System for the transdermal delivery of active ingredient

Abstract

The invention relates to a transdermal therapeutic system (TTS) for delivering pharmaceutical active ingredients. The TTS includes a cover layer and at least one active-ingredient-containing carrier material. At least one retaining element is located between the active-ingredient-containing carrier material and the cover layer, with the retaining element fixing the active-ingredient-containing carrier material onto the cover layer. The invention further relates to a method for fastening an active-ingredient-containing carrier material to a cover layer of a TTS in the presence of hook-and-loop strip segments and the use of a hook-and-loop strip in transdermal or iontophoretic administration of pharmaceutical or therapeutic active ingredients to patients.

Claims

1. A method of attaching an active-containing carrier material to a TTS backing layer in the presence of hook and loop tape segments, wherein the active-containing carrier material is liquid saturated and the method comprises opening an upward side of a package containing the active-containing carrier material by removing a closure film from the package; approximating the active-containing carrier material in the opened package to the backing layer and the hook and loop tape segments disposed thereon, then pressing the package together with the active-containing carrier material present therein against the hook and loop tape segments on the backing layer, thereafter releasing and removing the package and leaving the active-containing carrier material secured to the hook and loop tape segments and to the backing layer.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) FIG. 1 illustrates in schematic form an inventive TTS as viewed from below;

(2) FIG. 2 illustrates in schematic form an inventive TTS as viewed from above:

(3) FIG. 3a illustrates in schematic form, the active-containing carrier material lying in an upwardly opened package that is disposed below hook and loop tape segments on a backing layer;

(4) FIG. 3b illustrates in schematic form approximating the active-containing carrier material together with the backing layer and the hook and loop tape segments;

(5) FIG. 3c illustrates in schematic form the pressing of the active-containing carrier material against the hook and loop tape segments and backing layer; and

(6) FIG. 3d illustrates in schematic form the securing of the active-containing carrier material to the hook and loop tape segments and hence the backing layer.

DETAILED DESCRIPTION OF ADVANTAGEOUS EMBODIMENTS OF THE INVENTION

(7) The reference to a hook and loop tape in the present application is to be understood as meaning a textile, arbitrarily often releasable fastening means based on the principle of burs. The bionic implementation consists, typically, of two woven strips of fiber, one displaying flexible barbed hooks or mushroom heads, the other by contrast loops. Pressed together they combine to form a more or less resistant, but at any rate reversible high-speed fastener. Woven hook and loop tapes consist of polyamide, polyester or polyolefin fibers. The hooks are incorporated in the hook tapes during weaving or later. Hook and loop tapes and touch fasteners may also be rendered self-adhesive on the reverse side by coating with pressure-sensitive adhesives.

(8) In the present invention, the hook and loop tape disposed on the backing layer of the TTS forms the hook side, while the active-containing carrier material assumes the function of the loop side. By pressing the retaining element which is mounted on the backing layer of the TTS onto the upper side of the package containing the active-containing carrier material and upwardly opened by prior removal of the closure film, the present invention causes the hook and loop tape to become hookingly engaged with the carrier material, to adhere to the retaining element of the TTS as the TTS is detached from the package and not to be left behind in the package when the latter is thereafter removed again.

(9) In general, the active-containing carrier material is situated in the package which is opened by removal of the closure film immediately before the transfer of the carrier material plus active to the backing layer of the TTS.

(10) The active-containing carrier material is liquid saturated and as such adheres to the packaging film. To release the carrier material from the packaging film therefore requires a force (x.sub.1). If, now, the carrier material is to be transferred to the TTS without additional aids such as, for example, fingers or gripping elements being used for this, then the TTS is laid flat onto the carrier material and pressed down. This causes the liquid-saturated carrier material to additionally adhere to the pressed-down TTS (polymeric film/polyester film). However, the adhering forces to the TTS (=F.sub.rts) are similar to the adhering forces to the packaging (=F.sub.pack). On removing the TTS again after it has been pressed down, the magnitude of the two adhering forces decides whether the active-containing carrier material remains adhering to the TTS or alternatively to the package. Unless the adhering force to the TTS (F.sub.rts) is significantly greater than the adhering force to the packaging film (F.sub.pack), there is a risk that the liquid-saturated carrier material remains behind in the package and not, as desired, adhering to the TTS.

