IL87538A - Apparatus for the delivery of substances from hot melt contact adhesives and process for the production of said apparatus - Google Patents

Abstract

phe invention concerns a device for the release of substances made of hot-melt adhesives, with uniform or non-uniform distribution of the substances. The hot-melt adhesive has a processing temperature between 40 and 80 degrees Celsius, preferably between 40 and 60 degrees Celsius, and ideally between 40 and 55 degrees Celsius. Also described is a process for manufacturing the device in which the melted hot melt-adhesive containing the substances to be released is applied continuously or intermittently to a support at a hot-melt adhesive temperature between 40 and 80 degrees Celsius, preferably 40 and 60 degrees Celsius, and ideally 45 and 55 degrees Celsius, and in which, if necessary, a protective coating material is applied.

Description

APPARATUS FOR THE DELIVERY OF SUBSTANCES FROM HOT MELT CONTACT ADHESIVES AND PROCESS FOR THE PRODUCTION OF SAID APPARATUS Apparatus for the delivery of substances, processes for the production thereof and use thereof.

The invention relates to an apparatus for the release of substances from hot melt contact adhesives, with a uniform or irregular distribution of the substances, process for the preparation thereof and the use thereof.

Typical representatives of such apparatuses are active substance-containing plasters, indicator systems, perfume-releasing apparatuses and the like, where they are frequently more particularly used in the medical field for the controlled or uncontrolled release of substances. Particular significance has been attached to the controlled apparatuses in the form of transdermally controlled systems. It is already known in connection therewith to apply an active substance-containing layer from the melt. EP-OS 0177893 discloses a nonadhesive cellulose ether gel which can be applied from the melt and in which active substances can be distributed. This gel is hot processed and is nonadhesive. DE-OS 32 22 800 discloses a transdermal system, in which active substance packed in microcapsules is present in a thermally shapeable, adhesive matrix material, which is applied from the melt.

For temperature-sensitive active substances with a low melting point or which can be easily decomposed, attempts have also been made to produce nonadhesive active substance-containing matrixes at ambient temperature.

For example, it is stated in US Patent A 379 454 (Campbell et al.) that an active substance solution brought to a desired viscosity value by means of gelling agents at ambient temperature can be used for the active substance layer. It is known from US Patent 4 559 222 (Enscore et al.) to use a mixture of mineral oil/polyisobutylene and colloidal silicon dioxide prepared at ambient temperature as a viscous active substance layer for oil-soluble active substances, whereby said layers can also be made in contact adhesive manner. DE-OS 32 22 800 (ALZA) describes an active substance layer from an active substance solution thickened by means of a rheological agent, such as cellulose, a polysaccharide or a silicon compound, which is nonadhesive and is also suitable for rapid active substance release.

US Patent 3 923 939 discloses shaping active substances, such as tetracycline, in an ethylene-vinyl acetate copolymer layer by melt pressing. In EP-OS 86 468 an oral antidiabetes sulphonyl urea derivative in a non-adhesive hot melt mass with a melting point of 30 to 90°C is filled into capsules in predetermined doses from the melt. US Patent 3 957 966 discloses that active substances can be processed in nonadhesive hot melt masses.

It is known from DE-OS 30 07 363 to use a contact adhesive mixture of a thermoplastic elastomer, preferably a block polymer of general formula A-B-A, a tackifying resin with oil or higher fatty acids and active substance for producing a simple transdermal system. The contact adhesive mixture described therein is only suitable for relatively temperature-resistant active substances, which are able to withstand temperatures of 120°C and higher. US Patent 3 699 963 discloses mixing oxytocin with contact adhesive for producing a transdermal therapeutic system and shaping thereof at a temperature above 90°C. The thus produced transdermal systems are inexpensive to produce and ensure a constant active substance transfer via the whole-area adhesion of the system to the skin.

The prior art processes for producing such systems are not suitable for transdermal systems containing temperature-sensitive substances, such as scopolamine. Therefore hitherto contact adhesive active substance layers with temperature sensitive active substances have preferably been formed from the solution and the solvent evaporated.

