WO1991009592A1 - Transdermal system - Google Patents

Transdermal system Download PDF

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Publication number
WO1991009592A1
WO1991009592A1 PCT/SE1990/000822 SE9000822W WO9109592A1 WO 1991009592 A1 WO1991009592 A1 WO 1991009592A1 SE 9000822 W SE9000822 W SE 9000822W WO 9109592 A1 WO9109592 A1 WO 9109592A1
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WO
WIPO (PCT)
Prior art keywords
drug
active substance
layer
transdermal
skin
Prior art date
Application number
PCT/SE1990/000822
Other languages
French (fr)
Inventor
Jens Hansen
Birgitte MÖLLGAARD
Original Assignee
Kabi Pharmacia Ab
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 Kabi Pharmacia Ab filed Critical Kabi Pharmacia Ab
Priority to JP03501897A priority Critical patent/JP3141110B2/en
Priority to DE69026837T priority patent/DE69026837T2/en
Priority to EP91901412A priority patent/EP0519926B1/en
Publication of WO1991009592A1 publication Critical patent/WO1991009592A1/en
Priority to GR960401809T priority patent/GR3020436T3/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7084—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
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present invention concerns a controlled release trans- dermal delivery system. Specifically the invention concerns a delivery system, from which the release rate of an active substance is governed or controlled by a new principle.
  • the delivery system according to the invention is of particular interest for the transdermal delivery of drugs.
  • Transdermal drug delivery systems can be categorized into three general types.
  • the earliest devices have a simple two- layer "Band-Aid" configuration composed of a backing layer coated with adhesive.
  • the drug is mixed in the adhe ⁇ sive layer that fixes the bandage to the skin.
  • These medica ⁇ ted bandages bring a known quantity of drug to a known area of skin for a known period of time, but have no mechanism for controlling the rate at which the drug is delivered to the patient.
  • the second type of device in this context referred to as a monolithic system, is a system incorporating a backing lay ⁇ er, a matrix layer, and an adhesive layer.
  • the matrix layer is made of a polymer material in which the solid drug is dispersed and the rate at which the drug is released from the device is controlled by the polymer matrix. With this type of system, the drug release rate falls off with time as the drug in the skin-contacting side of the matrix is deplet ⁇ ed.
  • transdermal drug delivery system is exemplified by the development and marketing of nitroglycerin-releasing transdermal therapeutic system (Nitro-Dur by Key), which has been approved by the FDA for once-a-day medication of angina pectoris.
  • the third type of device is the reservoir system.
  • the drug is contained in a reservoir seperated from the skin by an inert polymeric membrane that controls the rate, at which drug is delivered to the skin.
  • the rate of drug release from this type of transdermal drug delivery system can be tailored by varying the polymer com ⁇ position, the permeability coefficient, and/or the thickness of the rate-controlling membrane and adhesive.
  • transdermal therapeutic systems have been successfully deve- loped from this technology and are best exemplified by the development and marketing of a nitro-glycerin-releasing transdermal therapeutic system (Transderm-Nitro by Ciba), which has been approved by the U S Food and Drug Administra ⁇ tion (FDA) for once-a-day medication of angina pectoris a scopolamine-releasing transdermal therapeutic system (Transderm-Scop by Ciba) for 3-day protection from motion sickness and a clonidi ⁇ e-releasing transdermal therapeutic system.
  • FDA U S Food and Drug Administra ⁇ tion
  • a fourth type of device is a microreservoir-type drug deli ⁇ very system.
  • the drug reservoir is formed by first suspending the drug solids in the aqueous solution of a water-soluble polymer (e.g. polyethylene glycol) and then dispers-ing the drug suspension homogeneously in a li- pophilic polymer, by high-shear mechanical force, to form thousands of u ⁇ leachable, microscopic spheres of drug reser ⁇ voirs.
  • a water-soluble polymer e.g. polyethylene glycol
  • This thermody ⁇ amic ll unstable dispersion is quickly stabilized by immediately cross-l nking the polymer chains in situ, which produces a medicated polymer disc with a constant surface area and a fixed thickness.
  • a transdermal therapeutic system is then produced by positioning the medi ⁇ cated disc at the center of an adhesive pad.
  • This technology has been successfully utilized in the development and marke ⁇ ting of a nitroglyce ⁇ ' n-releasing transdermal therapeutic system (Nitrodisc by Searle) that has been approved by the FDA for once-a-day treatment of angina pectoris.
  • the pattern of drug release from the device is important. If drug is delivered to the skin at a rate less than the maxi ⁇ mum rate at which it can be absorbed by the skin, the device is the primary dosage controlling mechanism. When drug is delivered to the skin faster than the skin can absorb it, the skin surface is then saturated with drug at all times, and the limiting factor for systemic dosage is the rate of absorption through the skin.
  • the delivery rate is controlled by the skin in most real systems.
  • One approach to solve this problem is to administer a permeation enhancer alongside with the drug.
  • These enhan ⁇ cers can be used in the new system according to the present invention as well as in the old systems.
  • the release rate of an active substance is controlled by the dissociation of an inclusion complex of the substance in a drug depot.
  • the active sub ⁇ stance in the depot or reservoir is at least partly in the form of an inclusion complex.
  • the cyclo compound according to the invention is a cyclisized poly- saccharide. The best known of these compounds and the most preferred ones are the cyclo-dextrins. Derivatives and poly ⁇ mers of cyclodextrins are also of special interest in this connection.
  • the new concept of controlling the release rate from a devi- ce according to the present invention can be adapted to de ⁇ liver different active substances at different rates and have no obligatory need for a separate membrane for control- ling the release rate of the active substance.
  • the system according to the invention offers several possi ⁇ bilities of tailoring the release rate for a specific active substance. It will thus be possible to obtain a predetermin- ed release rate profile of the active substance from the system according to the invention.
  • a prede ⁇ termined release rate also includes a substantially constant release rate.
  • controlled release designates a gradual release at a predetermined time and at a desired ra ⁇ te during a predetermined release period.
  • the inclusion complex formed between the active drug substance and a cyclodextrin constitutes a drug depot from which the active substance is released in a controlled manner depending on the dissociati- on of the inclusion complex under the prevailing conditions.
  • the amount of free active substance present in the transder ⁇ mal drug delivery system will depend on the size of the dis ⁇ sociation constant and the rate at which the dissociation equilibration is established.
  • the control of the relea- se rate of the active substance from the transdermal drug delivery system is governed by the dissociation of the in ⁇ clusion complex.
  • a predetermined dissociation of the inclusion complex will result in a specific drug release profile.
  • a desired release rate profile can be achieved by:
  • cyclodextrine e.g. - , B- or ⁇ -cyclodextrine, derivatives or polymers thereof.
  • cyclodext ⁇ rins composed of from 6 to 8 a-l,4.D-glucopyranose units. These cyclodextrins are called ⁇ -, ⁇ -, and Y-cyclodextrins, respectively, and are preferred cyclo compounds in the con ⁇ text of this invention; especially preferred are the ⁇ -cyclodextrins.
  • ⁇ -Cyclodextrin consists of seven glucose units and the cavity has an internal diameter of about 7-8 A.
  • cyclodextrin polymers denotes mo ⁇ lecules which comprise two or more cyclodextrin units and have a molecular weight exceeding 2000.
  • Preferred cyclodext- rin polymers according to the invention are those composed of ⁇ , ⁇ -and/or Y-cyclodextrins.
  • cyclodextrin derivatives denotes substituted cyclodextrins or substituted cyclodextrin polymers.
  • the molar ratio of guest to host in an inclusion complex formed between the active substance and the cyclodextrin is from about 0.1:1 to about 10:1, especially from about 0.2:1 to about 5:1, in particular from about 0.3:1 to about 4:1.
  • the values given are the ratio between the active substance and the cyclo compound monomer. For example for an inclusion complex with a molar ratio of 1:1, one guest molecule is en ⁇ veloped in one cyclodextrin molecule.
  • a ratio of 1:1 denotes that one molecule of the guest is enveloped per monomeric cyclodextrin unit, i.e. one cyclodextrin polymer molecule will actually host three guest molecules.
  • a stoichiometry of 0.5:1 denotes that two cyclo- dextrin molecules (calculated as monomeric units) host one guest molecule. This situation may apply when the guest mo ⁇ lecule is too bulky to be included in one cyclodextrin cavi ⁇ ty, e.g.
  • steroid hormones usually need more than one cyclodextrin molecule for the inclusion.
  • a stoichiometry of e.g. 2:1 is obtained when two guest molecules are situated in one cyclodextrin molecule (calculated as monomeric units). This situation may apply when the guest molecule is much smaller than the cavity in the cyclodextrin molecule.
  • the most common inclusion complexes have a stoichiometry of about 1:1.
  • the equilibrium between the inclusion complex and the free active substance can be shifted in a direction which favours the existence of the drug-cyclodextrin inclusion complex by adding to the reservoir layer a calculated amount of free cyclodextrin compound and thus decrease the release rate of active substance from the system.
  • a suitable amount of free active substance to obtain a rapid access of the active substance to the skin in order to saturate bin ⁇ ding sites in the skin and/or to obtain a prompt therapeutic effect, a so called priming dose.
  • pH adjusting agents are agents which in- fluence the pH in the surrounding medium, e.g. pharmaceuti ⁇ cally acceptable salts such as alkali metal and alkaline earth metal salts and buffer substances such as acetate, citrate, phosphates, tartrates, bicarbonates and carbonates etc.
  • hydrophilic and/or hydrophobic solvents examples include polyols such as propylene glycol, polyethylene glycols, glycerol and the like
  • hydrophobic solvents include fatty acid glycerides such as miglyol, fatty acid esters such as isopropyl myristate, polysorbates etc., liguid paraffin, si ⁇ licone fluid and the like and mixtures thereof.
  • transdermal delivery sys ⁇ tem encompasses systems that are applied onto the surface of intact, or diseased skin of a mammal, in particular a hu ⁇ man, for the purpose of delivering an active substance to the skin to obtain a localized effect on the skin or in the skin, to obtain a systemic effect after entry of the active substance in the circulatory system through the skin or to obtain an effect via the lymphatic system.
  • the invention relates to a transdermal delivery system in the form of a ultilaminar device to be applied on the skin of a mammal for controlled release of an active substance to the mammal, comprising the following layers:
  • a transdermal delivery system comprises one or more active substances.
  • the active substan ⁇ ce may be present in one or more layers or laminas of adhe ⁇ sive and/or be present in a reservoir layer or lamina comprising the active substance as a depot. At least part of the active substance is in the form of an inclusion complex formed between the active substance and a cyclo compound.
  • the active substance or substances included in the delivery system of the invention may be selected from many therapeu- tic groups including anti nflammatory drugs (e.g. ibuprofen, indo ethacin, naproxen, diclofenac, tolfenamic acid, piroxicam), analgesics (e.g. buprenorphine, codeine, fenta- nyl , morphine, hydromorphone) , tranquilizers (e.g. diazepam, droperidol, fluspirilene, haloperidol, lorazepam, cardiac glycosides (e.g. digoxin, ouabain), narcotic antagonists (e.g.
  • anti nflammatory drugs e.g. ibuprofen, indo ethacin, naproxen, diclofenac, tolfenamic acid, piroxicam
  • analgesics e.g. buprenorphine
  • naloxone, nalorphine antiparkinsonis agents
  • antiparkinsonis agents e.g. bro ocripti ⁇ e, biperiden, benzhexol , benztropine
  • antidep- ressants e.g. imipramine, nortriptyline, protriptylene
  • antineoplastic agents and immunosuppressants e.g. bleomy- cin, cyclospo ⁇ ' n A, fluorouracil , ercaptopurine, ethotre- xate, mitomycin
  • antiviral agents e.g. idoxuridine, acyclovir, interferons, vidarabin
  • antibiotic agents e.g.