(11) In order for a successful transfer of the active-containing carrier material from the packaging film to the TTS to take place, the adhering forces have to be changed such that they are significantly different:
F.sub.tts>>F.sub.pack

(12) The adhering force of the active-containing carrier material to the packaging film can scarcely be reduced. Even anti-stick coatings reduce this adhering force but insignificantly owing to the viscosity of the liquid. Even a profiling of the surface does not elicit any change in the adhering forces, since the liquid fills the surface profiling and displaces air inclusions.

(13) Increasing the adhering forces to the TTS (F.sub.tts) would therefore be a solution to the problem of reliably ensuring the transfer process. The invention deploys a hook and loop tape to increase the adhering forces to the TTS (F.sub.tts). Owing to the hook and loop tape, the adhering forces of the active-containing carrier material (F.sub.tts) increase significantly. This is because hook and loop tapes are even able to function in a moist state. As the active-containing carrier material is pressed against the hook and loop tape, the fibers of the carrier material become hookingly engaged with the hooks of the hook and loop tape. So the hook and loop tape increases the adhering force (F.sub.tts) significantly even in a moist environment, guaranteeing the transfer of the liquid-saturated carrier material from the package to the backing layer of the TTS.

(14) Backing layer refers for the purposes of the present application to a substantially self-supporting sheet body which covers that part of the skin where the transdermal delivery of pharmaceutic active to the organism takes place. If the TTS is not attached to the skin via a pressure-sensitively adhesive overplaster, then the backing layer conveniently also has the function to secure the system to the skin, this being accomplished by a uniformly or patternedly pressure-sensitively adhesive implementation of that side of the backing layer which faces the skin, wherein the area(s) for the active-containing carrier material(s) are free from pressure-sensitive adhesive at least.

(15) In a further embodiment of the invention, the backing layer is an occlusive backing layer. An occlusive backing layer is specifically a barrier layer for liquids and water vapor, preventing liquid or water vapor escaping to the outside through the backing layer, which would cause the system to dry out if the pharmaceutical active to be delivered is liquid or dissolved in a liquid. The occlusive backing layer in the present invention may consist of a self-supported film of a plastic such as polyethylene or polypropylene or polyester or polyurethane or polyamide, the essential property of which is that it constitutes a sufficiently reliable blocker to water, water vapor or water-mixed organic solvents. Suitable self-supported films of the plastics referred to have a thickness in the range from 5 to 300 m, preferably from 10 to 200 m, more preferably from 12 to 150 m.

(16) The occlusive backing layer may additionally further contain or be bonded to a non-occlusive carrier layer for reinforcement. Said non-occlusive carrier layer may suitably be a woven textile fabric or a fibrous nonwoven web or a felt material or some other cellulosic material. The bond between the non-occlusive carrier layer and the occlusive backing layer may be established by lamination under pressure or by extrusion or by bonding with a suitable adhesive. Suitable adhesives may consist of polyisoprene or polyisobutylene or polyacrylic esters or else of polysiloxane copolymers.

(17) A self-adhesive layer may also be provided to the occlusive backing layer at its underside, i.e., the side facing the skin. The aforementioned adhesives, preferably acrylic adhesives, are useful as self-adhesive materials.

(18) In a further embodiment, the active-containing carrier material is a hydrogel or a carrier material saturated with liquid or dusted with pulverulent active. A liquid in the present invention may comprehend a solution of an active in a solvent, preferably an aqueous solvent, or else, alternatively, a dispersion or emulsion of active in a suitable dispersing or emulsifying medium. By way of carrier materials, fibrous nonwoven web type materials or woven textile materials or knitted fabrics not produced by weft knitting with independently-movable needles or sponge-shaped materials are used with advantage or else, optionally, gel-forming polymers.

(19) In a preferred embodiment of the present invention, the shape of the elongately shaped hook and loop tape matches the shape of the active-containing carrier material. When the active-containing carrier material has a rectangular shape, the length of the elongatedly shaped hook and loop tape preferably corresponds to the length of one of the sides of the rectangularly shaped active-containing carrier material. When the active-containing carrier material has a round or oval shape, the shape of the elongatedly shaped hook and loop tape is preferably that of an arcuate circular segment with a radius corresponding to the radius of the round or oval active-containing carrier material.

(20) Hook and loop tapes suitable for the purposes of the present invention are self-adhesive, i.e., they adhere with their self-adhesive reverse side to the backing layer. But it is also possible for a suitable adhesive, for example an acrylic adhesive or a two-component adhesive or a hot-melt adhesive, to fasten a hook and loop tape to the backing layer.