The use of solvents in the preparation of active substance-containing adhesive layers is disadvantageous for several reasons. The preparation of the solutions requires at least one additional, complicated process stage. It leads to high technical effort and expenditure in connection with the handling of the solvents, whilst in addition for medical purposes it is necessary to use extremely pure and therefore expensive solvents, in order to ensure a corresponding freedom from residue in the apparatus for the dissolving of the adhesive or its starting materials. Another problem is to achieve freedom from solvent in the apparatus, for which purpose it is necessary to use expensive drying sections and suction installations. Costs are additionally incurred through the recovery or separation of the solvent, in order to avoid pollution of the environment. An additional risk is caused by the flammability of most solvents. In addition, most organic solvents are harmful to the human organism, so that complicated and costly protective measures must be taken for personnel working in the plant.

The problem of the present invention is therefore to avoid the aforementioned disadvantages of such apparatuses and processes acording to the prior art.

According to the present invention this problem is solved by providing a device for the release of substances from hot melt pressure sensitive adhesive having a non-uniform or uniform distribution of the substances in the hot melt pressure sensitive adhesive, characterized in that a mixture of hot melt pressure sensitive adhesive and substance or a solution of the substance in the hot melt pressure sensitive adhesive is present, the hot melt pressure sensitive adhesive having a processing temperature of between 40 and 80°C, preferably between 40 and 60°C and especially preferably between 40 and 55°C, with the exception of the mixture of indomethacine with isoprene-rubber-based adhesive with a processing temperature of 80°C.

This makes it possible to work without solvents at low temperatures, so that there is a considerable saving on materials, a speedier production of the apparatus without 3a 87538/2 the time consuming drying stages, as well as a production of the inventive apparatuses which leads to less pollution of the environment, which inter alia leads to a considerably less expensive and also solvent-free product.

The invention also relates to a method for producing the above defined device said method being characterized by continuously or discontinuously applying a molten mixture of hot melt pressure sensitive adhesive and substances to be released at a temperature of the mixture of between 40 and 80°C, preferably 40 to 60°C and especially preferably 45 to 55 °C, to a carrier and optionally applying a protective layer material.

US-PS 44 85 087 relates to precutaneous absorption type of pharmaceutical preparations which are incorporated in a pressure sensitive adhesive at room temperature which is coated onto a backing layer. The pressure sensitive adhesive layer admixed with active substance is produced by preparing a solution of the pressure sensitive adhesive and active substance in a solvent, applying this fluid onto a backing layer and evaporating the solvent.

The presence of solvent caused problems, as solvent residues remain in the active substance layer and the solvent itself is expensive as it must be pure not to irritate the skin.

Contrary to the teachings of said patent, the present invention does not use any solvent but uses a hot melt pressure sensitive adhesive, which is admixed in molten state with the active substance so that no solvent is used. Due to the fact that a hot melt pressure sensitive adhesive with a low melting point under 80°C is used it is possible to work with temperature sensitive active substances.

A further inventive process is characterized by continuously or discontinuously applying a molten mixture of hot melt pressure sensitive adhesive and substances to be released at a temperature of the mixture of between 40 and 80°C, preferably 40 to 60°C and especially preferably 45 to 55°C, to a protective layer material and optionally applying the carrier.

When using highly volatile and/or thermally unstable substances to be released, the following measures are appropriate for processing purposes: A. working at very low temperatures B. increasing the external pressure in order to reduce evaporation, C. saturation of the vapour chamber over the melt with the vaporous substance and D. working with a minumum volatile substance quantity in the melt.

Obviously these measures, such as e.g. working in an encapsulated plant, are limited by the rules known to the Expert through the intended use of the apparatus to be produced and also the material circumstances.

The inventive apparatuses, particularly transdermal systems can e.g. be used for local or systemic, transdermal active substance administration in human or veterinary medicine or cosmetics and are preferably used for the release of temperature-sensitive and/or highly volatile substances.

Hot melt contact adhesive is here understood to mean any contact adhesive, which is adequately liquid when hot to permit problem free application at a temperature above approximately 40°C.

As inventively usable hot melt contact adhesive can inter alia be used those which are known to the Expert and such as are inter alia described in DE-OS 15 94 268 (SUN OIL CO.), DE-OS 24 13 979 (E.I. DU PONT DE NEMOURS) , DE-OS 24 35 863 (DYNAMIT NOBEL AG) , DE-OS 28 00 302 (CIBA GEIGY) , EP-A-104 005 (PERSONAL PRODUCTS CO.), JP 6104 2583 and JP 61 281 810, EP-OS 131 460 (EXXON), EP-OS 234 856 (EXXON, EP-OS 185 992 (EASTMAN KODAK), as well as US Patents 36 99 963 and 4 358 557 (EASTMAN KODAK) and express reference is made to this prior art to avoid unnecessary repetition.

