania or mild anxiety states, particularly schizophrenia and schizophreniform illnesses.
  • Transdermal administration of olanzapine is conducted for a time period and at an administration rate effective to alleviate the symptoms at issue.
  • the preferred transdermal system used for administration of olanzapine or a pharmaceutically acceptable salt thereof is as described above, i.e., it will typically be a laminated composite comprised of a backing layer, the high capacity, polyurethane hydrogel reservoir, a means for affixing the composite to the skin, and, optionally, other membranes and components as well.
  • the transdermal system is preferably constructed such that an effective dose of olanzapine or a pharmaceutically acceptable acid addition salt thereof will be delivered for a period in the range of about three to seven days.
  • FIG. 1 illustrates in schematic form one embodiment of a superabsorbent drug reservoir-type transdermal delivery system which may manufactured so as to contain a superabsorbent drug reservoir as provided herein.
  • FIG. 2 is a graph illustrating the olanzapine skin flux from a system comprising a maleic anhydride-isobutylene copolymer superabsorbent material, as explained in Example l.
  • FIG. 3 is a graph illustrating the olanzapine skin flux from a system comprising a maleic anhydride-isobutylene copolymer superabsorbent material and a drug permeation rate-controlling membrane.
  • FIG. 4 represents in graph form the testosterone flux profiles from the superabsorbent systems of the invention as evaluated in Example 4.
  • FIG. 5 represents in graph form the cumulative permeation of testosterone using the superabsorbent systems of the invention, also as evaluated in Example 4.
  • transdermal delivery applicants intend to include both transdermal (or “percutaneous”) and transmucosal administration, i.e., delivery by passage of a drug through the skin or mucosal tissue and into the bloodstream.
  • body surface will sometimes be used herein to refer to either the skin or the mucosal tissue.
  • a “high capacity" drug reservoir is meant a drug reservoir containing a quantity of drug or drug formulation which is greater than that which is typically possible using conventional manufacturing techniques or transdermal drug delivery systems.
  • a "superabsorbent” material is intended a material capable of absorbing or adsorbing an amount of fluid corresponding to more than 15 grams, preferably more than 25 grams, most preferably more than 50 grams, per gram of superabsorbent material.
  • Superabsorbent materials are known that are capable of absorbing or adsorbing 300 to 1000 times their weight in fluids as well. Such superabsorbent materials not only absorb fluids but also are able to retain the fluid that has been absorbed, while remaining generally insoluble in the fluid absorbed.
  • the superabsorbent materials are typically crosslinked polymers, which may be either homopolymers or copolymers.
  • an “effective” amount of a drug is meant a nontoxic but sufficient amount of the drug to provide the desired therapeutic or prophylactic effect.
  • an “effective” amount of drug refers to that dose of drug which will be effective in relieving or preventing symptoms of psychosis, acute mania, mild anxiety, or the like.
  • An “effective" amount of a permeation enhancer as used herein means an amount that will provide the desired increase in skin permeability and, correspondingly, the desired depth of penetration, rate of administration, and amount of drug delivered.
  • predetermined area of skin is intended a defined area of intact unbroken living skin or mucosal tissue. That area will usually be in the
  • the area of skin or mucosal tissue through which drug is administered may vary significantly, depending on patch configuration, dose, and the like.
  • the present technology enables preparation of generally smaller patches, typically in the range of about 5 cnr 7 to about 20 cm7.
  • Poration enhancement or “permeation enhancement” as used herein relates to an increase in the permeability of skin to a pharmacologically active agent, i.e., so as to increase the rate at which the drug permeates through the skin and enters the bloodstream.
  • the enhanced permeation effected through the use of such enhancers can be observed by measuring the rate of diffusion of drug through animal or human skin using a diffusion cell apparatus as described in the Examples herein.
  • Carriers or “vehicles” as used herein refer to carrier materials suitable for transdermal drug administration, and include any such materials known in the art, e.g., any liquid, gel, solvent, liquid diluent, solubilizer, or the like, which is nontoxic and which does not interact with other components of the composition in a deleterious manner.
  • suitable carriers for use herein include water, silicone, liquid sugars, waxes, petroleum jelly, and a variety of other materials.
  • carrier or “vehicle” as used herein may also refer to stabilizers, crystallization inhibitors, or other types of additives useful for facilitating transdermal drug delivery.
