FI96577B - Apparatus for dispensing substances, method of making them and its use - 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

96577 APPARATUS FOR DELIVERY OF SUBSTANCES, METHOD OF PREPARATION AND USE

The invention relates to a device for delivering a substance (s) from pressure-sensitive hot-melt contact adhesives, wherein the device (s) is intended to distribute the substance (s) unevenly or evenly in a pressure-sensitive hot-melt contact adhesive, to a method of manufacturing the device and to use it.

10 Typical representatives of such devices are active substance patches, indicator systems, fragrance delivery devices, etc., which are often used, especially in the medical field, for controlled or uncontrolled delivery of substances. In this context, controlled devices in the form of transdermal controlled systems have become particularly important. These also include the application of a layer containing a known active ingredient from the melt. EP 0 177 893 discloses a non-adhesive, melt-applied cellulose ether gel from which the active ingredients can be divided. This gel is treated hot and is not adhesive. An application from DE 32 22 800 has become known for a transdermal system in which the active substance packed in microcapsules is contained in a thermally formable, adhesive matrix material which can be applied from a melt.

Attempts have also been made to prepare matrices containing heat-sensitive active ingredients with a low boiling point or sensitive degradability at room temperature. For example, U.S. Pat. No. 4,379,454 (Cam-pbell et al.) Discloses the use of an active agent-containing solution with a gelling agent adjusted to the desired viscosity value at room temperature to prepare an active agent-containing layer. It is known from U.S. Pat. No. 4,559,222 (Enscore et al.) To use a mixture of mineral oil / polyisobutylene and colloidal silica prepared at room temperature as a viscous active substance layer when applying oil-soluble active substances, these layers also being able to be formed into contact adhesives. DE 32 22 800 (ALZA) describes an active substance layer made of a solution of an active substance thickened by means of a theological substance, such as cellulose, polysaccharide or silicon compound, which is non-adhesive and suitable for rapid delivery of the active substance 10.

It has become known from U.S. Pat. No. 3,923,939 to melt active ingredients such as tetracycline into an ethylene vinyl acetate copolymer layer. According to EP 86 468 15, an oral antidiabetic drug, a sulphonylurea derivative, is placed in a non-adhesive hot melt mass having a m.p. is 30-90 ° C, in predetermined doses from melt to capsules. U.S. Pat. No. 3,957,966 describes that active ingredients can be treated in non-adhesive hot melt compositions.

It has become known from DE 30 07 363 to use a contact adhesive mixture comprising a thermoplastic elastomer, here preferably a block copolymer of the general formula A-B-A, an adhesive resin with oil or higher fatty acids and an active substance for preparing a simple transdermal system. The contact adhesive composition described in the publication is only suitable for 30 relatively heat-resistant active substances which can withstand temperatures from 120 ° C and above. U.S. Pat. No. 3,699,963 discloses that oxytocin and contact adhesive can be mixed to make a transdermal therapeutic system and formulated at a temperature above 90 ° C. The transdermal systems thus prepared are advantageous to manufacture and the full-surface adhesive system

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3 96577 application to the skin ensures a standard transfer of the active substance.

Prior art methods for making such systems are not suitable for making transdermal systems containing heat-sensitive substances such as scopolamine. Until now, contact-adhesive layers containing heat-sensitive active ingredients have preferably been prepared from a solution and the solvent has evaporated.

10 The use of solvents in the manufacture of adhesive layers containing the active substance is detrimental for a number of reasons. The preparation of solutions requires at least one extensive additional preparation step. It requires high technical costs and the costs of handling 15 solvents - moreover, in medical applications, very pure and thus expensive solvents must be used to dissolve adhesives or their starting materials to ensure their low residual content in the device. Another problem is the removal of solvent 20 from the device, which requires expensive drying steps and suction equipment. In addition, there are costs associated with solvent recovery or separation to avoid burdening the environment. In addition, the flammability of most solvents is an additional hazard. Besides, most organic solvents are harmful to humans, so expensive protective measures must be taken for the persons working in the plant.

Thus, it is an object of the invention to avoid the disadvantages of the prior art devices and methods listed above.

“The task is solved according to the invention by a device for delivering a substance (s) from contact hot melt adhesives, wherein the device (s) is (are) evenly or evenly distributed in the pressure-sensitive hot melt contact adhesive, the device is intended to contain a mixture of 4 96577 hot-melt contact adhesive or solution in the pressure-sensitive hot-melt contact adhesive, and that the processing temperature of the pressure-sensitive hot-melt contact adhesive is about 40 to 80 ° C, preferably about 40 to 60 ° C, and particularly preferably about 40 to 55 ° C.