The basic polymers can be constituted e.g. by polyamides, polyesters, polycaprolactams, polycaprolactone, ethylene-vinyl acetate copolymers (EVA), ethylene-ethylacrylate copolymers (EEA), polyvinylethers, poly-acrylate esters, pol vinylacetals, polyvinylacetates, styrene-butadiene block polymers, isoprene block polymers, polyurethanes, ethylcellulose, cellulose acetate-butyrate, synthetic rubbers (e.g. neoprene rubber), polyisobutylene, butyl rubber, acrylonitrile-butadiene copolymers, epoxy resins, melamine resins, phenol-formaldehyde resins and resorcinol-formal-dehyde resins and inter alia the following modifying resins can be used: hydrogenated colophony, polymerized colophony, dimerized resin acids, disproportionated colophony, colophony methyl esters, hydrogenated colophony glycerol esters, hydrogenated colophony methyl esters, pentalesters, hydrogenated colophony triethyleneglycolesters, hydroabiethyl alcohol and its derivatives, glycerol esters, ditriolesters and pentaesters of resin acids, polymerized colophony pentalesters, dimerized colophony pentalesters, dimerized colophony glycerol esters, esters of maleic acid or phenol-modified colophony, aromatic and aliphatic hydrocarbon resins, hydrogenated resins, polyterpene resins, modified terpene resins, waxes, low molecular weight polyethylene and polypropylene and alkyl-styrene copolymers. To these resins can optionally be added plasticizers, such as e.g. adipic acid esters, phosphoric acid esters, phthalic acid esters, polyesters, fatty acid esters, citric acid esters or epoxide plasticizers. It is also possible to admix stabilizers, such as tocopherol, substituted phenols, hydroquinones, pyrocatechols, aromatic amines and optionally also fillers, such as e.g. titanium dioxide, magnesium oxide, zinc oxide and silicon dioxide.

The formation of components of the apparatus having hot melt contact adhesive with a processing temperature between 40 and 80°C can take place by extrusion, pouring, roller application, knife coating, spraying or printing processes. - 6 - A limit value for the processability of the hot melt contact adhesive in many of these processes is at a viscosity of approximately 80,000 Pa.

If the substrate to be treated with the adhesive, a component of the apparatus, could be damaged by the temperature of the hot-applied adhesive, either by decomposition, reaction or partial melting, it is possible to use a cooled substrate. Cooling can take place by per se known processes, such as the introduction of cold inert gases or contacting with a cooling surface.

The hot melt contact adhesive can e.g. be applied in layer form or in individual areas in accordance with a predetermined pattern to the protective layer or the covering material.

As a function of the intended use and e.g. if the substance to be released is to be released through the backing layer, such as can be the case with essential oils, such as fragrances, the hot melt contact adhesive can be finished with a carrier permeable with respect to the substance or substances to be released, whilst in the embodiment of the apparatus as a transdermal system, where the substance is only to be delivered to the skin, preference is given to a backing layer which is impermeable for the substance to be delivered.

The inventive process makes it possible to obviate the use of solvent-containing, contact adhesive materials in the processing of temperature-sensitive, highly volatile substances, which considerably increases the safety of production, because it is now certain that no toxic solvent residues can remain in the medicinal administration form, as well as bringing about a greatly simplified application process and considerable production cost savings. The process can naturally also be used in advantageous manner for less temperature-sensitive substances, because this also leads to considerable cost savings.

The expression "substances" in connection with the present invention is understood to mean chemical elements, organic and inorganic compounds, - 7 - which can migrate out of the components containing them in such an apparatus and can thereby bring about a sought effect. Among the uses of the inventive apparatus particular significance is attached to human and veterinary medicine, a realization of the invention in plaster form being particularly preferred.