  • saturated as used in conjunction with the transdermal delivery of androgenic agents, is meant a pharmaceutical formulation in which the drug is present at saturation; when the present systems are used for the administration of an androgenic agent, the drug is present in the pharmaceutical formulation contained in the drug reservoir at or above saturation.
  • the high capacity drug reservoirs of the invention are comprised of a superabsorbent material and a drug formulation.
  • the nature of the superabsorbent material is not critical.
  • crosslinked polymer (including copolymer) compositions are preferred, such as poly(acrylates) , poly(maleic anhydrides), poly(vinyl alcohols), poly(ethylene oxides), poly(hydroxy methylenes) , polysaccharides, and the like, as described in Chen et al. (1985) Synthetic and Natural Polymers , in Chatterjee (Ed.) Absorbency, chapter VI, pp. 197-216 (Elsevier, Amsterdam) .
  • superabsorbent materials include, but are not limited to: the reaction product at elevated temperature and pressure of hydrolyzed starch polyacrylonitrile graft copolymer, optionally having added thereto a polyhydric alcohol such as glycerol (see , U.S. Patent Nos.
  • a skeletal network of a cellular polymeric foam preferably a polyurethane, containing a superabsorbent material such as carboxymethyl cellulose, starch-grafted sodium polyacrylate or sodium polyacrylate (as described, for example, in U.S. Patent No.
  • a superabsorbent crosslinked ampholytic ion pair copolymer for example, the ammonium cation 3- methacrylamidopropyltrimethylammonium and a sulfonate anion such as sulfonate, 2-methylacryloyloxyethane sulfonate, vinyl sulfonate, styrene sulfonate, or the like, as disclosed in U.S. Patent No. 5,216,098 to Ahmed et al.
  • suitable superabsorbent materials which may be obtained commercially or synthesized using known techniques, may be used as well, as will be appreciated by those of ordinary skill in the art.
  • the superabsorbent material is an olefin/alkyl carboxylate copolymer such as a maleic anhydride-isobutylene copolymer, as may be obtained from Camelot Superabsorbents Incorporated (Charlotte, NC) as Fiberdri® superabsorbent fibers.
  • a superabsorbent film comprising such a copolymer may be obtained from Concert Industries Limited (Thurso, Quebec, Canada) .
  • the drug delivery system is in the form of a laminated composite, generally designated as 10, and comprises a backing layer 11, a superabsorbent reservoir layer 12 containing drug 12a absorbed by a superabsorbent material 12b, a contact adhesive 13 and a release liner 14.
  • the rate- controlling membrane 15 interposed between drug reservoir layer 12 and contact adhesive 13 is optional.
  • the backing layer 11 functions as the primary structural element of the system and provides the system with much of its flexibility, drape and, preferably, occlusivity.
  • the material used for the backing layer should be inert and incapable of absorbing drug, enhancer or other components of the pharmaceutical composition contained within the system.
  • the backing is preferably made of one or more sheets or films of a flexible elastomeric material that serves as a protective covering to prevent loss of drug and/or vehicle via transmission through the upper surface of the system, and will preferably impart a degree of occlusivity to the system, such that the area of the skin covered on application becomes hydrated.
  • the material used for the backing layer should permit the system to follow the contours of the skin and be worn comfortably on areas of skin such as at joints or other points of flexure, that are normally subjected to mechanical strain with little or no likelihood of the system disengaging from the skin due to differences in the flexibility or resiliency of the skin and the system.
  • materials useful for the backing layer are polyesters, polyethylene, polypropylene, polyurethanes and polyether amides.
  • the layer is preferably in the range of about 15 microns to about 250 microns in thickness, and may, if desired, be pigmented, metallized, or provided with a matte finish suitable for writing.
  • Drug reservoir layer 12 provides a means for containing drug 12a, and is comprised of a superabsorbent material 12b.
  • the reservoir layer will generally although not necessarily range in thickness from about 1 to about 100 mils, preferably about 25 to 60 mils. It will be appreciated that the thickness of the reservoir will depend on a variety of considerations, including the quantity of drug to be incorporated in the reservoir, desired patch size, and the like.
  • a pharmaceutically acceptable contact adhesive layer 13 functions to secure the system to the skin during use. In an alternate embodiment, a peripheral ring of contact adhesive is provided on the basal surface of the system.