In this way, it is possible to work at low temperatures without a solvent, which results in considerable material savings, accelerated production of the device, time-consuming drying steps and less environmentally harmful production of the devices according to the invention, which results in e.g. significantly cheaper and also solvent-free product.

In the process according to the invention for the production of the device according to the invention, a molten mixture of pressure-sensitive hot-melt contact adhesive and substance (s) to be delivered is continuously or discontinuously applied at a temperature of about 40 to 80 ° C, preferably 40 to 60 ° C and particularly preferably 40 to 55 ° C. possibly a protective layer material is placed.

In another method according to the invention, a molten mixture of pressure sensitive hot melt contact adhesive and the substance (s) to be delivered is continuously or discontinuously applied at a temperature of about 40-80 ° C, preferably about 40-60 ° C and particularly preferably about 40-25 ° C to the protective layer material and optionally the carrier is placed.

When volatile and / or thermally unstable donors are used, the following special measures may be applied in 30 treatments: A. Working at the lowest possible temperatures, B. Raising the external pressure to prevent evaporation, C. Saturating the vapor space on the melt with substance in the form of steam D, Working with the smallest possible amount of volatile matter in the melt.

5,96577

Obviously, these operations, such as working in encapsulated equipment, are limited due to the provisions of the law known to the person skilled in the art, considering the intended use of the device to be manufactured as well as the conditions related to the substances.

The devices according to the invention, in particular transdermal systems, can be used e.g. for the application of the active substance (s) in cosmetics, preferably for the delivery of heat-sensitive and / or volatile substances.

As used herein, a contact hot melt adhesive is any contact adhesive that, when hot, is sufficiently fluid to be easily applied at a temperature above about 40 ° C.

As the contact adhesive adhesives used according to the invention, e.g. those which are familiar to a person skilled in the art and which have been presented e.g. DE 15 94 268 (SUN OIL CO.), DE 24 13 979 (E.I. DU PONT NE NEMOURS), DE 24 35 863 (DYNAMIT NOBEL 20 AG); DE 28 00 302 (CIBA GEIGY); EP 104 005 (PERSONAL PRODUCTS CO), JP 6104 2583 AND JP 61 281 810, EP 131 460 (EXXON) AND EP 234 856 (EXXON), EP 185 992 (EASTMAN KODAK) and US 36 99 963 and US 4 358 557 ( EASTMAN KODAK), where reference is made to this prior art to avoid duplication.

This allows the base polymer used, for example, the following:. Polyamides, polyesters, polykaprolak-taamit, polycaprolactones, ethylene-vinyl acetate polymers (EVA), etyleenietyyliakrylaattikopolymeerit 30 (EEA), polyvinyl ether, polyacrylate esters, polyvinyl acetals, polyvinyl acetates, styreenibu-tadieeniblokkipolymeerit, isopreeniblokkipolymeerit, polyurethanes, ethyl cellulose, cellulose acetate butyrate, synthetic rubbers (e.g. neoprene rubber), polyisobutylene, butyl rubber, acrylonitrile butadiene copolymers, epoxy resins, melamine resins, phenol formaldehyde resins, and resorcinol formaldehyde can also be used. the following modified resins: hydrogenated rosin, polymerized rosin, dimerized rosin acids, disproportionated rosin, rosin methyl ester, glycerol ester of hydrogenated rosin, methyl ester of hydrogenated rosin glycol ester, pentaalester ester and pentaester, polymerized rosin pental ester, dimerized rosin glycerol ester, maleic acid or phenol-modified rosin ester, aromatic and aliphatic hydrocarbon resins, hydrogenated resins, polyterpene resin-polyene-ethylene, polyethylene resin-modified terpene resins, va Optionally, plasticizers such as adipic acid ester, phosphoric acid ester, phthalic acid ester, polyester, fatty acid ester, citric acid ester, or epoxy plasticizer may be added to these resins. In addition, stabilizers such as tocopherol, substituted phenols, hydroquinones, pyrocatechins, aromatic amines and possibly also fillers such as titanium dioxide, magnesium oxide, zinc oxide and silica can also be mixed.

The formation of parts of the device, such as a contact hot melt adhesive having a processing temperature between 40 and 80 ° C, can be carried out by extrusion, casting, roll coating, granular coating, spraying or printing.

The limit value for the processability of the hot melt adhesive in several of these methods is in the viscosity range of about 80,000 Pa.

