DK175442B1 - Apparatus for dispensing substances and method of manufacture and use thereof - 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

DK 175442 B1 i

The invention relates to a device for dispensing substances from melt adhesives, with a uniform or uniform distribution of substance in the melt adhesives, a method of making them and its use.

Typical representatives of such devices are patches containing active substance, indicator systems, fragrance-releasing devices and the like, which are why they are especially used in the medical field for controlled or unregulated drug delivery. In this way, the regulating devices have gained a special importance in the form of transdermally regulated systems. For such systems, it is already known in the molten state to apply a layer of active substance. EP-A-0177893 discloses a non-sticky cellulose ether gel which can be applied in the molten state in which the active substance can be distributed. This gel is processed hot and is non-sticky. DE-OS 32 22 800 discloses a transdermal system in which the active substance contained in microcapsules is present in a thermally malleable, adhesive matrix material which is applied in a molten state.

US-P-4515909 discloses articles in which polymers at solid temperature are impregnated with fragrance. According to this patent, the polymer is not melted, but a somewhat softened polymer is impregnated with the fragrance at elevated temperatures.

This method is not suitable for accurate application of defined amounts in a polymer. 1 2 3 4 5 6

For temperature sensitive active substances with low melting point or easily degradable 2 substances, it has also been attempted at room temperature to produce non-sticky 3 matrices with active substance. For example, in US Patent 4,379,454 (Campbell 4 et al.), It is stated as the active substance layer to use a solution of active substance which has been brought to a desired viscosity by means of a gelling agent at room temperature. From US Pat. No. 4,559,222 (Enscore et al.), It is known to use a room-temperature mixture of mineral oil / polyisobutylene and colloidal silica as viscous active substance layer for oil-soluble active substances, as these layers can also be made adhesive. DE-OS 32 22 800 (ALZA) describes an active substance layer consisting of a solution of active substance thickened with a rheological agent such as cellulose,

DK 175442 B1 I

a non-adhesive polysaccharide or a silicon compound suitable for use in

for rapid release of active substance. IN

From US-PS 3,923,939 it is known to form active substances such as tetracydine into an I

5 ethylene-vinyl acetate copolymer layers by melt pressing. EP-A 86 468 becomes an oral I

antidiabetic sulfonylurea derivative in a non-adhesive hot melt with an I

melting point from 306C to 90C filled capsules in predetermined doses and in melted I

condition. U.S. Pat. No. 3,957,966 discloses that active substances can be processed in I

non-adhesive hot melt. IN

From DE-A 30 07 363 it is known to use an adhesive mixture of an I

thermoplastic elastomer, preferably a block polymer of general formula A-I

B-A, an adhesive resin with oil or higher fatty acids and active substance for I

preparation of a simple transdermal system. The adhesive composition described herein

15 is suitable only for relatively temperature resistant active substances which can withstand temperature

temperatures of 120 ° C or more. J I

U.S. Pat. No. 3,699,963 discloses oxytocin for the preparation of a transdermal I

therapeutic system can be mixed with adhesive and formed at a temperature of

20 above 90 ° C. The therapeutic transdermal systems thus produced are I

economical in preparation and ensures a constant transfer of active substance, I

the entire system flat adheres to the skin.

The prior art method of producing such systems is suitable for H

25 does not apply to transdermal systems containing temperature sensitive substances I

such as scopolamine. Heretofore, such adhesive active fabric layers are temperature sensitive

some active substances preferably formed from solution and evaporation of solution

driving means. I 1 2 3 4 5 6

The use of solvents for the production of adhesive layers with active substance is unforeseen

2

participating for several reasons. The preparation of the solution requires at least one additional I

3

process steps. It requires high technology and additional costs for handling I

4

solvent. In addition, for medical purposes, very clean I

5

and thus expensive solvents for dissolving the adhesive or its starting H

6

materials to ensure a corresponding lack of residue in the device. And H

Another problem consists in removing the solvents from the device to which expensive drying lines and extraction systems are needed. In addition, the cost of recycling and disposal of the solvent to avoid environmental impact. In addition, the flammability of the solvent presents an additional 5 risks. In addition, most organic solvents are harmful to the human organism, so the necessary protective measures must be taken for the persons working with them. It is thus the object of the invention to avoid the above-mentioned disadvantages of such types of devices and the method of manufacture according to the prior art.