  • the contact adhesive material is a pressure-sensitive adhesive suitable for long-term skin contact, and is also physically and chemically compatible with the drug formulation, i.e., the drug itself and any carriers and vehicles employed.
  • Preferred materials for this layer include polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, plasticized ethylene-vinyl acetate copolymers, low molecular weight polyether amide block polymers (e.g., PEBAX), tacky rubbers such as polyisobutene, polystyrene-isoprene copolymers, polystyrene-butadiene copolymers, and mixtures thereof.
  • PEBAX low molecular weight polyether amide block polymers
  • a release liner 14 is provided to cover the adhesive layer.
  • the release liner is a disposable element which serves solely to protect the system prior to application.
  • the release liner is formed from a material which is impermeable to the drug, vehicle and adhesive, and easily stripped from the contact adhesive.
  • Release liners are typically treated with silicone or fluorocarbons; an example of an optimal material is silicone-coated polyester.
  • any number of drugs may be delivered transdermally using the reservoirs and drug delivery systems of the invention, i.e., any compound suitable for transdermal or transmucosal administration which induces a desired systemic or local effect.
  • Such substances include the broad classes of compounds normally delivered through body surfaces and membranes, including skin.
  • anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations; anorexics; antihelminthics; antiarthritics; antiasthmatic agents; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihistamines; antiinflammatory agents; anti igraine preparations; antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations including calcium channel blockers and beta-blockers such as pindolol and antiarrhythmics; antihypertensives; diuretics; vasodilators including general coronary, peripheral and cerebral; central nervous system stimulants; cough and cold preparations, including decongestants; hormones such as estradiol and other steroids, including corticoster
  • the present invention enables transdermal delivery of drugs which typically display low skin flux, as the quantity of drug which may be loaded into the high capacity drug reservoir is significantly greater than with conventional systems.
  • Other preferred drugs are those that require high flux to achieve a desired therapeutic effect and thus may require the presence of an enhancer in the drug formulation.
  • the present invention provides a drug reservoir comprising a superabsorbent material that, for the same size patch, is capable of absorbing not only more drug than prior patches but is also capable of absorbing more enhancer as well.
  • Steroids represent one class of drugs with which the present reservoirs and transdermal systems are particularly useful.
  • steroid drugs which may be administered in conjunction with the invention include: progestogens such as flurogestone acetate, hydroxyprogesterone, hydroxyprogesterone acetate, hydroxyprogesterone caproate, medroxyprogesterone acetate, norethindrone, norethindrone acetate, norethisterone, norethynodrel, desogestrel, 3-keto desogestrel, gestadene and levonorgestrel; estrogens such as estradiol and its esters (e.g., estradiol benzoate, valerate, cypionate, decanoate and acetate), ethynyl estradiol, estriol, estrone and mestranol; and corticosteroids such as betamethasone, betamethasone acetate, cortisone, hydrocortis
  • the present transdermal systems are used to administer androgenic agents such as the naturally occurring androgens androsterone and testosterone; pharmaceutically acceptable esters of testosterone, typically esters formed from the hydroxyl group present at C-17, and particularly the enanthate, propionate, cypionate and phenylacetate esters; and pharmaceutically acceptable derivatives of testosterone such as methyltestosterone, testolactone, oxymetholone and fluoxymesterone. Testosterone and the 17-esters thereof, particularly the enanthate, propionate and cypionate esters, are preferred. Such agents are useful in a variety of applications, e.g.
  • agents in male hormone therapy, in treating hypogonadism, hypopituitarism, Addison's disease, impotence, male infertility disorders, anemia, and the like.
  • Other pharmaceutically active agents may be administered along with the selected androgenic agent.
  • These agents will generally be estrogens and/or progestogens.
  • the amount of each such additional agent incorporated into the drug reservoir will vary, depending on the intended dosage. Normally, the daily dosage of estrogenic agent will be at least about 0.03 mg/day, while the daily dosage of progestogen will be at least about 0.2 mg/day, depending, of course, on the particular estrogen and progestogen to be administered.
  • Administration of an androgenic agent in combination with an estrogen and/or a progestogen is useful, for example, in the treatment of menopausal symptoms, osteoporosis, or other conditions for which such combination therapy is indicated.
  • administration is conducted for a time period and at an administration rate effective to provide the necessary therapy, e.g., treatment of impotence, infertility disorders, or the like.