  • clindamycin, erythromyci ⁇ , fusidic acid, gentamicin), appe ⁇ tite suppressants e.g. fenflurami ⁇ e, mazindol, phentermin
  • antiemetics e.g. metoclopramide, droperidol, haloperidol, promethazi ⁇ e
  • a ⁇ tihistamines e.g. chlorpheni- ramine, terfe ⁇ adine, triprolidine
  • antimigraine agents e.g. dihydroergotamine, ergotamine, pizotyline
  • coronary cerebral or peripheral vasodilators
  • nifedipine, diltiazem nifedipine, diltiazem
  • antianginals e.g. glyceryl trinitrate, isosor- bide di ⁇ itrate, molsidomi ⁇ e, verapa il
  • calcium channel blockers e.g. verapamil, nifedipine, diltiazem, nicardipine
  • hormonal agents e.g. estradiol, estron, est- riol, polyestradiol , polyestriol, dienestrol, diethylstil- bestrol , progesterone, dydrogesterone, cyproterone, danazol , testosterone
  • contraceptive agents e.g.
  • ethinyl estradiol lynestrenol, etynodiol, norethisterone, mestranol , / orgest- rel , levonorgestrel , desogestrel , medroxyprogesterone
  • an- tithrombotic agents e.g. heparin, warfarin
  • diuretics e.g. hydrochlorothiazide, flunarizine, minoxidil
  • antihy- pertensive agents e.g. propanolol, metoprolol, clonidine, pindolol
  • chemical dependency drugs e.g.
  • ethadone nicotine, ethadone
  • local anaesthetics e.g. lidocaine, prilocaine, benzocaine
  • corticosteroids e.g. beclo ethasone, betamet- hasone, clobetasol, desonide, desoxymethasone, dexamethaso- ne, diflucortolone, flumethasone, fluocinolo ⁇ e acetonide, fluocinonide, hydrocortisone, methylprednisolon, triamcino- lone acetonide, budeso ⁇ ide, halcino ⁇ ide) , dermatological agents (e.g.
  • nitrofurantoin dithranol, clioquinol, hydroxy- quinoline, isotretinoin, methoxsalen, methotrexate, treti- noin, trioxsalen, salicylic acid, penicillamine), and the like.
  • steroids such as estradiol, progesterone, norethindrone, levonorgestrol , et- hynodiol, levenorgestrel , norgestimate, gestanin, desogest- rel , 3-keton-desogestrel , demegestone, promethoestrol , testosterone, spironolactone, and esters thereof; a nitro compound such as amyl nitrates, nitroglycerine and isosorbi- de nitrates; an amine compound such as prilocaine, oxybuty- ninchloride, lidocaine, benzocaine, nicotine, chlorpheniramine, terfenadine, triprolidine, propanolol and metoprolol; an oxicam derivative such as piroxicam; a muco- polysaccharide such as thiomucase; an opioid such as morphi ⁇ ne and
  • misoprostol and enaprostil a benzamide such as metoclopra- mide and scopolamine; a peptide such as growth-hormone rele ⁇ asing factors, growth factors (EGF, TGF, PDGF and the like), somatostatin and insulin; a xanthine such as caffeine and theophylline; a catecholamine such as ephedrine, salbutamol and terbutaline; a dihydropyridine such as nifedipine; a thiazide such as hydrochlorothiazide and flunarizine; a syd- nonimine such as molsidomine; and a sulfated polysaccharide such as heparin.
  • a benzamide such as metoclopra- mide and scopolamine
  • a peptide such as growth-hormone rele ⁇ asing factors, growth factors (EGF, TGF, PDGF and the like),
  • the active substance present in the transdermal delivery system in form of an inclusion complex or as a free, non- complex bond active substance can be in various forms, such as uncharged molecules, molecular complexes, or a pharmaceu ⁇ tically acceptable salt such as a hydrochloride, hydrobromi- de, sulfate, laurylate, palmitate, phosphate, nitrite, nitrate, borate, acetate, maleate, tartrate, oleate and sa- licylate.
  • salts of alkali me ⁇ tals such as sodium or potassium, alkaline earth metals, such as magnesium or calcium, amines, amino acids, organic cations or quaternary ammonium can be used.
  • the free or inclusion complex bond active substance in the transdermal delivery system can also be in the form of an ester, ether or amide, which prior to or after their relea ⁇ se from the delivery system can be converted by enzymes, hydrolyzed by action of body water at a physiologically re ⁇ levant pH or other metabolic processes to the original form or to a biologically active form.
  • Such bioreversible deriva ⁇ tives which are substantially inactive per se are denoted prodrugs.
  • the cyclodextrin inclusion complexes can be prepared accor ⁇ ding to methods well known to a person skilled in the art.
  • the most common procedures comprise stirring or shaking of an aqueous solution of the particular cyclodextrin with the guest substance or a solution thereof.
  • the reaction is pre ⁇ ferably carried out in a common solvent like water, or in different but miscible or immiscible solvents, or in no sol- vent at all, at acidic or neutral pH and at low, ambient or elevated temperature.
  • the solvent can be removed by filtration and subsequent oven-, ' vacuum-, freeze- or spray-drying, or the solvent is removed by any other suitable method well known to a person skilled in the art.
  • Prodrugs can be viewed as the therapeutically inactive deri ⁇ vatives of a therapeutically active drug that undergo bio- conversion, either by chemical or enzymatic transformation, in a biological environment, to regenerate the therapeuti ⁇ cally active parent drug prior to exhibiting their pharmaco- logical activities.
  • the prodrug concept can be applied in transdermal controlled drug delivery by altering skin permeability via modification of the physicochemical properties of the drug molecule to enhance its rate of transdermal permeation.
  • Prodrugs of a poorly skin-permeable drug may be synthesized to improve percutaneous absorption characteristics.
  • the prodrugs can be transformed, by the drug.
  • an active drug has a rather low affinity toward the skin, it will not easi ⁇ ly partition into it to any great extent.
  • the partition be ⁇ haviour of such a drug can be improved by a simple chemical modification to form a lipophilic prodrug.
  • the prodrug Upon absorption and penetration through the skin, the prodrug is rapidly me ⁇ tabolized to regenerate the active parent drug.
  • One typical example of this approach is the esterification of less skin- permeable estradiol to form lipophilic estradiol esters e.g.
  • Skin penetration enhancers are compounds which can improve the skin permeability of drugs.
  • the transdermal drug delive ⁇ ry systems release one or more skin permeation enhancers to the surface of the stratum corneum to modify the barrier properties of the skin before the controlled delivery of the active drug, and to render the skin more permeable to the drug.
  • the enhancers should be incorporated into the drug de ⁇ pot layer and/or the layer of adhesive of the transdermal delivery system.
  • One or more penetration enhancers may be present in the transdermal delivery system.
  • alkyl methyl sulfoxides e.g. decylmethyl sulfoxide, dimethyl sulfoxide
  • saturated fatty acids and alkyl esters thereof e.g. caproic acid, caprylic acid, capric acid, yristic acid, lauric acid, stearic acid, palmitic acid
  • - unsaturated fatty acids and alkyl esters thereof e.g. oleic acid, linoleic acid, linolenic acid, palmitoleic acid
  • saturated fatty alcohols e.g. myristyl alcohol, lauryl alcohol, stearyl alcohol, palmityl alcohol, cetyl alcohol
  • unsaturated fatty alcohols e.g.
  • oleyl alcohol palmito- leyl alcohol, elaidyl alcohol, linoleyl alcohol, linole- nyl alcohol; azocyclo-alkan-2-ones, e.g. l-dodecylazacycloheptan-2-one (AzoneTM) ; pyrrolidones, e.g. 2-pyrrolidone, alkyl-2-pyrrolidone,
  • glycols e.g. propylene glycol, polyethylene glycols, glycerol, dipropylene glycol, tripropylene glycol, diet- hylene glycol, triethylene glycol
  • alcohols e.g. ethanol , isopropyl alcohol, cyclohexanol ; others, e.g.
  • the active substance is present in a reservoir layer of the delivery system.
  • Suitable reservoir layer materials are materials which do not influence the active substance in any unappropriate way so as to e.g. decrease the mobility of the active substance in the reservoir layer.
  • the term "reservoir layer” designates any type of layer which serves as a drug reservoir layer.
  • the reservoir layer may comprise a solid polymer matrix in which the inclusion complex may be dispersed.
  • the reservoir layer may also comprise a viscous polymer mat ⁇ rix in which the inclusion complex is incorporated to form a cream-like suspension.
  • the layer is normally cove ⁇ red by a protective membrane to keep the integrity of the system, said protective membrane having substantially no in- fluence on drug release from the system.
  • a flexible layer of adsorbent material can give structure to the reservoir layer.
  • The.materials is preferably of a non-wowen fabric, e.g. polyester, polyethylene, polypropylene or polyamides. Wowen fabrics, however, can also be used if desired.
  • suitable matrix materials including semi-solid materials are those selected from the group consisting of cellulose derivatives such as cellulose esters [cellulose acetate, cellulose acetate butyrate (RabisanTM), cellulose acetate phthalate (Eastman C A P)], cellulose nitrates (Collodium), cellulose ethers [carboxymethyl cellulose (Cellogel CTM, CellosanTM), ethyl cellulose (EthocelTM), hydroxyethyl cellulose (Cellosize Polymer PCG-10TM, -HECTM) , hydroxypropyl cellulose (Klucel), methyl cellulose (MethocelTM, TylosenTM), methylethyl cellulose (Cellofas ATM), methyl hydroxypropyl cellulose (Celacol HPM)], polyethylene glycol, cellulose polymer
  • PolyglycolsTM PolyglycolsTM), dextranes (MacrodexTM, RheomacrodexTM) , si- licones (Dow CorningTM 470A, 471A, GE-SiliconesTM, Polysiloxanes), carrageen (SantiagelTM, SantiagumTM), silica (VeegumTM, LudoxTM, colloidal silica, MacoloidTM), polyoxyethylene-polyoxypropylene block polymers (Poloxamine, TetronicTM), methylvinyl ether-maleic acid anhydride copoly- er (ViscofasTM), karaya gums (Sterculia gum, Indian tragacanth), tragacanth (Gum DragonTM, TragantTM), xanthan gums (XB-23 biopolymer), polystyrenes (Polystyrol LG, LitexTM), styrene-butadiene copolymer (Amer
  • the layer is preferably on the order of 10 to 75 microns in thickness, and may or may not contain pigment.
  • the layer is preferably of a material that permits the device to mimic 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 device disengaging from the skin due to differences in the flexibility or resiliency of the skin and the device.
  • polymers that are useful are polyether block amide copolymers (e.g., PEBAX copolymers), polyethylene met ⁇ hyl methacrylate block copolymers (EMA) such as NUKRELL po ⁇ lymers, polyurethanes such as PELLATHANE or ESTANE polymers, silicone elastomers, polyester block copolymers that are composed of hard and soft segments (e.g. HYTREL polymers), rubber-based polyisobutylene, styrene, and styrene-butadiene and styreneisoprene copolymers.
  • PEBAX copolymers polyethylene met ⁇ hyl methacrylate block copolymers (EMA) such as NUKRELL po ⁇ lymers
  • polyurethanes such as PELLATHANE or ESTANE polymers
  • silicone elastomers silicone elastomers
  • polyester block copolymers that are composed of hard and soft segments e.
  • polymers that may be used include polyethylene, polypropylene, polyesters, e.g., polyester terephtalate (PET), which may be in the form of films or laminates.
  • PET polyester terephtalate
  • the preferred polymer used for the bac ⁇ king will depend on the material or drug incorporated into the device and on the nature of any vehicles, solubilizers, or the like that are used.
  • suitable materials for adhesive layer include polysiloxanes, polyisobutyle ⁇ es, polyacrylates, polyuretha ⁇ nes, plasticized ethylene-vinyl acetate copolymers, low mo ⁇ lecular weight polyether block amide copolymers (PEBAX copolymers), tacky rubbers such as polyisobutene, polystyrene-isoprene copolymers, polystyrene-butadiene copo ⁇ lymers, and mixtures thereof. Mixtures of polyisobutylenes and polyisobutenes are preferred.
  • the thickness of the anc ⁇ hor adhesive layer may vary, but is typically in the range of about 10 to about 125 microns.
  • the function of the protective membrane is only to protect the drug depot and the passage of this should not contribute to the controlled release of drugs from the transdermal system.
  • plastic materials polystyrene, styrene- butadien copolymer, polyvinyl chloride, polyethylene, polyp ⁇ ropylene, polysulfone, cellulose esters, polyvinylidene fluoride, ethylen-vinyl-acetat-copolymer.