Typical substances which can be administered by means of inventively produced apparatuses are: aceclidine, amphetaminil , amphetamine, amyl-nitrite, apophedrin, atebrin, alprostadil, azulene, arecoline, anethole, amylenehydrate, acetylcholine, acridine, adenosintriphosphoric acid, L-raalic acid, alimeraazine, allithiaraine, allyl isothiocyanate, amino-ethanol, apyzine, apiol, azatadine, alprenolol, ethinazone, benzoyl-peroxide, benzyl alcohol, bisabolol, bisnorephedrine, butacetoluid, benactyzine, campher, colecalciferol , chloralhydrate, clemastine, chloro-butanol, capsaicin, cyclopentamine, clobutinol, charaazulene, dimethocaine, codeine, chloroproraazine, quinine, chlorothyraol, cyclophosphamide, cinchocaine, chlorambucil, chlorphenesin, diethylethane, divinylethane , dexchlorpheniramine, dinoprostone, dixyrazine, ephedrine, ethosuximide, enallylpropymal, emylcaraate, erytroltetranitrate, emetine, enflurane, eucalyptol, etofenamate, ethylmorphine, fentanyl, fluanisone, guajazulene, halothane, hyoscyamine, histamine, fencarbamide, hydroxycaine', hexylre-sorcinol, isoaminilcitrate, isosorbidedinitrate, ibuprofen, iodine, iodoform, isoaminile, lidocaine, lopirine, levamisole, methadone, methy-prylone, methylphenidate, mephenesine, methylephedrine, meclastine, metho-proraazine, mesuximide, nicethamide, norpseudoephedrine , menthol, methoxy flurane, methylpentinol , metixen, misoprostol, oxytetracaine, oxy.prenolol, oxyphenbutazone, oxyquinoline, pinene, prolintane, procyclidine, pipe-razine, pivazide, phensuximide, procaine, phenindamine, promethazine, pentetrazole, profenamine, perazine, phenol, pethidine, pilocarpine, prenylamine, phenoxybenzamine, resochin, scopolamine, salicyclic acid ester, sparteine, trichloroethylene, timolol, trifluperazine, tetracaine, trimipramine, tranylcypromine, trimethadione, tybamate, thymol, thioridazine, valproic acid, verapamil, as well as other active substances which can be taken up through the skin. Obviously this list is not con elusive. - 8 - Typical compositions for hot melt contact adhesives to be used are those prepared from between 10 and 100% by weight, preferably 20 to 80% by weight and in particularly preferred manner 20 to -50% by weight of polymer, between 10 and 80% by weight, preferably 15 to 60% by weight of plasticizer, between 10 and 80% by weight, preferably 15 to 60% by weight of tackifier, optionally 0.1 to 5% by weight of antiagers and optionally 0 to 70% by weight of fillers, the sum of the percentages of the components always being 100.

Preferably the hot melt contact adhesive contains 10 to 50% by weight of styrene-isoprene-styrene synthetic rubber, such as is commercially available under the name CARIFLEX TR 1107 of SHELL, between 10 and 80% by weight of a hydrogenated alcohol, such as is commercially available under the name ABITOL from HERCULES, between 10 and 80% by weight of a hydrocarbon resin, e.g. HERCURES C from HERCULES, between 1 and 40% by weight of esters of vegetable fatty acids, e.g. MIGLY0L 812 of DYNAMIT NOBEL and optionally up to 5% by weight of antiagers, such as hydroquinone etc. as well as up to 70% by weight of fillers.

In a further preferred embodiment of the invention the hot melt contact adhesive has 10 to 50% by weight of a polycaprolactone, e.g. CAPA 650 of INTER0X, between 10 and 80% by weight of a hydrogenated alcohol, e.g. ABITOL of HERCULES, between 10 and 80% by weight of a hydrocarbon resin, e.g. HERCURES C of HERCULES, between 1 and 40% by weight of esters of vegetable fatty acids, such as MIGLY0L 812 of DYNAMIT NOBEL and optionally up to 5% by weight of antiagers, as well as up to 70% by weight of fillers.

It can be advantageous for the hot melt contact adhesive to have 10 to 50% by weight of polyethylene-vinyl acetate, such as EVATANE 28-25 of AT0CHEM, between 10 and 80% by weight of a hydrogenated alcohol, e.g.