  • the agent should be delivered at a dosage of at least about 3 mg/day, more preferably at least about 6 mg/day.
  • 9 patches on the order of 30 c ⁇ r or smaller may be used to deliver the selected androgenic agent, while still achieving a drug flux that is for all contemplated indications more than sufficient.
  • the androgenic agent patches are designed to be worn for 24-hour periods.
  • transdermal administration of androgenic agents be conducted at or above saturation. That is, the androgenic agent is present at or above saturation with respect to its concentration in the formulation contained in the drug reservoir.
  • the reservoirs and transdermal systems of the invention are also useful in the transdermal administration of olanzapine.
  • the specific method and drug delivery system for delivering olanzapine transdermally may vary, but necessarily involve application of a drug delivery system containing olanzapine or a pharmaceutically acceptable acid addition salt thereof to a predetermined area of the skin or mucosal tissue at an administration rate and for a period of time sufficient to provide an effective blood level of drug for a desired period of time.
  • the drug is present in a high capacity, superabsorbent drug reservoir within a transdermal delivery system such as the exemplary system described above.
  • this embodiment of the invention while primarily directed to the treatment of individuals suffering from or susceptible to psychosis, acute mania or mild anxiety states, may extend to any use of olanzapine deriving from its activity an antagonist of dopamine at the D-l and D-2 receptors, its antimuscarinic anti-cholinergic properties, and/or its antagonist activity at 5HT-2 receptor sites and noradrenergic ⁇ -receptors.
  • the transdermal olanzapine system formulated using the novel reservoirs are preferably constructed so that an effective dose of olanzapine or a pharmaceutically acceptable salt thereof will be delivered for a period in the range of about three to seven days.
  • Olanzapine or any other basic drug may be administered in the form of the base or as a pharmaceutically acceptable acid addition salt.
  • the base form of the drug can be converted to an acid addition salt by treatment with a stoichiometric excess of a selected acid.
  • Such acid addition salts may be formed, for example, with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, hydroxymaleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, naphthalene-2-sulfonic acid, salicylic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like
  • organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid
  • acidic drugs may be administered in the acid form or, as will be appreciated by those skilled in the art, as a pharmaceutically basic salt.
  • the salts may be derived from inorganic bases, e.g., the ammonium, potassium, sodium, calcium and magnesium salts.
  • the salts may be derived from pharmaceutically acceptable nontoxic bases, including isopropylamine, trimethylamine, dimethylamine, triethylamine, ethanolamine, dicyclohexylamine, choline, tromethylamine, and the like.
  • the high capacity reservoirs of the invention may in some cases eliminate the need for a permeation enhancer. However, enhancers may still be preferred or even required for administering certain drugs, e.g. , steroids, including androgenic agents, and olanzapine.
  • drugs e.g. , steroids, including androgenic agents, and olanzapine.
  • Suitable enhancers include, but are not limited to, dimethylsulfoxide (DMSO) , dimethyl formamide (DMF) , N,N-dimethylacetamide (DMA) , decylmethylsulfoxide (C I QMSO) , polyethylene glycol monolaurate (PEGML) , propylene glycol (PG) , propylene glycol monolaurate (PGML) , glycerol monolaurate (GML) , methyl laurate (ML) , lauryl lactate (LL) , methyl decanoate (MD) , isopropyl myristate (IPM) , terpenes such as menthone, C ⁇ -C ⁇ alkanediols, particularly 1,2- butanediol and 1,3-butanediol (1,2-BD and 1,3-BD), lecithin, the 1-substituted azacycloheptan-2-ones, particularly l-
  • Vegetable oil permeation enhancers as described in commonly assigned U.S. Patent No. 5,229,130 to Sharma, may also be used.
  • oils include, for example, safflower oil, cotton seed oil and corn oil.
  • Preferred enhancers for use in conjunction with the present invention, and particularly in the transdermal administration of androgenic agents and olanzapine are esters given by the formula [CH3(CH2) m C00] n R in which m is an integer in the range of 8 to 16, n is 1 or 2, and R is a lower alkyl (CJ-C3) residue that is either unsubstituted or substituted with one or two hydroxyl groups.
  • the ester component is a lower alkyl (C j -C-.) laurate (i.e., m is 10 and n is 1), and in a particularly preferred case is "PGML.”