If the adhesive-treated substrate - a component of the device - can be damaged by the temperature of the hot coating adhesive - be it decomposition, reaction or partial melting, a cooled substrate can be used. Cooling can occur per se

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7 96577 by a known method, such as conducting a cold in-inert gas or contacting a cooling surface.

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

Depending on the application - if e.g. the substance to be delivered is to be delivered through the backing layer, such as essential oils such as fragrances, the hot melt adhesive may be provided with a carrier permeable carrier, while in an embodiment where the device acts as a transdermal skin delivery device , a backing layer impermeable to 15 deliverables is preferred.

The process according to the invention can now avoid the use of solvent-containing contact adhesives in the treatment of heat-sensitive and volatile substances, which leads to a considerable increase in manufacturing safety, since no toxic solvent residues are now left in the drug concentrate, coating process simplification and manufacturing cost. In addition, the invention can, of course, be used for less heat-sensitive substances, since even then considerable cost savings can be achieved.

The term "substances" in the context of the present invention is understood to mean chemical elements, organic and inorganic compounds which can leave the parts of the device according to the invention which contain them.

. Typical agents to be applied by the device of the invention include: aceclidine, amphetaminil, amyl nitrite, apofedrine, atebrin, alprostadil, azulene, arecoline, anethole, amylenihydrate, acetylcholine, acridine, adenosine alpha-acid phosphorus, adenosine, phosphorus isothiocyanate, aminoethanol, apicin, apiol, azadine, alprenolol, etinazone, benzoyl peroxide, benzyl alcohol, bisabolol, bisnorephedrine, butacetoluide, benacticin, camphor, cholecalciferol, chloralcexirol, chlorolal clobutinol, shamatsulene, dimethocaine, codeine, chloropromazine, quinine, chlorothymol, cyclophosphamide, zincocaine, chloramputylsil, chloridenesine, diethylethylaxyl, eminopyrimethylen, ethinopyrin , emetine, enflurane, eucalyptol, etofenamate, ethylmorphine, fentanyl, fluanisone, guaazulene, halothane, hyoscyamine, histamine, fencurea, hydroxycaine, hexyl-resorcinol, isoamine citrate, isosorbide dinitrate, ibuprofen, iodine, iodoform, lidamine, iodoform, isoamine , methyl tenidate, mefenesin, methyl ephedrine, meclastine, metopromazine, mesuximide, nisetamide, norpseudoephedrine, menthol, methoxyflurane, methylpentinol, methixene, misoprostol, oxytetracaine, oxyprenolone, oxybenbutene, oxyphenbutene, oxyphenbutene pivatiz-25 di, fensuximide, procaine, phenindamine, promethazine, pentetrazole, profenamine, perazine, phenol, pethidine, pilocarpine, prenylamine, phenoxybenzamine, resokine, scopolamine, salicylic acid ester, tricolene, sparteine, trarthein, tetracaine, trimipramine, tranylcypromine, trimethadione, tybamate, thymol , thioridazine, valproic acid, verapamil, and other active ingredients known to those skilled in the art to be ingested through the skin and closed mucous membranes. It goes without saying that 35 this list is not exhaustive.

Typical compositions for the hot melt adhesives used are those prepared from 10 to 80% by weight, preferably from 20 to 80% by weight, particularly preferably from 20 to 50% by weight of polymer, from 1 to 80% by weight. %, preferably 1-60% by weight of plasticizer; 10-80% by weight, preferably 15-60% by weight of tackifier, e.g. 0.1-5% by weight of anti-aging agent and possibly 0-70% by weight of fillers, the sum of the percentages of the particles always being 100.

It is preferred that the hot melt adhesive contain from 10 to 50% by weight of styrene-isoprene-styrene-synthesis-10 rubber, commercially available as CARIFLEX TR 1107, SHELL; in addition 10-80% by weight of hydrogenated alcohol, such as is available under the name ABITOL, HERCULES; 10 to 80% by weight of a hydrocarbon resin, e.g. HERCURES C, HERCULES resin, 1 to 40% by weight of barrier acids of vegetable fatty acids, e.g. MIGLYOL 812, DYNAMIT NOBEL and possibly up to 5% by weight of an anti-aging agent, e.g. nonia, etc. and up to 70% by weight of fillers.

According to another preferred embodiment of the invention, the contact hot melt adhesive contains from 10 to 50% by weight of a polycaprolactone, e.g. CAPA 650, INTEROX; 10-80% by weight of hydrogenated alcohol, e.g. ABITOL, HERCULES, 10-80% by weight of hydrocarbon resin, e.g. HERCURES C, HERCULES, 1-40% by weight of esters of vegetable fatty acids, such as MIGLYOL 812, DYNAMIT NOBEL and possibly always 5 up to 25% by weight of anti-aging agent, and up to 70% by weight of fillers.