  • the transdermal system Prior to use, the transdermal system includes a release li- ner. Just prior to use, this layer is removed from the sys ⁇ tem to expose the contact adhesive layer.
  • the release liner will normally be made from a drug/vehicle/enhancer imperme ⁇ able material that is inherently “strippable” or rendered so by techniques such as silicone or fluorocarbon treatment.
  • Cinnamyl alcohol Zimtalkohol Kunststoff Synthese, Merck- Schuchardt: Cinnamyl alcohol is used as a model substance. Nicotine, (-)-Nicotin Kunststoff Synthese, Merck-Schuchardt Polyvidon 90, polyvinyl pyrrolido ⁇ e, BASF Propylene glycol, Ph. Eur. 2nd Ed.
  • Oppanol 120 BASF ⁇ -cyclodextrin, ( ⁇ -CD), Avebe ⁇ -cyclodextrin inclusion complexes of cinnamyl alcohol ( ⁇ -CD-CA) and nicotine ( ⁇ -CD-N) were prepared in our laboratory.
  • Polyester sheet Polyester sheet, Mylar type D, Dupont Release liner: Siliconized polyethylene (HDPE) foil, 4P Folie Forchheim GmbH.
  • HDPE Siliconized polyethylene
  • Drying equipment The drying equipment is constructed by Pharmacia.
  • Composition Ethanol 99.9 % 226 g Dem. water 200 g Polyvidon 90 125 g
  • An acrylic-type Acronal V 205, BASF, which according to the supplier is a dispersion of acrylic copolymers in water.
  • composition according to the supplier 18.5 % di ethyl- polysiloxane by weight in trichlorotrifluorethane. Exampl e 5
  • polyester sheets to become the backing membrane were exposed for corona treatment imme ⁇ diately before application of the drug gel.
  • the volatile solvents were evaporated from the gel coated sheets and the adhesive coated sheets by placing the sheets in a drying oven working according to the following princip ⁇ le; cleaned fresh air was blown onto the wet sheets by means of a propellar. The drying air, loaded with solvent, was exhausted.
  • Transdermal drug delivery systems with cinnamyl alcohol as the active substance.
  • 16 g ⁇ -CD-CA was suspended in 16 g de . water and the sus ⁇ pension was added to 15 g polyvidon 90 gel (example 3) to give the drug gel.
  • the drug gel was solvent cast onto a po ⁇ lyester sheet 75 ⁇ m thick by means of the coating machine in a thin layer (70 ⁇ m). After drying at room temperature adhe- sive preparation I (example 4) was solvent cast onto the gel coated sheet and subsequent drying at room temperature.
  • the adhesive layer was covered by the release liner and the sheets were kept at 8°C until use.
  • the resulting sheet with backing membrane, reservoir layer and adhesive layer was 120 ⁇ m thick.
  • the concentration of cinnamyl alcohol was determined according to example 8 to 0.15 mg cinnamyl alcohol per cm 2 .
  • 16 g ⁇ -CD-CA was suspended in 5 g propylene glycol mixed with 11 g dem. water. The suspension was added to 15 g poly- vidon 90 gel (example 3) to give the drug gel.
  • the drug gel was solvent cast onto a polyester sheet 75 ⁇ m thick by means of the coating machine in a thin layer (70 ⁇ m). After drying at room temperature adhesive preparation I (example 4) was solvent cast onto the gel coated sheet and subsequent drying at room temperature.
  • the adhesive layer was covered by the release liner and the sheets were kept at 8°C until use.
  • the resulting sheet with backing membrane, reservoir layer and adhesive layer was 128 ⁇ m thick.
  • the concentration of cinnamyl alcohol was determined according to example 8 to 0.16 mg cinnamyl alcohol per cm 2 .
  • Example 3 2.0 g cinnamyl alcohol was added to 32.0 g polyvidon 90 gel (example 3) to give the drug gel.
  • the drug gel was solvent cast onto a polyester sheet 75 ⁇ m thick by means of the coa- ting machine in a thin layer (70 ⁇ m). After drying at room temperature adhesive prepartion I (example 4) was solvent cast onto the gel coated sheet and subsequent drying at room temperature.
  • the adhesive layer was covered by the release liner and the sheets were kept at 8°C until use.
  • the resulting sheet with backing membrane, resevoir layer and adhesive layer was 112 ⁇ m thick.
  • the concentration was determined according to example 8 to 0.45 mg cinnamyl alco ⁇ hol per cm 2 .
  • In vitro release studies according to example 9 were carried out on the systems 1, 2 and 3 described above. The results of these studies are reported graphically in fig. 2. From system 1 which comprises ⁇ -cyclodextrin inclusion complex of cinnamyl alcohol in the reservoir layer cinnamyl alcohol is
  • ⁇ -cyclodextrin inclusion complexes as drug depots control the release of active substance and by adding solvents, e.g. propylene glycol, to the surrounding medium in the reservoir layer it is possible to influence the release rate.
  • solvents e.g. propylene glycol
  • 16 g ⁇ -CD-CA was suspended in 16 g dem. water, and the sus ⁇ pension was added to a mixture of 7.5 g polyethylene glycol 400 and 10.5 g polyethylene glycol 6000 to give the drug gel.
  • the drug gel was solvent cast onto a polyester sheet 75 ⁇ m thick by means of the coating machine in a thin layer (70 ⁇ m). After drying at room temperature adhesive prepara ⁇ tion III (example 4) was solvent cast onto the gel coated sheet and subsequent drying at room temperature.
  • the adhesive layer was covered by the release liner, and the sheets were kept at 8°C until use.
  • the resulting sheet with backing membrane, reservoir layer and adhesive layer was 136 ⁇ m thick.
  • the concentration of cinnamyl alcohol was determined according to example 8 to 0.14 mg per cm .
  • 16 g B-CD-CA was suspended in 16 g adhesive preparation II (example 4) mixed with 1.5 g dem. water to give the drug gel.
  • the drug gel was solvent cast onto a polyester sheet 75 ⁇ m thick by means of the coating machine in a thin layer (70 ⁇ m) , and subsequent drying at room temperature.
  • the reservoir layer which also is the adhesive layer was co ⁇ vered with the release liner, and the sheets were kept at 8°C until use.
  • the resulting sheet with backing layer and reservoir/adhesive layer was 97 ⁇ m thick.
  • the concentration of cinnamyl alcohol was determined according to example 8 to 0.25 mg cinnamyl alcohol per cm 2 :
  • the adhesive layer was covered by the release liner, and the sheets were kept at 8°C until use.
  • the resulting sheet with backing layer, reservoir layer and adhesive layer was 119 ⁇ m thick.
  • the concentration of nico ⁇ tine was determined according to example 8 to 0.4 mg nicoti ⁇ ne per cm 2 .
  • Example 3 1000 ⁇ l nicotine and 400 ⁇ l propylene glycol were added to 12.6 g polyvidon 90 gel (example 3) to give the drug gel.
  • the drug gel was solvent cast onto a polyester sheet 75 ⁇ m thick by means of the coating machine in a thin layer (70 ⁇ m). After drying at room temperature adhesive preparation II (example 4) was solvent cast onto the gel coated sheet and subsequent drying at room temperature.
  • the adhesive layer was covered by the release liner, and the sheets were kept at 8°C until use.
  • the resulting sheet with backing layer, reservoir layer and adhesive layer was 109 ⁇ m thick.
  • the concentration of nico- tine was determined according to example 8 to 0.2 mg nicoti ⁇ ne per cm 2 .
  • In vitro release studies according to example 9 were carried out on the systems 6 and 7 described above. The results of those studies are reported graphically in fig. 4. From sys ⁇ tem 6 which comprises ⁇ -cyclodextrin inclusion complex of nicotine in the reservoir layer nicotine is released with a slower rate than from system 7 which comprises neat nicotine without ⁇ -cyclodextrin in the reservoir layer. As shown, the release rate of nicotine from system 6 declined slightly over the period but more closely approximated zero order re- lease than first order release.
  • the diffusion cell used consisted of a 24 mm diameter Millipore cellulose ester GSWP type filter mounted on the detachable end of a stainless steel cylinder using silicone glue, thereby dividing the cell into two compartments: a do- nor and a larger stirred receptor compartment. Patches of 1.54 cm 2 were punched out and mounted on the Millipore filter. The diffusion of the active substance from the upper compartments was followed at room temperature by removing samples periodically and measuring the concentrati- on of the drugs.
  • the receptor phase was 15.00 ml 0.01 N HC1 in the studies with nicotine and 15.00 ml phosphate buffer 0.05 M pH 7.4 in the studies with cinnamyl alcohol.
  • the amount of active substance in the samples was determined by UV-spectrophotometry according to example 8.
  • the adhesive layer was covered by a release liner
  • Epidermis was heat separated from full thickness human skin and mounted in glass diffusion cells with an available dif ⁇ fusion area of 1.8 cm 2 . Patches of 1.54 cm 2 of system 8 was punched out and applied on the skin surface and the dermal side of the skin was exposed to 12.1 ml recipient phase, 0.01 M acetate buffer solution of pH 4.
  • Permeation of nicotine was followed by removing samples pe ⁇ riodically and measuring the concentration by a HPLC method according to example 11. The cumulative amount of nicotine appearing in the recipient phase versus time are shown in fig. 5. As it appears, system 8 revealed approximately zero order permeation kinetics although the permeation rate of nicotine declined slightly over the period. The initial per ⁇ meation rate was calculated to 22,2 ⁇ g cm ⁇ 2 h _1 .
  • Quantitative determination of nicotine content in the reci ⁇ pient phase samples from skin permeation studies was done by a HPLC method.
  • a LKB system comprising a LKB 2249 HPLC pump, a LKB 2141 variable wavelength monitor, a LKB 2221 integra ⁇ tor and a LKB 2157 autosampler (20 ul injected) was used.
  • the column used 12 cm long and 4 mm i.d., was packed with Nucleosil 5 CN.
  • the column was eluted isocratically at am ⁇ bient temperature with a mobile phase consisting of dem. water-acetonitril-diethylamine (400:100:0.38 v/v). The flow rate was 1.0 ml/min. and the column effluent was monitored at 254 nm.
  • the lamination was accomplished by solvent casting adhesive preparation 1 onto a si1iconized polyethylene foil in a 100 ⁇ m layer, drying at room tempera ⁇ ture and pressing the layer onto the dry drug gel layer by means of a steel roller (5,5 kg) after which the polyethyle- ne foil was removed.
  • the adhesive layer was covered by a release liner (PerlasticTM-L36, PETP-Folie) and the sheets were kept in heat-sealed pouches (BarexTM, polyacrylnitrit/aluminium- laminate) at 8°C, 25°C and 40°C to investigate the stability of the product at these three temperatures.
  • a release liner PerlasticTM-L36, PETP-Folie
  • BarexTM polyacrylnitrit/aluminium- laminate
  • the resulting sheet with backing layer, reservoir layer and adhesive layer was 413 ⁇ m thick.
  • the concentration of nico- tine was determined to 1,5 mg cm "2 according to the follow ⁇ ing method. Patches of 0,63 cm 2 was punched out and extract ⁇ ed with 5,00 ml heptane.
  • the heptane phase was extracted with 10,00 ml 0,01 N HC1 and after separation of the phases the amount of active substance in the aqueous phase was de- termined according to example 8.
  • 2,4 g nicotine was added to 91,6 g polyisobutylene-type gel composed of 2,0 g Oppanol 10, 1,5 g Oppanol 50, 1,0 g Oppanol 120 dissolved in 30 ml hexane whereafter 2,0 g li ⁇ quid paraffin was added to give the drug gel.
  • the drug gel was solvent cast onto a polyester sheet 75 ⁇ m thick by means of the coating machine in a 0,8 mm layer. After drying at room temperature adhesive preparation 1 (example 4) was la- minated onto the gel coated sheet.
  • the lamination was ac ⁇ complished by solvent casting adhesive preparation 1 onto a siliconized polyethylene foil in a 100 ⁇ m layer, drying at room temperature and pressing the layer onto the dry drug gel layer by means of a steel roller (5,5 kg) after which the polyethylene foil was removed.