  • PGML lower alkyl
  • the commercially available material sold as “PGML” is typically a mixture of propylene glycol monolaurate itself, propylene glycol dilaurate, and either propylene glycol, methyl laurate, or both.
  • PGML or "propylene glycol monolaurate” as used herein are intended to encompass both the pure compound as well as the mixture that is typically obtained commercially.
  • fatty acids and fatty alcohols corresponding to the above-defined fatty esters.
  • fatty acids useful as permeation enhancers herein will generally have the formula CH3(CH2) m C00H, where m is as above, while the fatty alcohols will have the formula CHo (CH2) m CH2 ⁇ H.
  • enhancers are wherein a fatty ester as described above is combined with an ether component selected from the group consisting of diethylene glycol monoethyl ether and diethylene glycol monomethylether.
  • ether component selected from the group consisting of diethylene glycol monoethyl ether and diethylene glycol monomethylether.
  • Particularly preferred permeation enhancers are selected from the group consisting of ⁇ - ⁇ alkanediols, fatty esters having the structural formula [CH3(CH2) m C00] n R, fatty acids having the structural formula CH-j i (CH2) m COOH, fatty alcohols having the structural formula CH ⁇ fC ⁇ J j - r -C ⁇ OH, and mixtures thereof, where m and n are as defined above.
  • ternary vehicle combinations in which such a fatty alcohol or acid is combined with a fatty ester and a ⁇ - ⁇ alkanediol, e.g., 1,2- butanediol, 1,3-butanediol, and the like, are particularly effective enhancer compositions for use in conjunction with the present invention.
  • an enhancer is used, the type and amount of enhancer will similarly depend on a number of factors, e.g., the strength of the particular enhancer, the desired increase in skin permeability, rate of administration, and amount of drug delivered.
  • the drug formulations contained in the high capacity reservoirs may also include standard carriers or vehicles useful for facilitating drug delivery, e.g., stabilizers, antioxidants, anti-irritants and crystallization inhibitors.
  • Preferred drug formulations i.e., the drug- containing composition which is loaded into the drug reservoir, will typically contain on the order of about 0.1 wt.% to 20 wt.%, preferably about 1 wt.% to 10 wt.% drug, with the remainder of the formulation representing other components such as enhancers, vehicles or the like. If enhancers are present, they will generally represent on the order of approximately 1 wt.% to 25 wt.% of the drug formulation.
  • the superabsorbent reservoir is prepared by dissolving the drug in water or other suitable solvent, incorporating any desired carriers, vehicles, enhancers or the like in the solution, and contacting the superabsorbent material with the drug solution to permit absorption thereof.
  • the drug solution may be applied to the superabsorbent material by any conventional method such as by dipping, coating, spraying or printing; a suitable method for "printing" drug formulation on the superabsorbent material is disclosed in U.S. Patent No. 4,915,950 to Miranda et al.
  • This drug-containing reservoir may then be incorporated into a transdermal drug delivery system in the form of a laminated composite, using any number of techniques.
  • the superabsorbent drug reservoir may be laminated to the selected backing layer and subsequently laminated to a contact adhesive layer.
  • a transdermal system containing a superabsorbent reservoir may be prepared as follows by first casting a selected contact adhesive material, present in solution, onto a release liner. Solvent is evaporated therefrom, and the adhesive is then laminated to the superabsorbent drug reservoir, which is in turn transfer-laminated onto the backing film.
  • Solvent is evaporated therefrom, and the adhesive is then laminated to the superabsorbent drug reservoir, which is in turn transfer-laminated onto the backing film.
  • Other suitable manufacturing techniques may be used as well, as will be appreciated by those working in the field of transdermal drug delivery.
  • rate- controlling membrane between the superabsorbent reservoir and a contact adhesive layer, when present.
  • Representative materials useful for forming rate- controlling membranes include polyolefins such as polyethylene and polypropylene, polyamides, polyesters, ethylene-ethacrylate copolymer, ethylene- vinyl acetate copolymer, ethylene-vinyl methylacetate copolymer, ethylene-vinyl ethylacetate copolymer, ethylene-vinyl propylacetate copolymer, polyisoprene, polyacrylonitrile, ethylene-propylene copolymer, and the like.
  • a preferred material useful to form the rate-controlling membrane is ethylene-vinyl acetate copolymer.