(21) The width of the elongatedly shaped hook and loop tape may vary between wide limits. The hook and loop tape need not cover the entire area whereover the active-containing carrier material in the TTS extends, it being instead sufficient for the elongatedly shaped hook and loop tape to cover only a or one part of the area irrespective of the geometry of the active-containing carrier material. It is also possible in this context for the hook and loop tape to be situated only in the side edge near regions or for it to be configured as a circumferential strip having a width in the range from 2 to 15 mm, preferably from 3 to 10 mm.

(22) The present invention may also comprise two or more hook and loop tapes arranged, for example, on opposite sides of the area whereto the active-containing carrier material is or is to be fastened to the TTS.

(23) The invention also provides a method of attaching an active-containing carrier material to a TTS backing layer in the presence of hook and loop tape segments. This involves approximating the active-containing carrier material in a package upwardly opened by a closure film being removed beforehand to the occlusive backing layer and the hook and loop tape segments disposed thereon. Then, the package is pressed together with the active-containing carrier material present therein against the hook and loop tape segments on the occlusive backing layer. Thereafter, the package can be released and removed, leaving the active-containing carrier material secured to the hook and loop tape segments and to the occlusive backing layer.

(24) The invention further provides the method of using a hook and loop tape as a constituent part of a transdermal therapeutic system (TTS) or as a constituent part of an iontophoretic transdermal therapeutic system.

(25) The invention further comprehends the method of using a hook and loop tape in a method for transdermal or iontophoretic administration of cationic actives to patients in need of treatment with such actives.

(26) The system of the present invention is particularly useful specifically in connection with therapeutic actives having a cationic structure, in particular actives having amino or imino groups in their molecule.

(27) The present invention is accordingly suitable for the transdermal, specifically the iontophoretic, administration of analgesics such as fentanyl or morphine, antiemetics such as granisetron or other central nervous system drugs such as rivastigmine or galantamine.

(28) When the system of the present invention is used for transdermal administration of such actives, the liquid-saturated carrier material serves as a matrix or reservoir wherefrom the cationic actives are delivered to the skin and then pass through the skin either passively or with iontophoretic assistance.

(29) Actives having a cationic structure are generally actives which are in the form of positively charged ions (cations) or which are capable of forming positively charged ions in aqueous media. Many biologically active agents for example have functional groups which readily dissociate in an aqueous medium into a positively charged ion and a counterion, examples being soluble salts of basic actives.

(30) The term actives comprehends specifically therapeutically active agents, pharmacologically active agents or other agents having advantageous effects when administered to a human being or to an animal.

(31) The term actives in general designates pharmaceutical actives or drugs, i.e., therapeutic actives. The expression actives further also comprehends agents for use in veterinary medicine.

(32) The present invention is particularly suitable for the transdermal, specifically the iontophoretic, administration of actives such as opioid agonists, including analgesics such as fentanyl, sufentanyl, morphine, morphine derivatives such as codeine or such as heroin, dihydrocodeine, hydromorphine, oxycodone, hydrocodone, pethidine, loperamide, diphenoxylate, methadone, tramadol or tilidine; opioid antagonists such as naloxone, naltrexone; mixed opiate agonists/antagonists, such as buprenorphine, pentazocine, nalbuphine; antiemitics including 5-HT.sub.3 receptor antagonists such as granisetron, lerisetron, ondansetron, dolasetron, metoclopramide and also antidopaminergic medicaments such as domperidone, and also HI receptor antagonists such as, for example, promethazine or meclozine and also muscarine antagonists such as scopolamine; drug compounds which act on the central nervous system, such as rivastigmine, galantamine, tacrine, donepezil, and also pramipexole, adrenaline, dopamine, ropinirole, nicotine, fluphenazine, chlorpromazine, benzodiazepines, monoamine reuptake inhibitors such as amitriptyline, antidepressives such as mianserine; alkaloids such as ergotamine, dihydroergotamine, methysergide or lisuride, belladonna alkaloids; peptides, in particular peptide hormones such as insulin and oxytocin or blood coagulation factors and growth hormones; cationically active indole compounds such as N-dimethyltryptamine, sumatriptan or psilocine; local anesthetics such as lidocaine, buprivacaine, articaine, procaine; gastrointestinally active therapeutics, such as carnitine chloride or metoclopramide; muscle relaxants such as vancuronium bromide; antibiotics such as tetracycline, tetracycline-based preparations, kanamycine, kanamycine-based preparations, gentamycine, gentamycine-based preparations or quinine; anorexics such as fenfluramine or ephedrine; antidiabetics such as metformin; inhibitors of thrombocyte aggregation, e.g., ticlopidine or clopidogrel; antiarrhythmics such as quinidine or lidocaine; cardiac or cardiovascular agents such as dopamine, noradrenaline, methoxamine, adrenaline, verapamil, diltiazem, propranolol, clonidine, tolazoline; sympathomimetics such as salbutamol or terbutaline; antihistamines such as clemastine, cetirizine or chlorphenoxamine.