  • the adhesive layer was covered by a release liner (PerlasticTM-L36, PETP-Folie) and the sheets were kept in heat-sealed pouches (BarexTM, polyacrylnitrit/aluminiumlaminate) at 8°C until use.
  • the resulting sheet with backing layer, reservoir layer and adhesive layer was 293 ⁇ m thick.
  • the concentration of nico ⁇ tine was determined to 0,8 mg cm -2 according to the follow ⁇ ing method. Patches of 0,63 cm 2 was punched out and extract ⁇ ed with 5,00 ml heptane.
  • the heptane phase was extracted with 10,00 ml 0,01 N HCl and after separation of the phases the amount of active substance in the aqueous phase was de ⁇ termined according to example 8.
  • Epidermis was heat separated from full thickness human skin and mounted in glass diffusion cells with an available dif ⁇ fusion area of 1,8 cm 2 . Patches of 1,54 cm 2 of system 9 and 10 were punched out and applied on the skin surface and the dermal side of the skin was exposed to 12,1 ml recipient phase, 0,01 M acetate buffer solution of pH 4.
  • Permeation of nicotine was followed by removing samples pe ⁇ riodically and measuring the concentration by a HPLC method according to example 11. The cumulative amount of nicotine appearing in the recipient phase versus time are shown in fig. 7. As it appears, system 9 revealed zero order permea- tion kinetics with a permeation rate of 6,7 ⁇ g cm ⁇ h-1. For comparison purposes permeation studies were carried out on system 10 which comprises neat nicotine without ⁇ -cyclo- dextrin in the reservoir layer. System 10 revealed a curve- linear profile and the active substance permeated very fast as about 80 % of the dose is released in about 30 hours.
  • the la ⁇ mination was accomplished by solvent casting adhesive prepa- ration 1 onto a si1iconized polyethylene foil in a 100 ⁇ m layer, drying at room temperature and pressing the layer on- to the dry drug gel layer by means of a steel roller (5,5 kg) after which the polyethylene foil was removed.
  • the adhe ⁇ sive layer was covered by a release liner (PerlasticTM-L36, PETP-Folie) and the sheets were kept in heat-sealed pouches (Barex , polyacrylnitri ⁇ t/aluminiumlaminate) at 8°C until use.
  • the resulting sheet with backing layer, reservoir layer and adhesive layer was 290 ⁇ m thick.
  • the concentration of nico- tine was determined to 2,1 mg cm -2 according to the follow ⁇ ing method. Patches of 0,63 cm 2 was punched out and extract ⁇ ed with 5,00 ml heptane.
  • the heptane phase was extracted with 10,00 ml 0,01 N HCl and after separation of the phases the amount of active substance in the aqueous phase was de- termi ⁇ ed according to example 8.
  • Oppanol 120 dissolved in 30,0 ml hexane whereafter 1,2 g ni ⁇ cotine and 2,0 g liquid paraffin was added to give the drug gel.
  • the drug gel was solvent cast onto a polyester sheet 75 ⁇ m thick by means of the coating machine in a 0,8 mm layer. After drying at room temperature adhesive preparation 1
  • example 4 was laminated onto the gel coated sheet.
  • the la ⁇ mination was accomplished by solvent casting adhesive prepa ⁇ ration 1 onto a si1iconized polyethylene foil in a 100 urn layer, drying at room temperature and pressing the layer on- to the dry drug gel layer by means of a steel roller (5,5 kg) after which the polyethylene foil was removed.
  • the adhe ⁇ sive layer was covered by a release liner (PerlasticTM-L36, PETP-Folie) and the sheets were kept in heat-sealed pouches (BarexTM, polyacrylnitrit/aluminiumlaminate) at 8°C until use.
  • the resulting sheet with backing layer, reservoir layer and adhesive layer was 290 ⁇ m thick.
  • the concentration of nico ⁇ tine was determined to 1,8 mg cm "2 according to the follow ⁇ ing method. Patches of 0,63 cm 2 was punched out and extract- ed with 5,00 ml heptane. The heptane phase was extracted with 10,00 ml 0,01 N HCl and after separation of the phases the amount of active substance in the aqueous phase was de ⁇ termined according to example 8.
  • Epidermis was heat separated from full thickness human skin and mounted in glass diffusion cells with an available dif ⁇ fusion area of 1,8 cm 2 . Patches of 1,54 cm of system 11 and 12 were punched out and applied on the skin surface and the dermal side of the skin was exposed to 12,1 ml recipient phase, 0,01 M acetate buffer solution of pH 4.
  • Permeation of nicotine was followed by removing samples pe ⁇ riodically and measuring the concentration by a HPLC method according to example 11. The cumulative amount of nicotine appearing in the recipient phase versus time are shown in fig. 8. As it appears, addition of neat nicotine (e.g. a priming dose) resulted in a fast permeation rate initially which eventually declines to a constant permeation rate of 4,1 ⁇ g cm "2 h-1.
  • neat nicotine e.g. a priming dose
  • Inclusion complex of ⁇ -CD and estradiol was prepar ⁇ ed as follows. 104,2 g ⁇ -CD and 12,5 g 17 ⁇ -estradiol were mixed with 1.570 ml water while stirring and heating to the boiling point in 1,5 hours. The mixture was stirred for 42,5 hours at room temperature. The obtained complex was filtered and washed twice with 250 ml ethanol 99,9 % to remove un ⁇ bounded estradiol whereafter it was dried in a drying oven at room temperature.
  • the adhesive layer was covered by the release liner and the sheets were kept at 8°C until use.

Abstract

The present invention concerns a transdermal system with a reservoir layer comprising an active substance, at least part of which is in the form of an inclusion complex formed between a cyclo compound and the active substance. The release rate from the system is controlled by the dissociation of the complex.

Description

TRANSDERMAL SYSTEM
Field of invention
The present invention concerns a controlled release trans- dermal delivery system. Specifically the invention concerns a delivery system, from which the release rate of an active substance is governed or controlled by a new principle. The delivery system according to the invention is of particular interest for the transdermal delivery of drugs.
Background
Transdermal drug delivery systems can be categorized into three general types. The earliest devices have a simple two- layer "Band-Aid" configuration composed of a backing layer coated with adhesive. Usually the drug is mixed in the adhe¬ sive layer that fixes the bandage to the skin. These medica¬ ted bandages bring a known quantity of drug to a known area of skin for a known period of time, but have no mechanism for controlling the rate at which the drug is delivered to the patient.
The second type of device, in this context referred to as a monolithic system, is a system incorporating a backing lay¬ er, a matrix layer, and an adhesive layer. The matrix layer is made of a polymer material in which the solid drug is dispersed and the rate at which the drug is released from the device is controlled by the polymer matrix. With this type of system, the drug release rate falls off with time as the drug in the skin-contacting side of the matrix is deplet¬ ed.
This type of transdermal drug delivery system is exemplified by the development and marketing of nitroglycerin-releasing transdermal therapeutic system (Nitro-Dur by Key), which has been approved by the FDA for once-a-day medication of angina pectoris. The third type of device is the reservoir system. In this case, the drug is contained in a reservoir seperated from the skin by an inert polymeric membrane that controls the rate, at which drug is delivered to the skin. These devices offer an important advantage over the monolithic geometry because as long as the drug solution in the reservoir re¬ mains saturated, the drug release rate through the membrane is constant.
The rate of drug release from this type of transdermal drug delivery system can be tailored by varying the polymer com¬ position, the permeability coefficient, and/or the thickness of the rate-controlling membrane and adhesive. Several transdermal therapeutic systems have been successfully deve- loped from this technology and are best exemplified by the development and marketing of a nitro-glycerin-releasing transdermal therapeutic system (Transderm-Nitro by Ciba), which has been approved by the U S Food and Drug Administra¬ tion (FDA) for once-a-day medication of angina pectoris a scopolamine-releasing transdermal therapeutic system (Transderm-Scop by Ciba) for 3-day protection from motion sickness and a clonidiπe-releasing transdermal therapeutic system.
A fourth type of device is a microreservoir-type drug deli¬ very system. In this approach, the drug reservoir is formed by first suspending the drug solids in the aqueous solution of a water-soluble polymer (e.g. polyethylene glycol) and then dispers-ing the drug suspension homogeneously in a li- pophilic polymer, by high-shear mechanical force, to form thousands of uπleachable, microscopic spheres of drug reser¬ voirs. This thermodyπamic ll unstable dispersion is quickly stabilized by immediately cross-l nking the polymer chains in situ, which produces a medicated polymer disc with a constant surface area and a fixed thickness. A transdermal therapeutic system is then produced by positioning the medi¬ cated disc at the center of an adhesive pad. This technology has been successfully utilized in the development and marke¬ ting of a nitroglyceπ'n-releasing transdermal therapeutic system (Nitrodisc by Searle) that has been approved by the FDA for once-a-day treatment of angina pectoris.
The pattern of drug release from the device is important. If drug is delivered to the skin at a rate less than the maxi¬ mum rate at which it can be absorbed by the skin, the device is the primary dosage controlling mechanism. When drug is delivered to the skin faster than the skin can absorb it, the skin surface is then saturated with drug at all times, and the limiting factor for systemic dosage is the rate of absorption through the skin.
As the skin is substantially impermeable to most drugs the delivery rate is controlled by the skin in most real systems. One approach to solve this problem is to administer a permeation enhancer alongside with the drug. These enhan¬ cers can be used in the new system according to the present invention as well as in the old systems.
Summary of the invention
According to the present invention the release rate of an active substance, e.g. a drug, from a transdermal system, is controlled by the dissociation of an inclusion complex of the substance in a drug depot. Specifically the active sub¬ stance in the depot or reservoir is at least partly in the form of an inclusion complex. It is preferred that the cyclo compound according to the invention is a cyclisized poly- saccharide. The best known of these compounds and the most preferred ones are the cyclo-dextrins. Derivatives and poly¬ mers of cyclodextrins are also of special interest in this connection.
It is previously known to use cyclodextrins in transdermal systems. The most important purposes for which these com¬ pounds have been used is to achieve superior properties as to solubility, releasing properties, stability, bioavailabi- lity and efficacy of certain active substances, e.g. some steroids (Japanese patent application 113275/1983),
2-nitroxymethyl-6-chloro-ρyridine (US patent 4,749,574) and nitroglycerin (Japanese patent application 81 123912).
It is thus previously known that active substances e.g. drugs can be included in transdermal patches in the form of cyclodextriπ complexes for various reasons. To the best of our knowledge, however, it has not been disclosed or suggest¬ ed that such complexes can be used for controlling the re- lease rate from the system in accordance with the present invention.
The new concept of controlling the release rate from a devi- ce according to the present invention can be adapted to de¬ liver different active substances at different rates and have no obligatory need for a separate membrane for control- ling the release rate of the active substance. Furthermore, the system according to the invention offers several possi¬ bilities of tailoring the release rate for a specific active substance. It will thus be possible to obtain a predetermin- ed release rate profile of the active substance from the system according to the invention. In this context a prede¬ termined release rate also includes a substantially constant release rate. These possiblities are of course based on fac¬ tors which influence the dissociation of the inclusion comp- lex in the surrounding medium.
In the following, the term "controlled release" designates a gradual release at a predetermined time and at a desired ra¬ te during a predetermined release period.
According to the present invention the inclusion complex formed between the active drug substance and a cyclodextrin constitutes a drug depot from which the active substance is released in a controlled manner depending on the dissociati- on of the inclusion complex under the prevailing conditions.
For an inclusion complex in solution, some of the enclosed active substance will be displaced by solvent molecules. The extent thereof will depend on the dissociation constant of the inclusion complex under the prevailing conditions, as, according to the partition behaviour/affinity of the active substance the molecules of the active substance, will distri¬ bute between the surrounding medium and the cavity of the cyclo compound. This competitive process determines the amount of active substance molecules present as free molecu¬ les and as complex bound molecules, respectively. Active substance present as free molecules will diffuse much easier than the complex bound active substance due to the large difference in molecular size and, thus, the amount of free active substance present is determinative for the release rate of active substance from the transdermal drug delivery system. For the 1:1 complex the equilibration equation of the disso¬ ciation process will be
CyD-drug CyD + drug
and hence, the dissociation constant of the complex will be
[CyD] x [drug] Kd =
[CyD-drug]
The amount of free active substance present in the transder¬ mal drug delivery system will depend on the size of the dis¬ sociation constant and the rate at which the dissociation equilibration is established. Thus the control of the relea- se rate of the active substance from the transdermal drug delivery system is governed by the dissociation of the in¬ clusion complex.