  • the particular material selected will be such that the flux of drug component or of one or more non-drug components, i.e., will be controlled as desired.
  • Olanzapine free base was provided by Eli Lilly. Testosterone was purchased from Sigma Chemical Company and used as received. All chemicals used were of reagent grade.
  • Assay methodology For evaluation of skin flux, samples were analyzed by HPLC using UV-detection at 265 nm and 220 nm. Chromatographic resolution was achieved using a Brownlee RP-18 column, 100 mm x 4.6 mm, with a 5 ⁇ m particle size (for olanzapine) , and a Zobrax Cg column, 250 mm x 4.6 mm, also with a 5 ⁇ m particle size (for testosterone) , run at a flow rate of 1.5 ml per min (olanzapine) or 1.0 ml per minute (testosterone) at ambient temperature. The mobile phase was a mixture of 47%-48% acetonitrile: 52%-53% water. The retention time for olanzapine was about 3.0 min; the retention time for testosterone was about 4.0 min.
  • Skin Preparation Human cadaver skin was used for the permeation studies. The frozen skins were thawed and the epidermal layers (stratum corneum and viable epidermis) were separated from the full- thickness skin by immersing it in water at 60°C for two min. This epidermis was either used immediately for flux studies or stored at -20°C for later studies.
  • Skin flux ( ⁇ g/cirr/hr) was determined at each time point by dividing the amount of drug penetrating the skin during that period of time corrected for the surface area by the duration of time.
  • Example 1 Olanzapine base was dissolved in a combination of vehicles as indicated in Table 1 and absorbed onto a highly absorbent maleic anhydride- isobutylene polymeric film obtained from Concert
  • Example 2 Olanzapine base was dissolved in a combination of vehicles as indicated in Table 2 and absorbed onto a highly absorbent polymeric film as in Example 1. At the same time, an ethylene-vinyl acetate (“EVA”) membrane was cut into 2 c ⁇ r circles and mounted onto the skin. Following this procedure, the polymeric film having drug absorbed thereon was applied and the procedure of Example 1 was followed. The formulations are listed in Table 2 and the results are shown in FIG. 3.
  • EVA ethylene-vinyl acetate
  • Formulation olanzapine saturated in 10% lauric acid + 45% methyl laurate + 45% 1,2-butanediol and absorbed on superabsorbent film (Concert 100136 #95068) with EVA 19%, 4 mil membrane.
  • olanzapine saturated in 10% oleic acid + 45% methyl caprate + 45% 1,2-butanediol and absorbed on superabsorbent film (Concert 100136 #95068) with EVA 19%, 4 mil membrane.
  • the data obtained show that the flux of drug from the superabsorbent material can be regulated using a rate-controlling membrane.
  • a skin flux study was conducted to evaluate the flux of testosterone from superabsorbent systems.
  • Testosterone was dissolved in a combination of vehicles as indicated in Table 3 and absorbed on a highly absorbent polymeric film, with and without an associated "rate-controlling" EVA membrane (as in Examples 1 and 2, respectively).
  • the superabsorbent material containing testosterone was then applied to the skin as 1/2 inch diameter disks.
  • the formulations evaluated are listed in Table 4; the platforms were evaluated with respect to both skin flux and cumulative permeation.
  • the flux of testosterone from the superabsorbent platforms exhibited the desired phasic profiles, with a ternary vehicle and superabsorbent design, the testosterone delivered at 24 hr was about 250 ⁇ g/cm .
  • the results are also illustrated graphically in FIGS. 4 and 5.

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Abstract

L'invention porte sur des réservoirs à médicament de grande capacité destinés à être incorporés à des dispositifs d'administration transdermique de médicament. Ces réservoirs sont constitués de matériau superabsorbant, généralement un polymère réticulé, capable d'absorber une quantité de formulation pharmaceutique correspondant à au moins 15 grammes de formulation par gramme de matériau. L'invention porte également sur des procédés de fabrication de dispositifs transdermiques contenant ces réservoirs ainsi que sur leur utilisation.