(33) In one preferred embodiment, the active comes from the group of cationic indole compounds, particularly from the group of cationic indole compounds, N-dimethyltryptamine and psilocine, this group also comprehending the pharmaceutically suitable salts of these cationically active indole compounds.

(34) The aforementioned cationic actives can also be present in the form of pharmaceutically suitable salts. Examples of pharmaceutically suitable salts include chloride, bromide, iodide, sulfur, phosphate, lactate, citrate, tartrate, salicylate, succinate, maleate, gluconate, mesylate, laurate, dodecylate, myristate, palmitates and stearate salts, but are not limited to these.

(35) The intensity of the current during iontophoresis should ideally not exceed a value of 600 A/cm.sup.2 so as to avoid burning the skin or a burning sensation on the skin. The starting voltage is generally in the range from 0.5 to 10 V, depending on the resistance between the two electrodes and the in-between region of the skin, which may normally be 50 k or more.

(36) In a further embodiment, the liquid-saturated carrier material contains the cationic active or a salt thereof in an amount from 0.1 to 20 wt %, preferably from 0.2 to 10 wt %, more preferably from 2 to 10 wt %, most preferably from 3 to 5 wt %, based on the overall weight of liquid in the carrier material.

(37) The liquid in the liquid-saturated carrier material of the present invention is preferably water or an aqueous solvent mixture. The proportion of water in the solvent mixture is preferably at least 15 wt %, more preferably at least 40 wt %, based on the overall weight of liquid.

(38) In a further embodiment of the invention, the water content or the proportion of the solvent mixture is in the range from 80 to 99 wt %.

(39) The term aqueous solvent mixture comprehends in general liquid mixtures which contain water and at least one further solvent which is generally a polar water-miscible organic solvent, e.g., an alcohol such as ethanol, isopropanol or glycerol.

(40) The present invention also comprehends applications where a cationic active is employed in combination with at least one further active which is selected from the group consisting of active agents having a neutral charge and which may even also comprehend anionic actives.

(41) The system of the present invention generally employs actives capable of passing through the skin by passive diffusion or suitable for iontophoretic permeation of the skin.

(42) In a further embodiment, the liquid-saturated carrier material may be a hydrogel composition, in which case additionally gel-forming polymers which may be selected from the group consisting of polyacrylates and cellulose derivatives, such as hydroxypropylmethylcellulose, hydroxypropylcellulose or hydroxyethylcellulose, are present. The use of hydrogel preparations in iontophoresis is particularly advantageous because, in this case, the ionic strength is adjustable by varying the proportion of water within the hydrogel. It is thus an easy matter to adjust the ionic strength in order to optimize the efficacy of the iontophoretic process in any one specific case.

(43) In a further embodiment, the liquid in the liquid-saturated carrier material has a pH in the range from 3 to 8, preferably from 5.5 to 7 more preferably of about 6.

(44) It is generally preferable to establish a pH that does not differ significantly from the skin pH when the TTS is applied to the skin. In a further embodiment, the skin pH changes by 4.0 or less, approximately 3.5 or less, approximately 3.0 or less, approximately 2.5 or less, approximately 2.0 or less, about 1.5 or less, approximately 1.0 or less, or about 0.5 or less. Substances and buffers to adjust or establish the pH are known to a person skilled in the art.

(45) The liquid-saturated carrier material may optionally contain further additives, in which case the additives may be selected from the group of solubilizers, skin penetration enhancers, preservatives and antimicrobial agents.

(46) In this context, the term solubility improvers is to be understood as meaning in general compounds capable of contributing to enhancing the solubility of the cationically active agent in the liquid. This is attainable either by modulating the possible interactions between the cationic active and the other components present in the liquid, or by the additional incorporation of suitable auxiliary materials.

(47) Alternatively, solubility is attainable for the active by altering the crystal form. Examples of solubilizers include water, diols, such as propylene glycol and glycerol, monoalcohols such as ethanol, propanol and higher alcohols, dimethyl sulfoxide (DMSO), dimethylformamide, N,N-dimethylacetamide, N-substituted alkylazacycloalkyl-2-ones.