A predetermined dissociation of the inclusion complex will result in a specific drug release profile. According to the invention a desired release rate profile can be achieved by:
1. choice of cyclodextrine, e.g. - , B- or γ-cyclodextrine, derivatives or polymers thereof.
2. choice of molar ratio of drug to cyclodextrine in the inclusion complex.
3. mixing different cyclodextrine inclusion complexes.
4. adding excess amount of cyclodextrine to the system. 5. adding free drug to the system, i.e. priming dose.
6. adding pH-adjusting agents to the system.
7. adding hydrophilic or lipophilic solvents to the systems.
For economic reasons it has been preferred to use cyclodext¬ rins composed of from 6 to 8 a-l,4.D-glucopyranose units. These cyclodextrins are called α-, β-, and Y-cyclodextrins, respectively, and are preferred cyclo compounds in the con¬ text of this invention; especially preferred are the β-cyclodextrins. β-Cyclodextrin consists of seven glucose units and the cavity has an internal diameter of about 7-8 A.
In this context the term "cyclodextrin polymers" denotes mo¬ lecules which comprise two or more cyclodextrin units and have a molecular weight exceeding 2000. Preferred cyclodext- rin polymers according to the invention are those composed of α , β-and/or Y-cyclodextrins.
In this context the term "cyclodextrin derivatives" denotes substituted cyclodextrins or substituted cyclodextrin polymers.
Principles and methods for the preparation of cyclodextrin derivatives are well known to a person skilled in the art and are reviewed in e.g. Szejtli, J. "Cyclodextrins and their inclusion complexes", Akademia Kiado, Budapest 1982, pp. 75-81 to which reference is made.
The molar ratio of guest to host in an inclusion complex formed between the active substance and the cyclodextrin is from about 0.1:1 to about 10:1, especially from about 0.2:1 to about 5:1, in particular from about 0.3:1 to about 4:1. The values given are the ratio between the active substance and the cyclo compound monomer. For example for an inclusion complex with a molar ratio of 1:1, one guest molecule is en¬ veloped in one cyclodextrin molecule. If the inclusion comp¬ lex is formed between a cyclodextrin polymer comprising three cyclodextrin units (three monomeric units) and a guest molecule, a ratio of 1:1 denotes that one molecule of the guest is enveloped per monomeric cyclodextrin unit, i.e. one cyclodextrin polymer molecule will actually host three guest molecules. A stoichiometry of 0.5:1 denotes that two cyclo- dextrin molecules (calculated as monomeric units) host one guest molecule. This situation may apply when the guest mo¬ lecule is too bulky to be included in one cyclodextrin cavi¬ ty, e.g. steroid hormones usually need more than one cyclodextrin molecule for the inclusion. A stoichiometry of e.g. 2:1 is obtained when two guest molecules are situated in one cyclodextrin molecule (calculated as monomeric units). This situation may apply when the guest molecule is much smaller than the cavity in the cyclodextrin molecule. The most common inclusion complexes have a stoichiometry of about 1:1.
The equilibrium between the inclusion complex and the free active substance can be shifted in a direction which favours the existence of the drug-cyclodextrin inclusion complex by adding to the reservoir layer a calculated amount of free cyclodextrin compound and thus decrease the release rate of active substance from the system.
In some cases it is desirable to incorporate a suitable amount of free active substance to obtain a rapid access of the active substance to the skin in order to saturate bin¬ ding sites in the skin and/or to obtain a prompt therapeutic effect, a so called priming dose.
Agents which can influence the dissociation constant for complexes containing drugs in form of acids/bases include pH adjusting agents. pH adjusting agents are agents which in- fluence the pH in the surrounding medium, e.g. pharmaceuti¬ cally acceptable salts such as alkali metal and alkaline earth metal salts and buffer substances such as acetate, citrate, phosphates, tartrates, bicarbonates and carbonates etc.
Other agents which may influence the dissociation of the in¬ clusion complex include hydrophilic and/or hydrophobic solvents. Examples of hydrophilic solvents include polyols such as propylene glycol, polyethylene glycols, glycerol and the like, and examples of hydrophobic solvents include fatty acid glycerides such as miglyol, fatty acid esters such as isopropyl myristate, polysorbates etc., liguid paraffin, si¬ licone fluid and the like and mixtures thereof.
In the present context the term "transdermal delivery sys¬ tem" encompasses systems that are applied onto the surface of intact, or diseased skin of a mammal, in particular a hu¬ man, for the purpose of delivering an active substance to the skin to obtain a localized effect on the skin or in the skin, to obtain a systemic effect after entry of the active substance in the circulatory system through the skin or to obtain an effect via the lymphatic system.
Accordingly, the invention relates to a transdermal delivery system in the form of a ultilaminar device to be applied on the skin of a mammal for controlled release of an active substance to the mammal, comprising the following layers:
A) at the skin-distal side, a backing membrane which is substantially impermeable to the active substance,
B) optionally one or more layers of adhesive, optionally comprising an active substance,
C) a reservoir layer comprising an active substance and op- tionally an adhesive agent,
D) optionally a protecting membrane situated adjacent to the reservoir layer opposite to the backing membrane, and E) a release liner at the side of the device to be applied to the skin, which release liner is adapted to be remo¬ ved prior to use.
A transdermal delivery system according to the invention comprises one or more active substances. The active substan¬ ce may be present in one or more layers or laminas of adhe¬ sive and/or be present in a reservoir layer or lamina comprising the active substance as a depot. At least part of the active substance is in the form of an inclusion complex formed between the active substance and a cyclo compound.
The active substance or substances included in the delivery system of the invention may be selected from many therapeu- tic groups including anti nflammatory drugs (e.g. ibuprofen, indo ethacin, naproxen, diclofenac, tolfenamic acid, piroxicam), analgesics (e.g. buprenorphine, codeine, fenta- nyl , morphine, hydromorphone) , tranquilizers (e.g. diazepam, droperidol, fluspirilene, haloperidol, lorazepam, cardiac glycosides (e.g. digoxin, ouabain), narcotic antagonists (e.g. naloxone, nalorphine), antiparkinsonis agents (e.g. bro ocriptiπe, biperiden, benzhexol , benztropine), antidep- ressants (e.g. imipramine, nortriptyline, protriptylene), antineoplastic agents and immunosuppressants (e.g. bleomy- cin, cyclospoπ'n A, fluorouracil , ercaptopurine, ethotre- xate, mitomycin), antiviral agents (e.g. idoxuridine, acyclovir, interferons, vidarabin), antibiotic agents (e.g. clindamycin, erythromyciπ, fusidic acid, gentamicin), appe¬ tite suppressants (e.g. fenfluramiπe, mazindol, phentermin), antiemetics (e.g. metoclopramide, droperidol, haloperidol, promethaziπe), aπtihistamines (e.g. chlorpheni- ramine, terfeπadine, triprolidine) , antimigraine agents (e.g. dihydroergotamine, ergotamine, pizotyline), coronary, cerebral or peripheral vasodilators (e.g. nifedipine, diltiazem), antianginals (e.g. glyceryl trinitrate, isosor- bide diπitrate, molsidomiπe, verapa il), calcium channel blockers (e.g. verapamil, nifedipine, diltiazem, nicardipine) , hormonal agents (e.g. estradiol, estron, est- riol, polyestradiol , polyestriol, dienestrol, diethylstil- bestrol , progesterone, dydrogesterone, cyproterone, danazol , testosterone), contraceptive agents (e.g. ethinyl estradiol, lynestrenol, etynodiol, norethisterone, mestranol , / orgest- rel , levonorgestrel , desogestrel , medroxyprogesterone) , an- tithrombotic agents (e.g. heparin, warfarin), diuretics (e.g. hydrochlorothiazide, flunarizine, minoxidil), antihy- pertensive agents (e.g. propanolol, metoprolol, clonidine, pindolol), chemical dependency drugs (e.g. nicotine, ethadone), local anaesthetics (e.g. lidocaine, prilocaine, benzocaine), corticosteroids (e.g. beclo ethasone, betamet- hasone, clobetasol, desonide, desoxymethasone, dexamethaso- ne, diflucortolone, flumethasone, fluocinoloπe acetonide, fluocinonide, hydrocortisone, methylprednisolon, triamcino- lone acetonide, budesoπide, halcinoπide) , dermatological agents (e.g. nitrofurantoin, dithranol, clioquinol, hydroxy- quinoline, isotretinoin, methoxsalen, methotrexate, treti- noin, trioxsalen, salicylic acid, penicillamine), and the like.
Examples of specific active substances are steroids such as estradiol, progesterone, norethindrone, levonorgestrol , et- hynodiol, levenorgestrel , norgestimate, gestanin, desogest- rel , 3-keton-desogestrel , demegestone, promethoestrol , testosterone, spironolactone, and esters thereof; a nitro compound such as amyl nitrates, nitroglycerine and isosorbi- de nitrates; an amine compound such as prilocaine, oxybuty- ninchloride, lidocaine, benzocaine, nicotine, chlorpheniramine, terfenadine, triprolidine, propanolol and metoprolol; an oxicam derivative such as piroxicam; a muco- polysaccharide such as thiomucase; an opioid such as morphi¬ ne and morphine-like drugs such as buprenorphine, oxymorphone, hydromorphone, levorphanol, fentanyl and fenta- nyl derivatives and analogs; a prostaglandin such as a mem¬ ber of the PGA, PGB, PGE and PGF series, such as e.g. misoprostol and enaprostil; a benzamide such as metoclopra- mide and scopolamine; a peptide such as growth-hormone rele¬ asing factors, growth factors (EGF, TGF, PDGF and the like), somatostatin and insulin; a xanthine such as caffeine and theophylline; a catecholamine such as ephedrine, salbutamol and terbutaline; a dihydropyridine such as nifedipine; a thiazide such as hydrochlorothiazide and flunarizine; a syd- nonimine such as molsidomine; and a sulfated polysaccharide such as heparin.
The active substance present in the transdermal delivery system in form of an inclusion complex or as a free, non- complex bond active substance can be in various forms, such as uncharged molecules, molecular complexes, or a pharmaceu¬ tically acceptable salt such as a hydrochloride, hydrobromi- de, sulfate, laurylate, palmitate, phosphate, nitrite, nitrate, borate, acetate, maleate, tartrate, oleate and sa- licylate. For acidic active substances, salts of alkali me¬ tals, such as sodium or potassium, alkaline earth metals, such as magnesium or calcium, amines, amino acids, organic cations or quaternary ammonium can be used. Furthermore, the free or inclusion complex bond active substance in the transdermal delivery system can also be in the form of an ester, ether or amide, which prior to or after their relea¬ se from the delivery system can be converted by enzymes, hydrolyzed by action of body water at a physiologically re¬ levant pH or other metabolic processes to the original form or to a biologically active form. Such bioreversible deriva¬ tives which are substantially inactive per se are denoted prodrugs.
The cyclodextrin inclusion complexes can be prepared accor¬ ding to methods well known to a person skilled in the art. The most common procedures comprise stirring or shaking of an aqueous solution of the particular cyclodextrin with the guest substance or a solution thereof. The reaction is pre¬ ferably carried out in a common solvent like water, or in different but miscible or immiscible solvents, or in no sol- vent at all, at acidic or neutral pH and at low, ambient or elevated temperature. After an equilibrium is reached, the solvent can be removed by filtration and subsequent oven-,' vacuum-, freeze- or spray-drying, or the solvent is removed by any other suitable method well known to a person skilled in the art.
For drugs, which cannot be administered transdermally at a rate high enough to achieve a therapeutic blood level it is required to involve methods to reduce the skin's barrier properties. Two approaches of enhancing the permeation of drug can be used; bioconvertible prodrugs and penetration enhancers.
Prodrugs can be viewed as the therapeutically inactive deri¬ vatives of a therapeutically active drug that undergo bio- conversion, either by chemical or enzymatic transformation, in a biological environment, to regenerate the therapeuti¬ cally active parent drug prior to exhibiting their pharmaco- logical activities.