ABITOL of HERCULES, between 10 and 80% by weight of a hydrocarbon resin, e.g. HERCURES C of HERCULES, between 1 and 40% by weight of esters of vegetable fatty acids, e.g. MIGLY0L 812 of DYNAMIT NOBEL and optionally up to 5% by weight of antiagers, such as hydroquinone, etc. and up to 70% by weight of fillers. - 9 - A suitable hot melt contact adhesive can contain up to 10 to 50% by weight of polyurethane, such as e.g. LUPHEN P 1110 of BASF, between 10 and 80% by weight of a hydrogenated alcohol, e.g. ABIT0L of HERCULES, between 10 and 80% by weight of a hydrocarbon resin, e.g. HERCURES C of HERCULES, between 1 and 40% by weight of esters of vegetable fatty acids, e.g.

MIGLY0L 812 of DYNAMIT NOBEL and optionally up to 5% by weight of anti-agers, as well as up to 70% by weight of fillers.

It is also possible for the hot melt contact adhesive to contain 10 to 50% by weight of polyaraide, such as e.g. EUREL0N 930 of SCHERING, between 10 and 80% by weight of a hydrogenated alcohol, e.g. ABIT0L of HERCULES, between 10 and 80% by weight of a hydrocarbon resin, e.g.

HERCURES C of HERCULES, between 1 and 40% by weight of esters of vegetable fatty acids, e.g. MIGLY0L 812 of DYNAMIT NOBEL and optionally up to 5% by weight of antiagers, as well as up to 70% by weight of fillers.

It is also possible to use a hot melt contact adhesive with 10 to 50% by weight of epoxide, e.g. EUREP0X 7001 of SCHERING, between 10 and 80% by weight of a hydrogenated alcohol, e.g. ABIT0L of HERCULES, between 10 and 80% by weight of a hydrocarbon resin, e.g. HERCURES C of HERCULES, between 1 and 40% by weight of esters of vegetable fatty acids,, e.g.

MIGLY0L 812 of DYNAMIT NOBEL and optionally up to 5% by weight of antiagers, such as hydroquinone, etc., as well as up to 70% by weight of fillers.

Another hot melt contact adhesive usable in the production of inventive transdermal systems has 10 to 50% by weight of polyisobutene with a tacky, rubber-like consistency, such as e.g. 0PPAN0L B 50 of BASF, between 10 and 80% by weight of a hydrogenated alcohol, e.g. ABIT0L of HERCULES, between 10 and 80% by weight of a hydrocarbon resin, e.g.

HERCURES C of HERCULES, between 1 and 40% by weight of esters of vegetable fatty acids, e.g. MIGLYOL 812 of DYNAMIT NOBEL and optionally up to 5% by weight of antiagers, as well as up to 70% by weight of fillers.

It is finally preferred to use hot melt contact adhesives with a polyester base and which e.g. contain between 10 and 80% by weight of a hydrogenated alcohol, e.g. ABITOL of HERCULES, between 10 and 80% by weight of a hydrocarbon resin, e.g. HERCURES C of HERCULES, between 1 and 40% by weight of esters of vegetable fatty acids, e.g. MIGLY0L 812 of DYNAMIT NOBEL and optionally up to 5% by weight of antiagers, as well as up to 70% by weight of fillers.

Inventive apparatuses can also contain one or more substance depots, in which the substance is present in a higher concentration than the active substance-possessing hot melt contact adhesive layer, so that higher substance doses can be processed and consequently the apparatus can remain in use longer before it has to be changed. Typical constructions appear e.g. in DE-OS 36 29 304. Preferred constructions of the invention are given in the subclaims, to which express reference is made.

Further features and advantages of the invention are explained in greater detail hereinafter relative to the drawings, wherein show: Fig. 1 a diagrammatically represented section through the layers of an inventive apparatus with a substance depot.

Fig. 2 a diagrammatically represented section through a further inventive apparatus with an active substance depot.

Fig. 3 a diagrammatically represented section through another embodiment of an inventive apparatus without a substance depot.

Fig. 1 shows an inventive apparatus, which is in this case in the form of a plaster-like, active substance-containing, transdermal, therapeutic system. It has a hot melt contact adhesive layer 12, an active substance depot 14 in which the active substance has a higher concentration than in the hot melt contact adhesive layer 12, as well as an active substance-impermeable carrier 10, on which rests the active substance depot 14 and which is stuck to the skin 18. Active substance now continuously migrates at a predetermined rate through the skin 18, so that the active - 11 - substance content of layer 12 decreases. The active substance decrease is compensated by an after-flow of active substance from the active substance depot 14, so that over a predeterminable period of time there is an equilibrium concentration of the active substance in the hot melt contact adhesive layer 12, which ensures the delivery of a constant active substance quantity to the skin 18.