PCT/US1996/014784 1995-09-14 1996-09-13 Reservoirs a medicament superabsorbant et de grande capacite a utiliser dans des systemes d'administration transdermique de medicaments WO1997009971A2 (fr)

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Cited By (9)

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WO1997024148A1 (fr) * 1995-12-29 1997-07-10 Cygnus, Inc. Systemes et procedes d'administration percutanee d'agents androgenes
US5807570A (en) * 1995-09-29 1998-09-15 Cygnus, Inc. Transdermal administration of ropinirole and analogs thereof
US5891461A (en) * 1995-09-14 1999-04-06 Cygnus, Inc. Transdermal administration of olanzapine
US5902603A (en) * 1995-09-14 1999-05-11 Cygnus, Inc. Polyurethane hydrogel drug reservoirs for use in transdermal drug delivery systems, and associated methods of manufacture and use
US5906830A (en) * 1995-09-08 1999-05-25 Cygnus, Inc. Supersaturated transdermal drug delivery systems, and methods for manufacturing the same
DE10128685A1 (de) * 2001-06-13 2002-12-19 Beiersdorf Ag Selbstklebendes, wirkstoffhaltiges Matrixpflaster auf Basis von Polyurethangelen
DE10220114A1 (de) * 2002-05-06 2003-11-20 Beiersdorf Ag Ätherische Öle enthaltendes Matrixpflaster auf Polyurethanbasis
US8754119B2 (en) 2003-07-26 2014-06-17 Ucb Pharma Gmbh Use of rotigotine for the treatment of depression
US10251844B2 (en) 1998-03-30 2019-04-09 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system and method of use thereof for treating parkinsonism

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DE10234673B4 (de) 2002-07-30 2007-08-16 Schwarz Pharma Ag Heißschmelz-TTS zur Verabreichung von Rotigotin und Verfahren zu seiner Herstellung sowie Verwendung von Rotigotin bei der Herstellung eines TTS im Heißschmelzverfahren

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EP0399432A2 (fr) * 1989-05-25 1990-11-28 Takeda Chemical Industries, Ltd. Composition thérapeutique transdermique
EP0405993A2 (fr) * 1989-06-28 1991-01-02 James River Corporation Of Virginia Pansemet superabsorbant
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EP0297769A1 (fr) * 1987-06-29 1989-01-04 E.R. Squibb & Sons, Inc. Procédé de fabrication d'un pansement comprenant une couche adhésive acrylique hydrophile.
EP0399432A2 (fr) * 1989-05-25 1990-11-28 Takeda Chemical Industries, Ltd. Composition thérapeutique transdermique
EP0405993A2 (fr) * 1989-06-28 1991-01-02 James River Corporation Of Virginia Pansemet superabsorbant
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US5328935A (en) * 1993-03-26 1994-07-12 The Procter & Gamble Company Method of makig a superabsorbent polymer foam

Cited By (10)

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Publication number Priority date Publication date Assignee Title
US5906830A (en) * 1995-09-08 1999-05-25 Cygnus, Inc. Supersaturated transdermal drug delivery systems, and methods for manufacturing the same
US5891461A (en) * 1995-09-14 1999-04-06 Cygnus, Inc. Transdermal administration of olanzapine
US5902603A (en) * 1995-09-14 1999-05-11 Cygnus, Inc. Polyurethane hydrogel drug reservoirs for use in transdermal drug delivery systems, and associated methods of manufacture and use
US5807570A (en) * 1995-09-29 1998-09-15 Cygnus, Inc. Transdermal administration of ropinirole and analogs thereof
WO1997024148A1 (fr) * 1995-12-29 1997-07-10 Cygnus, Inc. Systemes et procedes d'administration percutanee d'agents androgenes
US10251844B2 (en) 1998-03-30 2019-04-09 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system and method of use thereof for treating parkinsonism
US10322093B2 (en) 1998-03-30 2019-06-18 Ucb Biopharma Sprl Method for producing a transdermal therapeutic system which contains a D2 agonist
DE10128685A1 (de) * 2001-06-13 2002-12-19 Beiersdorf Ag Selbstklebendes, wirkstoffhaltiges Matrixpflaster auf Basis von Polyurethangelen
DE10220114A1 (de) * 2002-05-06 2003-11-20 Beiersdorf Ag Ätherische Öle enthaltendes Matrixpflaster auf Polyurethanbasis
US8754119B2 (en) 2003-07-26 2014-06-17 Ucb Pharma Gmbh Use of rotigotine for the treatment of depression

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AU7238896A (en) 1997-04-01

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