The prodrug concept can be applied in transdermal controlled drug delivery by altering skin permeability via modification of the physicochemical properties of the drug molecule to enhance its rate of transdermal permeation.
Prodrugs of a poorly skin-permeable drug may be synthesized to improve percutaneous absorption characteristics. During the course of transdermal permeation, the prodrugs can be transformed, by the drug. In other words, if an active drug has a rather low affinity toward the skin, it will not easi¬ ly partition into it to any great extent. The partition be¬ haviour of such a drug can be improved by a simple chemical modification to form a lipophilic prodrug. Upon absorption and penetration through the skin, the prodrug is rapidly me¬ tabolized to regenerate the active parent drug. One typical example of this approach is the esterification of less skin- permeable estradiol to form lipophilic estradiol esters e.g. estradiol-17-acetate and estradiol-3.17-diacetate. Skin penetration enhancers are compounds which can improve the skin permeability of drugs. The transdermal drug delive¬ ry systems release one or more skin permeation enhancers to the surface of the stratum corneum to modify the barrier properties of the skin before the controlled delivery of the active drug, and to render the skin more permeable to the drug. The enhancers should be incorporated into the drug de¬ pot layer and/or the layer of adhesive of the transdermal delivery system. One or more penetration enhancers may be present in the transdermal delivery system.
Some representative classes of potential skin penetration enhancers are:
- alkyl methyl sulfoxides, e.g. decylmethyl sulfoxide, dimethyl sulfoxide; saturated fatty acids and alkyl esters thereof, e.g. caproic acid, caprylic acid, capric acid, yristic acid, lauric acid, stearic acid, palmitic acid; - unsaturated fatty acids and alkyl esters thereof, e.g. oleic acid, linoleic acid, linolenic acid, palmitoleic acid; saturated fatty alcohols, e.g. myristyl alcohol, lauryl alcohol, stearyl alcohol, palmityl alcohol, cetyl alcohol; unsaturated fatty alcohols, e.g. oleyl alcohol, palmito- leyl alcohol, elaidyl alcohol, linoleyl alcohol, linole- nyl alcohol; azocyclo-alkan-2-ones, e.g. l-dodecylazacycloheptan-2-one (Azone™) ; pyrrolidones, e.g. 2-pyrrolidone, alkyl-2-pyrrolidone,
N-methylpyrrolidone; glycols, e.g. propylene glycol, polyethylene glycols, glycerol, dipropylene glycol, tripropylene glycol, diet- hylene glycol, triethylene glycol; alcohols, e.g. ethanol , isopropyl alcohol, cyclohexanol ; others, e.g. diethyltoluamide, tetrahydrofurfuryl alco¬ hol, dimethyl formamide, dimethyl acetamide, 2,2,2-trichloroethanol , 2,2,2-trifluoroethanol , urea, salicylic acid, ethylene glycol monomethyl ether, N,N-dialkylhydroxylamine, 1,2-isopropylidene glycerol , N,N-dialkylnicotinamide, alkylaminooxide, hyaluronidase, isopropyl myristate, saccharose monooleate, lecithins, non-ionic surfactants, cholic acid and derivatives thereof.
According to the present invention, the active substance is present in a reservoir layer of the delivery system. Suitable reservoir layer materials are materials which do not influence the active substance in any unappropriate way so as to e.g. decrease the mobility of the active substance in the reservoir layer. In the specification and claims, the term "reservoir layer" designates any type of layer which serves as a drug reservoir layer.
Thus the reservoir layer may comprise a solid polymer matrix in which the inclusion complex may be dispersed.
The reservoir layer may also comprise a viscous polymer mat¬ rix in which the inclusion complex is incorporated to form a cream-like suspension.
If the reservoir layer is fluid, the layer is normally cove¬ red by a protective membrane to keep the integrity of the system, said protective membrane having substantially no in- fluence on drug release from the system. A flexible layer of adsorbent material can give structure to the reservoir layer. The.materials is preferably of a non-wowen fabric, e.g. polyester, polyethylene, polypropylene or polyamides. Wowen fabrics, however, can also be used if desired.
Examples of suitable matrix materials including semi-solid materials are those selected from the group consisting of cellulose derivatives such as cellulose esters [cellulose acetate, cellulose acetate butyrate (Rabisan™), cellulose acetate phthalate (Eastman C A P)], cellulose nitrates (Collodium), cellulose ethers [carboxymethyl cellulose (Cellogel C™, Cellosan™), ethyl cellulose (Ethocel™), hydroxyethyl cellulose (Cellosize Polymer PCG-10™, -HEC™) , hydroxypropyl cellulose (Klucel), methyl cellulose (Methocel™, Tylosen™), methylethyl cellulose (Cellofas A™), methyl hydroxypropyl cellulose (Celacol HPM)], polyethylene glycol, cellulose polymer
(Alcoramπosan™, Idrora nosan™), polyvidones (Kollidon™, Periston™), alginates (Kelcoalgiπate™, Kelcogel™, Kelcosol™, Kelgine™, Kelmar™, Keltoπe™, Manucol-Ester™, Protanal™, Protatek™) , polyacrylic acids (Carbomer, Carbopol), polyacrylates (Permasorb™, Acronal™), polyacry- lamides (Cyanamer™, Gelamide™), poloxamer (Pluronics™), gelatines (Phar agel A, Thiogel™), polyvinyl alcohols (Elvanol™, Gelvatol™, Le ol™, Polyviol, Vinylon), polyvi- nylacetates (Mowilith™, Vinnapas™), pectines, pectine ami- des, polyethylene glycols (Carbowax™, Carbox™, Dow
Polyglycols™), dextranes (Macrodex™, Rheomacrodex™) , si- licones (Dow Corning™ 470A, 471A, GE-Silicones™, Polysiloxanes), carrageen (Santiagel™, Santiagum™), silica (Veegum™, Ludox™, colloidal silica, Macoloid™), polyoxyethylene-polyoxypropylene block polymers (Poloxamine, Tetronic™), methylvinyl ether-maleic acid anhydride copoly- er (Viscofas™), karaya gums (Sterculia gum, Indian tragacanth), tragacanth (Gum Dragon™, Tragant™), xanthan gums (XB-23 biopolymer), polystyrenes (Polystyrol LG, Litex™), styrene-butadiene copolymer (Ameripol™,
Austrapol™, Duradene™, Synapreπ™), polyvinyl chloride (Lutofaπ™, Rhenoflex™, Vinnol™), polyvinylidene chloride (Diafan™), polyethylenes (Aldurol™, Celipal™, Ludopal™, Dynapol™), polypropylenes (Alprodur™), polysulfones (Udel , Sulfil™), polyisobutylenes (Oppanol™, Luvitol™) polyiso- butenes (Parlea ™), polyurethaπes (Beckocoat™, Desmodur™). Backing membrane is preferably made of a sheet or film that is substantially impermeable to the selected drug. The layer is preferably on the order of 10 to 75 microns in thickness, and may or may not contain pigment. The layer is preferably of a material that permits the device to mimic 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 device disengaging from the skin due to differences in the flexibility or resiliency of the skin and the device. Examples of polymers that are useful are polyether block amide copolymers (e.g., PEBAX copolymers), polyethylene met¬ hyl methacrylate block copolymers (EMA) such as NUKRELL po¬ lymers, polyurethanes such as PELLATHANE or ESTANE polymers, silicone elastomers, polyester block copolymers that are composed of hard and soft segments (e.g. HYTREL polymers), rubber-based polyisobutylene, styrene, and styrene-butadiene and styreneisoprene copolymers. Other polymers that may be used include polyethylene, polypropylene, polyesters, e.g., polyester terephtalate (PET), which may be in the form of films or laminates. The preferred polymer used for the bac¬ king will depend on the material or drug incorporated into the device and on the nature of any vehicles, solubilizers, or the like that are used.
Examples of suitable materials for adhesive layer include polysiloxanes, polyisobutyleπes, polyacrylates, polyuretha¬ nes, plasticized ethylene-vinyl acetate copolymers, low mo¬ lecular weight polyether block amide copolymers (PEBAX copolymers), tacky rubbers such as polyisobutene, polystyrene-isoprene copolymers, polystyrene-butadiene copo¬ lymers, and mixtures thereof. Mixtures of polyisobutylenes and polyisobutenes are preferred. The thickness of the anc¬ hor adhesive layer may vary, but is typically in the range of about 10 to about 125 microns. The function of the protective membrane is only to protect the drug depot and the passage of this should not contribute to the controlled release of drugs from the transdermal system. Examples of plastic materials: polystyrene, styrene- butadien copolymer, polyvinyl chloride, polyethylene, polyp¬ ropylene, polysulfone, cellulose esters, polyvinylidene fluoride, ethylen-vinyl-acetat-copolymer.
Prior to use, the transdermal system includes a release li- ner. Just prior to use, this layer is removed from the sys¬ tem to expose the contact adhesive layer. The release liner will normally be made from a drug/vehicle/enhancer imperme¬ able material that is inherently "strippable" or rendered so by techniques such as silicone or fluorocarbon treatment.
The following examples further illustrate the invention. They are not intended to limit the invention in any way. Unless indicated otherwise proportions are by weight.
Materials and apparatus used in the examples
Mater al^
Cinnamyl alcohol, Zimtalkohol zur Synthese, Merck- Schuchardt: Cinnamyl alcohol is used as a model substance. Nicotine, (-)-Nicotin zur Synthese, Merck-Schuchardt Polyvidon 90, polyvinyl pyrrolidoπe, BASF Propylene glycol, Ph. Eur. 2nd Ed.
Liquid paraffin, Paraffinum liquidum, Ph.Eur. 2nd Ed.
Hexane, n-Hexan z.A., Merck
Acronal V 205, BASF
355 Medical Adhesive, Dow Corning
Oppanol 10, BASF Oppanol 50, BASF
Oppanol 120, BASF β-cyclodextrin, (β-CD), Avebe β-cyclodextrin inclusion complexes of cinnamyl alcohol (β-CD-CA) and nicotine (β-CD-N) were prepared in our laboratory.
Backing membrane: Polyester sheet, Mylar type D, Dupont Release liner: Siliconized polyethylene (HDPE) foil, 4P Folie Forchheim GmbH.
Apgaratus
Equipment for corona treatment: Vetaphone Elektronik A/S, Kolding, Denmark
Coating equipment: RK Print Coat Instrument Ltd.,
Littington, Great Britain, Type KCC 202, K-contol coater bar: No 7
Drying equipment: The drying equipment is constructed by Pharmacia.
Spectrophotometer: LKB Ultrospec™ II
Example 1
Preparation of inclusion complex of B-CD and nicotine (β-CD-N).
100 g water were heated to 75°C. 28 g of β-CD were added and dissolved while stirring the solution. 3.5 ml of nicotine were added. The mixture was stirred for about 4 h at ambient temperature. The obtained mixture was filtered and dried in a drying oven at 35°C.
Example 2
Preparation of inclusion complex of β-CD and cinnamyl alcohol (β-CD-CA). 227 g B-CD were dissolved in 1750 ml water while stirring and heating to 70°C. 26.83 g melted cinnamyl alcohol were added. The mixture was stirred for about 2 h at ambient temperature. The obtained mixture was filtered and dried in a drying oven at room temperature.
Example 3
Preparation of polyvidon 90 gel for use in the reservoir lay- er
Composition: Ethanol 99.9 % 226 g Dem. water 200 g Polyvidon 90 125 g
Ethanol and water were mixed and polyvidon 90 was added gra¬ dually while stirring. The stirring was continued in further 10 minutes, after which the gel was left to swell for at le¬ ast 16 h.
Example 4
Composition of adhesive preparations
I A polyisobutylene-type: Oppanol 10 1.0 g
Oppanol 50 1.5 g
Oppanol 120 2.0 g
Hexane 30.0 ml
Liquid paraffin 5.5 g
II An acrylic-type: Acronal V 205, BASF, which according to the supplier is a dispersion of acrylic copolymers in water.
III A silicone-type: 355 Medical Adhesive, Dow Corning.