10

According to the invention, the task is solved by a device for dispensing substances from melt adhesives having a uniform or even distribution of the substances dissolved in the melt adhesives, where there is a melt adhesive / fabric mixture or a solution of the substance in the melt adhesive, where a melt adhesive has a melt adhesive. 40 ° C and 80 ° C, preferably between 40 ° C and 60 ° C and especially between 40 ° C and 55 ° C.

Hereby, it is possible to work at low temperatures without solvent, thereby enabling substantial material savings, faster production of the device without time-consuming drying steps and a less environmentally harmful production of the device according to the present invention, which leads, among other things, to a more economical and solvent-free product.

Thus, the device may have the substance (s) to be dispensed and the hot melt adhesive in one or more layers. It is preferred that the hot melt adhesive be provided with a carrier which is permeable or impervious to the substance (s) to be released.

The melt adhesive may be, for example, one made on the basis of styrene-isoprene-styrene block polymers, polyaprolactones, ethylene-vinyl acetate copolymers, polyurethane, polyepoxides, polyisobutylene, polyvinyl ethers, optionally with the addition of plasticizers, adhesives, adhesives, adhesives, and / or thixotropic agents.

I DK 175442 B1 I

I I

I A method according to the invention for producing a device according to the invention

In the present invention, the molten adhesive comprising the substance to be contained

You are delivered, continuously or discontinuously placed on a carrier at a temp

At a temperature of the melt adhesive of between 40 ° C and 80 ° C, preferably 40 ° C to 60 ° C and I

In particular, 40 ° C to 55 ° C, and the protective layer optionally applied. IN

In a further method according to the invention, the molten melt adhesive comprises

Container containing the substance to be delivered continuously or continuously

You are placed on a protective layer material at a temperature of the melt adhesive I

In the range of 40 ° C to 80 ° C, preferably 40 ° C to 60 ° C and especially 40 ° C to 55 ° C, and I

If applicable, apply in the carrier. IN

By using volatile and / or thermally unstable substances to be emitted, you can:

The following processing measures are indicated:

I 15 I

In A. work at the lowest possible temperatures

B. raising the external pressure to reduce evaporation,

In C. saturation of the steam room over the molten mass with vaporous I

In fabric, I

In 20 D. work with the least amount of volatile matter in I according to the task

In the molten mass. IN

Of course, these are measures, such as working in an encapsulated I

In facilities limited by the laws known to those skilled in the art with respect to I

In the application of the device manufactured and also of the substances I

In properties.

For example, in the devices of the invention, especially the transdermal systems, I

I is used for local or systemic transdermal administration of active substances in I

In human or veterinary medicine or for cosmetics, preferably for the delivery of tem

In periorally sensitive substances and / or volatile substances. IN

In this context, a hot melt adhesive may be any adhesive which you

In hot, sufficient liquid to be applied at a tem- perature without difficulty

In 35 rature of over approx. 40 ° C. IN

5 DK 175442 B1

As used in the invention, melt adhesives which can be used, among others, are known to those skilled in the art and which can be derived, inter alia, from DE-A 15 94 268 (SUN OIL CO.), DE-A 24 13 979 (EI DU PONT DE NEMOURS ), 5 DE-A 24 35 863 (DYNAMIT NOBEL AG); DE-A 28 00 302 (CIBAGEIGY); EP-A-104 005 (PERSONAL PRODUCTS CO), JP 6104 2583 and JP 61 281 810, EP-A 131 460 (EXXON) and EP-A 234 856 (EX-XON), EP-A 185 992 (EASTMAN KODAK) as well as US-PS 36 99 963 and US-PS 4,358,557 (EASTMAN KODAK), to which reference is made explicitly to the state of the art for avoidance of repetition.