Fig. 2 shows another embodiment of an inventive apparatus, in which an active substance depot 14 is surrounded on all sides by the hot melt contact adhesive layer 12. This embodiment is particularly suitable if a large contact surface between the active substance depot and the hot melt contact adhesive layer is desired for a rapid active substance delivery to the hot melt contact adhesive layer.

Fig. 3 shows a further simple embodiment of an inventive apparatus, in which an active substance-containing hot melt contact adhesive layer 12 is applied to an impermeable carrier material 10 in such a way that the latter covers the layer 12 on three sides. With the free hot melt contact adhesive surface it is stuck to the skin 18, so that a whole-area contact is ensured over the application time and the transfer of the active substance to the skin always takes place over a constant surface and at a constant speed.

The inventively improved production of an inventive apparatus will now described. Firstly the mixture of the components of the hot melt contact adhesive and the substance to be administered is prepared. This mixture is then brought to the processing temperature and then applied from the melt to a carrier material. The further processing, such as the application of an abhesively finished protective layer material take place in the conventional way.

Claims (9)

- 12 - 87538/2 WHAT IS CLAIMED IS:

1. Device for the release of substances from hot melt pressure sensitive adhesive having a non-uniform or uniform distribution of the substances in the hot melt pressure sensitive adhesive, characterized in that a mixture of hot melt pressure sensitive adhesive and substance or a solution of the substance in the hot melt pressure sensitive adhesive is present, the hot melt pressure sensitive adhesive having a processing temperature of between 40 and 80°C, preferably between 40 and 60°C and especially preferably between 40 and 55°C, with the exception of the mixture of indomethacine with isoprene-rubber-based adhesive with a processing temperature of 80°C.

2. Device according to claim 1, characterized in that the hot melt pressure sensitive adhesive, having the substance (s) to be released, is present as one or more layers .

3. Device according to one of claims 1 or 2, characterized in that the hot melt pressure sensitive adhesive is provided with a carrier, which is permeable or impermeable to the substance (s) to be released. - 13 - 87538/2

4. Device according to one of the preceding claims, characterized in that the hot melt pressure sensitive adhesive is produced on the basis of styrene-isoprene-styrene block polymers, polycaprolactones, ethylene-vinylacetate copolymers, polyurethane, polyepoxides polyisobutene, polyvinyl ethers, optionally with the addition of plasticizers, tackifiers, filler material, anti-agers, and/or thixotropic agents.

5. Device according to claim 4, characterised in that the hot melt pressure sensitive adhesive is produced from between 10 and 80 wt%, preferably 20 to 80 wt.% and especially preferably 20 to 50% by wt. polymer, between 1 and 80%, preferably 1 to 60 wt% plasticizer, between 10 and 80% wt, preferably 15 to 60 wt% tackifier, optionally 0.1 to 5 wt% filler materials, the sum of the percentages of the ocmponents always being 100.

6. Device according to one of the preceeding claims, characterized in that it has a removable protective layer.

7. Method of producing a device according to one of the preceding claims, characterized by continuously or discontinuously applying a molten mixture of hot melt pressure sensitive adhesive and substances to be released at a temperature of the mixture of between 40 and 80°C , - 14 - 87538/2 preferably 40 to 60°C and especially preferably 45 to 55°C, to a carrier and optionally applying a protective layer material.

8. Method of producing a device according to one of the preceding claims, characterized by continuously or discontinuously applying a molten mixture of hot melt pressure sensitive adhesive and substances to be released at a temperature of the mixture of between 40 and 80°C, preferably 40 to 60°C and especially preferably 45 to 55°C, to a protective layer material and optionally applying the carrier.

9. Method of producing a device according to one of the preceding claims, characterized in that the formation of the components of the device, which have hot melt pressure sensitive adhesive with a processing temperature of between 40 and 80°C, is effected by extrusion, moulding, roller application, knife coating, spraying or by a printing process . FOR THE APPLICANT WOLFF, BREGMAN AMD GOLLER