Composition according to the supplier: 18.5 % di ethyl- polysiloxane by weight in trichlorotrifluorethane. Exampl e 5
The general manufacturing procedures for preparing transder¬ mal drug delivery systems are outlined in fig. 1.
In order to secure good attachment of the drug reservoir layer to the backing membrane the polyester sheets to become the backing membrane were exposed for corona treatment imme¬ diately before application of the drug gel.
The volatile solvents were evaporated from the gel coated sheets and the adhesive coated sheets by placing the sheets in a drying oven working according to the following princip¬ le; cleaned fresh air was blown onto the wet sheets by means of a propellar. The drying air, loaded with solvent, was exhausted.
Example 6
Transdermal drug delivery systems with cinnamyl alcohol as the active substance.
System 1
16 g β-CD-CA was suspended in 16 g de . water and the sus¬ pension was added to 15 g polyvidon 90 gel (example 3) to give the drug gel. The drug gel was solvent cast onto a po¬ lyester sheet 75 μm thick by means of the coating machine in a thin layer (70 μm). After drying at room temperature adhe- sive preparation I (example 4) was solvent cast onto the gel coated sheet and subsequent drying at room temperature.
The adhesive layer was covered by the release liner and the sheets were kept at 8°C until use.
The resulting sheet with backing membrane, reservoir layer and adhesive layer was 120 μm thick. The concentration of cinnamyl alcohol was determined according to example 8 to 0.15 mg cinnamyl alcohol per cm2. System 2
16 g β-CD-CA was suspended in 5 g propylene glycol mixed with 11 g dem. water. The suspension was added to 15 g poly- vidon 90 gel (example 3) to give the drug gel. The drug gel was solvent cast onto a polyester sheet 75 μm thick by means of the coating machine in a thin layer (70 μm). After drying at room temperature adhesive preparation I (example 4) was solvent cast onto the gel coated sheet and subsequent drying at room temperature.
The adhesive layer was covered by the release liner and the sheets were kept at 8°C until use.
The resulting sheet with backing membrane, reservoir layer and adhesive layer was 128 μm thick. The concentration of cinnamyl alcohol was determined according to example 8 to 0.16 mg cinnamyl alcohol per cm2.
System 3
2.0 g cinnamyl alcohol was added to 32.0 g polyvidon 90 gel (example 3) to give the drug gel. The drug gel was solvent cast onto a polyester sheet 75 μm thick by means of the coa- ting machine in a thin layer (70 μm). After drying at room temperature adhesive prepartion I (example 4) was solvent cast onto the gel coated sheet and subsequent drying at room temperature.
The adhesive layer was covered by the release liner and the sheets were kept at 8°C until use.
The resulting sheet with backing membrane, resevoir layer and adhesive layer was 112 μm thick. The concentration was determined according to example 8 to 0.45 mg cinnamyl alco¬ hol per cm2. In vitro release studies according to example 9 were carried out on the systems 1, 2 and 3 described above. The results of these studies are reported graphically in fig. 2. From system 1 which comprises β-cyclodextrin inclusion complex of cinnamyl alcohol in the reservoir layer cinnamyl alcohol is
-? 1 released slowly with a constant rate of 4.37 μg cm h . From system 2 which comprises β-cyclodextrin inclusion comp¬ lex of cinnamyl alcohol and propylene glycol in the reser¬ voir layer cinnamyl alcohol is released with a somewhat higher constant rate of 7.91 μg cm"2 h"1. As shown, both system 1 and 2 revealed approximately zero order release kinetics. For comparison purposes release studies were car¬ ried out on system 3 which comprises neat cinnamyl alcohol without β-cyclodextrin in the reservoir layer. System 3 re- vealed a curvelinear profile and the active substance was released very fast as about 40 % of the dose is released in about 100 minutes.
Thus in conclusion, β-cyclodextrin inclusion complexes as drug depots control the release of active substance and by adding solvents, e.g. propylene glycol, to the surrounding medium in the reservoir layer it is possible to influence the release rate.
System 4
16 g β-CD-CA was suspended in 16 g dem. water, and the sus¬ pension was added to a mixture of 7.5 g polyethylene glycol 400 and 10.5 g polyethylene glycol 6000 to give the drug gel. The drug gel was solvent cast onto a polyester sheet 75 μm thick by means of the coating machine in a thin layer (70 μm). After drying at room temperature adhesive prepara¬ tion III (example 4) was solvent cast onto the gel coated sheet and subsequent drying at room temperature.
The adhesive layer was covered by the release liner, and the sheets were kept at 8°C until use. The resulting sheet with backing membrane, reservoir layer and adhesive layer was 136 μm thick. The concentration of cinnamyl alcohol was determined according to example 8 to 0.14 mg per cm .
In vitro release studies according to example 8 were carried out on system 4 described above. The release profile was substantially similar to that obtained for system 1, fig. 2.
System 5
16 g B-CD-CA was suspended in 16 g adhesive preparation II (example 4) mixed with 1.5 g dem. water to give the drug gel. The drug gel was solvent cast onto a polyester sheet 75 μm thick by means of the coating machine in a thin layer (70 μm) , and subsequent drying at room temperature.
The reservoir layer which also is the adhesive layer was co¬ vered with the release liner, and the sheets were kept at 8°C until use.
The resulting sheet with backing layer and reservoir/adhesive layer was 97 μm thick. The concentration of cinnamyl alcohol was determined according to example 8 to 0.25 mg cinnamyl alcohol per cm2:
In vitro release study according to example 9 was carried out on system 5 described above. The result of the study is reported graphically in fig. 3. As shown, system 5 revealed approximately zero order release kinetics with a release ra¬ te of 11.19 μg cm-2 h"1.
Example 7
Transdermal drug delivery system with nicotine as the active substance. System 6
3 g β-CD-N was suspended in 2.8 g dem. water mixed with 190 mg propylene glycol. The suspension was added to 2.8 g polyvidon 90 gel (example 3) to give the drug gel. The drug gel was solvent cast onto a polyester sheet 75 μm thick by means of the coating machine in a thin layer (70 μm). After drying at room temperature adhesive preparation II (example 4) was solvent cast onto the gel coated sheet and subsequent drying at room temperature.
The adhesive layer was covered by the release liner, and the sheets were kept at 8°C until use.
The resulting sheet with backing layer, reservoir layer and adhesive layer was 119 μm thick. The concentration of nico¬ tine was determined according to example 8 to 0.4 mg nicoti¬ ne per cm2.
System 7
1000 μl nicotine and 400 μl propylene glycol were added to 12.6 g polyvidon 90 gel (example 3) to give the drug gel. The drug gel was solvent cast onto a polyester sheet 75 μm thick by means of the coating machine in a thin layer (70 μm). After drying at room temperature adhesive preparation II (example 4) was solvent cast onto the gel coated sheet and subsequent drying at room temperature.
The adhesive layer was covered by the release liner, and the sheets were kept at 8°C until use.
The resulting sheet with backing layer, reservoir layer and adhesive layer was 109 μm thick. The concentration of nico- tine was determined according to example 8 to 0.2 mg nicoti¬ ne per cm2. In vitro release studies according to example 9 were carried out on the systems 6 and 7 described above. The results of those studies are reported graphically in fig. 4. From sys¬ tem 6 which comprises β-cyclodextrin inclusion complex of nicotine in the reservoir layer nicotine is released with a slower rate than from system 7 which comprises neat nicotine without β-cyclodextrin in the reservoir layer. As shown, the release rate of nicotine from system 6 declined slightly over the period but more closely approximated zero order re- lease than first order release.
Example 8
Quantitive determination of the active substance content in the transdermal drug delivery systems.
Patches of 0.63 cm2 were punched out and extracted with 5.00 ml ethanol in the case of cinnamyl alcohol, and 5.00 ml 0.01 N HC1 in the case of nicotine. The extracted amount of active substance was determined by UV-spectrophotometry (λ max. (cinnamyl alcohol) = 251 nm, λ max. (nicotine) = 260 nm), and the concentration of the systems was expressed in mg active substance per cm2.
Example 9
In vitro release studies of the transdermal drug delivery systems.
The diffusion cell used consisted of a 24 mm diameter Millipore cellulose ester GSWP type filter mounted on the detachable end of a stainless steel cylinder using silicone glue, thereby dividing the cell into two compartments: a do- nor and a larger stirred receptor compartment. Patches of 1.54 cm2 were punched out and mounted on the Millipore filter. The diffusion of the active substance from the upper compartments was followed at room temperature by removing samples periodically and measuring the concentrati- on of the drugs. The receptor phase was 15.00 ml 0.01 N HC1 in the studies with nicotine and 15.00 ml phosphate buffer 0.05 M pH 7.4 in the studies with cinnamyl alcohol.
The amount of active substance in the samples was determined by UV-spectrophotometry according to example 8.
Example 10
In vitro permeation from transdermal drug delivery system with nicotine as the active substance
System 8
18.0 g β-CD-N was suspended in 40.0 g dem.water. The suspen¬ sion was added to 26.0 g polyvidon 90 gel (example 3) where¬ after 6.0 g propylene glycol was added to give the drug gel. The drug gel was solvent cast onto a polyester sheet 75 μm thick by means of the coating machine in a layer of 1.0 mm and the gel layer was dried at room temperature. Adhesive preparation I (example 4) was solvent cast onto a siliconi- zed polyethylene foil and after drying laminated onto the gel coated sheet by means of a steel cylinder (5.5 kg).
The adhesive layer was covered by a release liner
(Perlastic™-L36, PETP-Folie) and the sheets were kept in heat-sealed pouches (Barex™, polyacrylnitrit/aluminium- laminate) at 8°C until use. The resulting sheet with backing layer, reservoir layer and adhesive layer was 0,5 mm thick and the concentration of ni- cotine was determined according to example 8 to 1,4 mg cm .
In vitro permeation of nicotine from transdermal system 8 across human epidermis was investigated with Franz diffusion cells.
Epidermis was heat separated from full thickness human skin and mounted in glass diffusion cells with an available dif¬ fusion area of 1.8 cm2. Patches of 1.54 cm2 of system 8 was punched out and applied on the skin surface and the dermal side of the skin was exposed to 12.1 ml recipient phase, 0.01 M acetate buffer solution of pH 4.
Permeation of nicotine was followed by removing samples pe¬ riodically and measuring the concentration by a HPLC method according to example 11. The cumulative amount of nicotine appearing in the recipient phase versus time are shown in fig. 5. As it appears, system 8 revealed approximately zero order permeation kinetics although the permeation rate of nicotine declined slightly over the period. The initial per¬ meation rate was calculated to 22,2 μg cm~2h_1.
Example 11
Quantitative determination of nicotine content in the reci¬ pient phase samples from skin permeation studies was done by a HPLC method. A LKB system comprising a LKB 2249 HPLC pump, a LKB 2141 variable wavelength monitor, a LKB 2221 integra¬ tor and a LKB 2157 autosampler (20 ul injected) was used. The column used, 12 cm long and 4 mm i.d., was packed with Nucleosil 5 CN. The column was eluted isocratically at am¬ bient temperature with a mobile phase consisting of dem. water-acetonitril-diethylamine (400:100:0.38 v/v). The flow rate was 1.0 ml/min. and the column effluent was monitored at 254 nm. Exampl e 12
In vitro permeation and release from transdermal drug deli¬ very system with nicotine as the active substance.
System 9
24 g β-CD-N was added to 70 g polyisobutylene-type gel com¬ posed of 2.0 g Oppanol 10, 1,5 g Oppanol 50, 1,0 g Oppanol 120 dissolved in 30,0 ml hexane whereafter 2,0 g liquid pa¬ raffin was added to give the drug gel. The drug gel was sol¬ vent cast onto a polyester sheet 75 μm thick by means of the coating machine in a 0,8 mm layer. After drying at room tem¬ perature adhesive preparation 1 (example 4) was laminated onto the gel coated sheet. The lamination was accomplished by solvent casting adhesive preparation 1 onto a si1iconized polyethylene foil in a 100 μm layer, drying at room tempera¬ ture and pressing the layer onto the dry drug gel layer by means of a steel roller (5,5 kg) after which the polyethyle- ne foil was removed.
The adhesive layer was covered by a release liner (Perlastic™-L36, PETP-Folie) and the sheets were kept in heat-sealed pouches (Barex™, polyacrylnitrit/aluminium- laminate) at 8°C, 25°C and 40°C to investigate the stability of the product at these three temperatures.