It may be advantageous for the hot melt adhesive to contain 10-50% by weight of polyethylene vinyl acetate, such as EVATANE 28-25, ATOCHEM, 10-80% by weight of hydrated alcohols, e.g. ABITOL, HERCULES, 10-80% by weight of % hydrocarbon resin, e.g. HERCURES C resin, HERCULES, 1. - 40% by weight of esters of vegetable fatty acids, e.g.

MIGLYOL 812, DYNAMIT NOBEL, and possibly up to 5% by weight of an anti-aging agent such as hydroquinone, etc. and up to 35% by weight of fillers.

A suitable contact hot melt adhesive may contain 10-50% by weight of polyurethane; such as LUPHEN P 1110, 96577

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BASF. 10-80% by weight of hydrogenated alcohols, e.g. ABITOL, HERCULES, 10-80% by weight of hydrocarbon resins, e.g. HERCURES C, HERCULES resin, 1-40% by weight of esters of vegetable fatty acids, e.g. MIGLYOL 812, DYNAMIT NOBEL, 5 and optionally up to 5% by weight of an anti-aging agent and up to 70% by weight of fillers.

It is also possible that the contact sizing adhesive contains 10-50% by weight of polyamide, such as EURE-LON 930, SCHERING, 10-80% by weight of hydrogenated alcohols, 10 e.g. ABITOL, HERCULES, 10-80% by weight of hydrocarbon resins , e.g. HERCURES C, HERCULES resin, 1 to 40% by weight of esters of vegetable fatty acids, e.g. MIGLYOL 812, DYNAMIT NOBEL and possibly up to 5% by weight of anti-aging agents and up to 70% by weight of fillers.

15 It is also possible to use a hot melt adhesive containing 10-50% by weight of epoxide, e.g. EURE-POX 7001, SCHERING, 10-80% by weight of hydrogenated alcohols, e.g. ABITOL HERCULES, 10-80% by weight of hydrocarbon resins e.g. HERCURES C, HERCULES, 1-40% by weight of esters of vegetable fatty acids, e.g. MIGLYOL 812, DYNAMIT NOBEL and possibly up to 5% by weight of an anti-aging agent such as hydroquinone, etc. and up to 70% by weight of fillers.

Another contact type used in the manufacture of the transdermal systems of the invention

the hot melt adhesive contains 10-50% by weight of polyisobutene with a viscous rubber-like consistency, such as in OPPANOL B 50, BASF, 10-80% by weight of hydrogenated alcohols, e.g. ABITOL, HERCULES, 30 -80 wt% hydrocarbon resins, e.g., HERCURES resin

C, HERCULES, 1 to 40% by weight of esters of vegetable fatty acids, e.g. MIGLYOL 812, DYNAMIT NOBEL, and possibly up to 5% by weight of anti-aging agent and up to 70% by weight of fillers.

Finally, it is preferred to use polyester-based hot melt adhesives which contain, for example, 10 to 80% by weight of hydrogenated alcohols, such as ABITOL, HER-

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11 96577 CULES, 10 to 80% by weight of hydrocarbon resins, such as resin HERCURES C, HERCULES, 1 to 40% by weight of esters of vegetable fatty acids, e.g. MIGLYOL 812, DYNAMIT NOBEL and possibly up to 5% by weight of anti-aging agent, 5 and 70% by weight of up to% fillers.

The device according to the invention may furthermore have one or more reservoirs of the substance, in which the substance is opposite the active substance-containing hot-melt adhesive layer with an elevated concentration, whereby higher doses of the substance can be applied and thus the device can be used longer. must change. Typical examples can be found, for example, in DE 36 29 304.0. Preferred embodiments of the invention are set out in the dependent claims, to which reference is made specifically.

Other features and advantages of the invention will now be described with reference to the accompanying drawings, in which Figure 1 shows a schematic section through layers of a device-20-containing device according to the invention, Figure 2 shows a cross-section of a material-containing device according to the invention and Figure 3 shows a device-based device according to the invention. 25 schematic cross-section of a tea without material stock.

Figure 1 shows a device according to the invention formed into a patch-like, active substance-containing, transdermal system. The device 30 has a contact hot melt adhesive layer 12, an active substance reservoir 14 in which the active substance has a higher concentration than the contact hot melt adhesive layer 12, and an active substance impermeable carrier 10 on which the active substance reservoir 14 is glued on the skin 18. The active substance now passes continuously through the skin 18 at a predetermined rate, whereby the content of the active substance in the layer 12 is reduced. The reduction of the active substance is compensated by the post-flow of the active substance from the active substance reservoir 14, so that for a predetermined time there is a balanced concentration of the active substance in the contact hot melt adhesive layer 12 responsible for delivering a constant amount of active substance to the skin 18.