(48) The term skin permeation enhancers further comprehends in particular compounds which contain an increase in the permeability of the skin for an active, in particular for a cationic active. Owing to this enhancement in skin perviousness, the rate at which the active penetrates through the skin and into the blood circulation increases.

(49) Examples of permeation enhancers include dimethyl sulfoxide (DMSO), N,N-dimethylacetamide (DMA), decyl methyl sulfoxide (C10 MSO), polyethylene glycol monolaurate (PEGML), propylene glycol (PG), propylene glycol monolaurate (PGML), glycerol monolaurate (GML), lecithin, the 1-substituted alkylazacycloalkyl-2-ones, in particular indodecylcylazacycloheptan-2-one, alcohols and the like.

(50) The permeation enhancer may also be selected from vegetable oils, e.g., safflower oil, cottonseed oil or maize (corn) oil.

(51) Combinations containing two or more different permeation enhancers are likewise usable.

(52) The term antimicrcbial agent is further to be understood as meaning in general agents suitable for preventing the growth of microbes in a pharmaceutical preparation, in particular in the liquid of the liquid-saturated carrier material of the present invention.

(53) Examples of suitable antimicrobial agents include salts of chlorhexidine, such as iodopropynyl butylcarbamates, diazolidinylurea, chiorhexidine digluconate, chiorhexidine acetate, chlorhexidine isothionate or chlorhexidine hydrochloride. Other cationic antimicrobial agents are likewise usable, for example benzalkonium chloride, benzethonium chloride, triclocarbon, polyhexamethylenebiguanide, cetylpyridinium chloride, methylbenzethonium chloride.

(54) Other antimicrobial agents include halogenated phenolic compounds, such as 2,4,4-trichloro-2-hydroxydiphenyl ether (triclosan), parachiorometa xylenol (PCMX), methyl para-hydroxybenzoate and short-chain alcohols, such as ethanol, propanol and the like. The overall concentration of antimicrobial agents is preferably in the range from 0.01 to 2 wt %, based on the overall weight of the liquid in which it is present. Suitable carrier materials may be fiberplies, wovens, knits other than weft knits produced with independently-movable needles, sponges, sponge cloth, knit-stitched fibrous nonwoven web or felted-woven fabrics or feltlike materials etc.

(55) The present invention further provides the method of using the above-described system as an integral constituent part of an iontophoretic patch, preferably as the anodic reservoir of the patch.

Example

(56) The invention and its effectiveness will now be illustrated by way of example with reference to the accompanying drawings, where

(57) FIG. 1 shows in schematic form an invention TTS from below, i.e., from the skin side;

(58) FIG. 2 shows in schematic form an invention TTS from above, i.e., from the skin-remote side;

(59) FIGS. 3a, 3b, 3c and 3d show in schematic form, in component steps, how the active-containing carrier material is removed from its separately stored package and secured to the backing layer of the TTS.

(60) FIG. 1 shows at 1 the active-containing carrier material which has a round shape and which has already been brought into position on the left-hand area of the TTS, while a covering film 2 having an opening 3 on the right-hand side gives a view of the electrode 4, the electrical in-line 5 and four arcuately shaped hook and loop tapes 6a, 6b, 6c and 6d. A further active-containing carrier material (not depicted) is then, in the next step, pressed onto the hook and loop tapes 6a, 6b, 6c and 6d and firmly secured with the hook and loop tapes 6a, 6b, 6c and 6d.

(61) FIG. 2 shows essentially the backing layer 7 wherethrough the current supplies 5 and 5 are visible at left and at right, respectively. The current supply unit 8 with battery and electronic controls can be seen in the center of the depiction.

(62) FIG. 3a shows at the top the backing layer 7 whereon are disposed two hook and loop tape segments 6a and 6c and at the bottom the active-containing carrier material 11 lying in an upwardly opened package 10 opened by a closure film being peeled off beforehand (not depicted).

(63) FIG. 3b shows how the active-containing carrier material 11 while still in the opened package 10 has been approximated together therewith to the backing layer 7 and the hook and loop tape segments 6a and 6c.

(64) FIG. 3c shows how the active-containing carrier material 11 together with the package 10 is pressed from below in the arrow direction against the hook and loop tape segments 6a and 6c and against the backing layer 7.

(65) FIG. 3d shows how the package 10 is removed downwardly while the active-containing carrier material 11 remains secured to the hook and loop tape segments 6a and 6c and hence to the backing layer 7.