The resulting sheet with backing layer, reservoir layer and adhesive layer was 413 μm thick. The concentration of nico- tine was determined to 1,5 mg cm"2 according to the follow¬ ing method. Patches of 0,63 cm2 was punched out and extract¬ ed with 5,00 ml heptane. The heptane phase was extracted with 10,00 ml 0,01 N HC1 and after separation of the phases the amount of active substance in the aqueous phase was de- termined according to example 8. S stem_10
2,4 g nicotine was added to 91,6 g polyisobutylene-type gel composed of 2,0 g Oppanol 10, 1,5 g Oppanol 50, 1,0 g Oppanol 120 dissolved in 30 ml hexane whereafter 2,0 g li¬ quid paraffin was added to give the drug gel. The drug gel was solvent cast onto a polyester sheet 75 μm thick by means of the coating machine in a 0,8 mm layer. After drying at room temperature adhesive preparation 1 (example 4) was la- minated onto the gel coated sheet. The lamination was ac¬ complished by solvent casting adhesive preparation 1 onto a siliconized polyethylene foil in a 100 μm layer, drying at room temperature and pressing the layer onto the dry drug gel layer by means of a steel roller (5,5 kg) after which the polyethylene foil was removed. The adhesive layer was covered by a release liner (Perlastic™-L36, PETP-Folie) and the sheets were kept in heat-sealed pouches (Barex™, polyacrylnitrit/aluminiumlaminate) at 8°C until use.
The resulting sheet with backing layer, reservoir layer and adhesive layer was 293 μm thick. The concentration of nico¬ tine was determined to 0,8 mg cm-2 according to the follow¬ ing method. Patches of 0,63 cm2 was punched out and extract¬ ed with 5,00 ml heptane. The heptane phase was extracted with 10,00 ml 0,01 N HCl and after separation of the phases the amount of active substance in the aqueous phase was de¬ termined according to example 8.
In vitro release studies according to USP paddle method (USP XXII p. 1581, apparatus 3, paddle over disc) were carried out on the systems 9 and 10 described above. The results of those studies are reported graphically in fig. 6. From sys¬ tem 9 which comprises β-cyclodextrin inclusion complex of nicotine in the reservoir layer nicotine is released with a slower rate than from system 10 which comprises neat nicoti¬ ne without β-cyclodextrin in the reservoir layer. As shown, the release profile for system 9 are approximately linear corresponding to a zero order release. In vitro permeation of nicotine from transdermal system 9 and 10 across human epidermis was investigated with Franz diffusion cells.
Epidermis was heat separated from full thickness human skin and mounted in glass diffusion cells with an available dif¬ fusion area of 1,8 cm2. Patches of 1,54 cm2 of system 9 and 10 were punched out and applied on the skin surface and the dermal side of the skin was exposed to 12,1 ml recipient phase, 0,01 M acetate buffer solution of pH 4.
Permeation of nicotine was followed by removing samples pe¬ riodically and measuring the concentration by a HPLC method according to example 11. The cumulative amount of nicotine appearing in the recipient phase versus time are shown in fig. 7. As it appears, system 9 revealed zero order permea- tion kinetics with a permeation rate of 6,7 μg cm~ h-1. For comparison purposes permeation studies were carried out on system 10 which comprises neat nicotine without β-cyclo- dextrin in the reservoir layer. System 10 revealed a curve- linear profile and the active substance permeated very fast as about 80 % of the dose is released in about 30 hours.
System 11
24 g β-CD-N was added to 68,4 g polyisobutylene-type gel composed of 2,0 g Oppanol 10, 1,5 g Oppanol 50, 1,0 g Oppanol 120 dissolved in 30,0 ml hexane whereafter 2,4 g ni¬ cotine and 2,0 g liquid paraffin was added to give the drug gel. The drug gel was solvent cast onto a polyester sheet 75 μm thick by means of the coating machine in a 0,8 mm layer. After drying at room temperature adhesive preparation 1 (example 4) was laminated onto the gel coated sheet. The la¬ mination was accomplished by solvent casting adhesive prepa- ration 1 onto a si1iconized polyethylene foil in a 100 μm layer, drying at room temperature and pressing the layer on- to the dry drug gel layer by means of a steel roller (5,5 kg) after which the polyethylene foil was removed. The adhe¬ sive layer was covered by a release liner (Perlastic™-L36, PETP-Folie) and the sheets were kept in heat-sealed pouches (Barex , polyacrylnitriδt/aluminiumlaminate) at 8°C until use.
The resulting sheet with backing layer, reservoir layer and adhesive layer was 290 μm thick. The concentration of nico- tine was determined to 2,1 mg cm-2 according to the follow¬ ing method. Patches of 0,63 cm2 was punched out and extract¬ ed with 5,00 ml heptane. The heptane phase was extracted with 10,00 ml 0,01 N HCl and after separation of the phases the amount of active substance in the aqueous phase was de- termiπed according to example 8.
Sys_tem_12
24 g β-CD-N was added to 68,8 g polyisobutylene-type gel composed of 2,0 g Oppanol 10, 1,5 g Oppanol 50, 1,0 g
Oppanol 120 dissolved in 30,0 ml hexane whereafter 1,2 g ni¬ cotine and 2,0 g liquid paraffin was added to give the drug gel. The drug gel was solvent cast onto a polyester sheet 75 μm thick by means of the coating machine in a 0,8 mm layer. After drying at room temperature adhesive preparation 1
(example 4) was laminated onto the gel coated sheet. The la¬ mination was accomplished by solvent casting adhesive prepa¬ ration 1 onto a si1iconized polyethylene foil in a 100 urn layer, drying at room temperature and pressing the layer on- to the dry drug gel layer by means of a steel roller (5,5 kg) after which the polyethylene foil was removed. The adhe¬ sive layer was covered by a release liner (Perlastic™-L36, PETP-Folie) and the sheets were kept in heat-sealed pouches (Barex™, polyacrylnitrit/aluminiumlaminate) at 8°C until use. The resulting sheet with backing layer, reservoir layer and adhesive layer was 290 μm thick. The concentration of nico¬ tine was determined to 1,8 mg cm"2 according to the follow¬ ing method. Patches of 0,63 cm2 was punched out and extract- ed with 5,00 ml heptane. The heptane phase was extracted with 10,00 ml 0,01 N HCl and after separation of the phases the amount of active substance in the aqueous phase was de¬ termined according to example 8.
In vitro permeation of nicotine from transdermal system 11 and 12 across human epidermis was investigated with Franz diffusion cells.
Epidermis was heat separated from full thickness human skin and mounted in glass diffusion cells with an available dif¬ fusion area of 1,8 cm2. Patches of 1,54 cm of system 11 and 12 were punched out and applied on the skin surface and the dermal side of the skin was exposed to 12,1 ml recipient phase, 0,01 M acetate buffer solution of pH 4.
Permeation of nicotine was followed by removing samples pe¬ riodically and measuring the concentration by a HPLC method according to example 11. The cumulative amount of nicotine appearing in the recipient phase versus time are shown in fig. 8. As it appears, addition of neat nicotine (e.g. a priming dose) resulted in a fast permeation rate initially which eventually declines to a constant permeation rate of 4,1 μg cm"2 h-1.
Example 13
Transdermal drug delivery systems with 17β-estradiol as the active substance.
Inclusion complex of β-CD and estradiol (β-CD-E) was prepar¬ ed as follows. 104,2 g β-CD and 12,5 g 17β-estradiol were mixed with 1.570 ml water while stirring and heating to the boiling point in 1,5 hours. The mixture was stirred for 42,5 hours at room temperature. The obtained complex was filtered and washed twice with 250 ml ethanol 99,9 % to remove un¬ bounded estradiol whereafter it was dried in a drying oven at room temperature.
System_13
18 g β-CD-E was suspended in 40 g dem. water whereafter 26 g polyvidon 90 gel (example 3) and 6 g propylene glycol were added to give the drug gel. The drug gel was solvent cast onto a polyester sheet 75 μm thick by means of the coating machine in a layer of 0,8 mm and the gel layer was dried at room temperature. Adhesive preparation 1 (example 4) was solvent cast onto a si1iconized polyethylene foil and after drying laminated onto the gel coated sheet by means of a steel cylinder (5,5 kg).
The adhesive layer was covered by the release liner and the sheets were kept at 8°C until use. The concentration of est¬ radiol was determined to 1,2 mg/cm2. Patches of 0,63 cm2 were punched out and extracted with ethanol. The extracted amount of estradiol was determined by UV-spectrophoto etry (max.=282).
In vitro release studies according to USP paddle method (USP XXII p. 1581, apparatus 3, paddle over disc) were carried out on system 13. The cumulative amount of estradiol appear¬ ing in the recipient phase versus time are shown in fig. 9. As it appears, system 13 revealed zero order release kinetics. The release rate was calculated to 28 μg cm"2 h-1.

Claims

1. A transdermal system with a reservoir layer comprising an active substance, at least part of which is in the form of an inclusion complex formed between a cyclo com¬ pound and the active substance, wherein the release rate from the system is controlled by the dissociation of the complex in the system, whereby the dissociation for a specific reservoir layer is governed by:
a) a choice of cyclo compound; b) a choice of molar ratio of active substance to cyclo compound in the inclusion complex; c) mixing different inclusion complexes; d) adding excess amount of cyclo compound to the sys¬ tem; e) adding free active substance to the system; f) adding pH adjusting agents to the system; and/or g) adding hydrophilic or lipophilic solvents to the system, in such a way that a predetermined release rate can be obtained for delivering the active agent to intact or diseased skin.
2. A transdermal system according to claim 1, wherein the release rate is substantially constant.
3. A transdermal system according to claim 1, wherein the release rate is substantially constant after an initial priming dose.
4. A transdermal system according to claim 1, wherein the system is in the form of a multilaminar device compri¬ sing the following layers: a) at the skin-distal side, a backing membrane, which is substantially impermeable to the active subs¬ tance; optionally, one or more layers of adhesive, optio¬ nally comprising the active substance; a reservoir layer comprising the active substance and optionally, and adhesive agent, and
Figure imgf000038_0001
optionally, a protecting membrane situated adjacent to the reservoir layer opposite to the backing mem¬ brane; and e) a release liner situated at the side to be applied to the skin, which release liner is removed prior to use.
5. A transdermal system according to claim 1, wherein the system also comprises a permeation enchaπcer.
6. A transdermal system according to claim 1, wherein the cyclo compound is a cyclisized polysaccaπ'de, preferably a cyclodextrin.
7, A transdermal system according to claim 1, wherein the active substance is a drug.
8. A transdermal system according to claim 8, wherein the drug is selected from the group consisting of steroids, nitro or amino compounds, oxicam derivatives, opoides, prostaglandines, benzamides, peptides, xantines, ca- techolamines, dihydropyridines, thiazides, sydπomimines, sulfated polysaccarides and mucopolysaccarides.
g. A transdermal system according to claim 8 or 9 wherein the drug is nicotine or estradiol.
SUBSTITUTESHEET
PCT/SE1990/000822 1989-12-21 1990-12-12 Transdermal system WO1991009592A1 (en)

Priority Applications (4)

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DE69026837T DE69026837T2 (en) 1989-12-21 1990-12-12 TRANSDERMAL SYSTEM
EP91901412A EP0519926B1 (en) 1989-12-21 1990-12-12 Transdermal system
GR960401809T GR3020436T3 (en) 1989-12-21 1996-07-02 Transdermal system

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DE (1) DE69026837T2 (en)
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DE69026837T2 (en) 1997-01-02
AU6973591A (en) 1991-07-24
ES2086529T3 (en) 1996-07-01
US5120546A (en) 1992-06-09
JPH05504895A (en) 1993-07-29
EP0519926A1 (en) 1992-12-30
GR3020436T3 (en) 1996-10-31
SE8904296D0 (en) 1989-12-21
EP0519926B1 (en) 1996-05-01
ATE137405T1 (en) 1996-05-15
DK0519926T3 (en) 1996-06-17
DE69026837D1 (en) 1996-06-05
JP3141110B2 (en) 2001-03-05

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