Figure 2 shows another embodiment of the device according to the invention, in which the active substance reservoir 14 is surrounded on all sides by a contact melt adhesive layer 12. This embodiment is particularly suitable when a large contact surface between the active substance reservoir and the contact melt adhesive layer is desired for rapid delivery to the contact adhesive layer. .

Figure 3 shows another simple embodiment of the device according to the invention, in which a contact hot melt adhesive layer 20 12 containing the active substance is arranged on the impermeable carrier material 10 so that the carrier material 10 covers the layer 12 on three sides. From its free contact hot melt surface, it is glued to the skin 18 so as to ensure full-surface contact for the application time and the transfer of the active substance to the skin always takes place via the same permanent surface at the same constant speed.

The following describes an improved manufacture of the device according to the invention according to the invention. First, a mixture of the hot melt adhesive components 30 with the material to be applied is prepared. This mixture is brought to the processing temperature and then applied from the melt to the support material. Other treatments, such as coating with an adhesive protective layer material, take place in the usual way.

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Claims (11)

Apparatus for dispensing substance (s) from pressure-sensitive melt contact adhesive, wherein the substance (s) in the container is intended to be distributed unevenly or evenly to the pressure-sensitive melt contact adhesive, the device being intended to contain a mixture of the pressure-sensitive adhesive. and the substance (s) or a solution of the substance (s) in the pressure sensitive melt contact adhesive, and the treatment temperature of the pressure sensitive melt contact adhesive is approx. 40 - 80 ° C, advantageously approx. 40 - 60 ° C, especially advantageously approx. 40 - 55 ° C. Device according to claim 1, characterized in that the pressure-sensitive melt contact adhesive, which is intended to contain the substance (s) to be delivered, is in one or more layers. 3. Device according to claim 1 or 2, characterized in that the pressure-sensitive melt contact adhesive is provided with a transmitting or impermeable carrier (s). 4. Apparatus according to any one of claims 1 to 3, characterized in that the pressure-sensitive melt contact adhesive is prepared by using as base 25 styrene-isoprene-styrene block polymers, polycaprolactones, ethylene-vinyl acetate copolymers, polyurethane, polyepoxides and polyisobutylene / polyisobutylene and polyisobutylene / polyisobutylene / polyisobutylene that the crusher may have been added to plasticizers, tackifiers, fillers, aging preventants and / or thixotropic agents. 5. Apparatus according to claim 4, characterized in that the pressure-sensitive contact adhesive is made using approx. 10-80% by weight, advantageously approx. 20 to 80% by weight, especially advantageously approx. 20 to 50% by weight of polymer, approx. 1-80% by weight, advantageously approx. 1 - 60% by weight plasticizer, approx. 10-80% by weight, advantageously approx. 15-60 wt.% Tackifier, possibly approx. 0.1 to 5% by weight of aging preventants, and possibly approx. 0-70% by weight of fillers, so that the percentage sum of the components is always 100. Apparatus according to any one of claims 1 to 5, characterized in that the device includes a removable protective layer. Process for the preparation of a device according to any one of claims 1 to 6, characterized in that a molten mixture of the pressure sensitive melt contact adhesive and the substance (s) to be delivered continuously or discontinuously at a mixture temperature of approx. 40 - 80 ° C, advantageously approx. 40 to 60 ° C, and especially advantageously approx. 45 to 55 ° C, brought to the carrier and the protective layer material possibly applied. Process for the preparation of a device according to any one of claims 1-6, characterized in that a molten mixture of the pressure sensitive melt contact adhesive and the substance (s) to be delivered continuously or discontinuously at a mixture temperature of approx. 40 - 80 ° C, advantageously approx. 40 to 60 ° C, and especially advantageously approx. 45-55 ° C, is applied to the protective layer material and the carrier 25 possibly applied. :. 9. A method according to claim 7 or 8, characterized in that the components of the device, part of which consists of pressure-sensitive melt contact adhesive, the treatment temperature of which is approx. 40 - 80 30 ° C, is formed by extrusion, casting, roll coating, blade coating, spraying or printing. Use of a device according to any one of claims 1 to 6 in cosmetic applications. Use according to claim 10 for the release of heat sensitive and / or easily evaporable substances. II