As base polymers, for example, polyamides, polyesters, poly-caprolactams, polycaprolactone, ethylene-vinyl acetate copolymers (EVA), ethylene-ethyl acrylate copolymers (EEA), polyvinyl ethers, polyacrylate esters, polyvinyl acetates, polyvinyl acetates, polyvinyl acetates, polyvinyl acetates, polyvinyl acetates, polyvinyl acetates, urethanes, ethyl cellulose, cellulose acetate butyrate, synthetic rubber (e.g. neoprene rubber), polyisobutylene, butyl rubber, acrylonitrile-butadiene blend polymers, epoxide resins, melamine resins, other resins and phenolic formaldehyde resins , 20 modified resins may be used: hydrogenated rosin, polymerized rosin, dimerized resin acids, disproportionate rosin, methyl esters of rosin, glycerin esters of hydrogenated rosin, methyl esters of hydrogenated rosin, pental ester, triethylene glycol esters of hydrogenated rosin, ather, glycerine esters, dithiol esters 25 and penta esters of resin acids, pental esters of polymerized rosin, pental esters of dimerized rosin, glycerin esters of dimerized rosin, esters of maleic acid or phenol modified rosin resins, aromatic and aliphatic hydrocarbon resins , low molecular weight polyethylene and polypropylene, alkyl-styrene copolymers. These resins may optionally be added to plasticizers such as adipic acid esters, phosphoric acid esters, phthalic acid esters, polyesters, fatty acid esters, citric acid esters or epoxide plasticizers. In addition, stabilizers such as tocopherol, substituted phenols, hydroquinone, pyrocatecols, aromatic amines, and optionally filler, for example titanium dioxide, magnesium oxide, zinc oxide and silica, may also be added.

I DK 175442 B1 I

I I

The formation of the constituents of the device, which comprises the melt adhesive with an I

At processing temperatures between 40 ° C and 80 ° C, extrusion, molding, can occur

coating, kiss-roll coating, smearing, spraying or by a printing method. IN

Is I

A limit value for the processability of the hot melt adhesive at several of these

In processes, at a viscosity of about 80,000 Pa. I.

I If the foundation, which is a component of the device, is to be treated with I

10 adhesive may be damaged by the temperature of the hot applied adhesive

In the medium, whether by decomposition, reaction or partial melting, you can

You use a cooled base. The cooling can be done by known methods, such as I

When using cold inert gas or in contact with a cooling surface. IN

For example, the hot melt adhesive may be applied occasionally or in individual areas where I

You exhibit a predetermined pattern on the protective layer or cover material. IN

For some applications - for example in the case of the substance to be released

ves, can be delivered through the cover, as can be done, for example, for essential oils such as I

In 20 fragrances, the hot melt adhesive may be provided with a carrier which is recovered.

In the case of the substance (s) to be released, in an embodiment

form of the device as a transdermal system in which the substance is to be delivered only to I

In the skin, it is preferable to use a coating which is impervious to the substance I

In there to be released. IN

I 25 I

In the process according to the invention, the use of solvent can

In dense adhesive materials are now bypassed by processing of temperature sensitive and · I

In volatile substances, which leads to increased safety during manufacture, since I

now, no toxic solvent residues are present in drug formula I

In the ring, leading to a greatly simplified application process and to a significant reduction of I

In manufacturing costs. The process can, of course, also advantageously I

You are used for less temperature sensitive substances, as here too you can be obtained

Substantially reducing costs. IN

7 DK 175442 B1

Under the term "substances" in connection with the present invention is understood chemical elements, organic and inorganic compounds which, as a component contained in one of the device types, can migrate out and thereby give rise to the desired effect. Among the application areas of the device according to the invention, the human and animal medicine is of particular importance, whereby an embodiment of the invention in the form of patches is particularly preferred.

Typical substances which can be administered via devices made according to the invention are: 10

Acedidine, amphetaminil, amphetamine, amyl nitrite, apophedrin, atebrin, alprostadil, azulen, arecoline, anethole, amylene hydrate, acetylcholine, acridine, adenosine triphosphoric acid, L-malic acid, alimemazine, allithiamine, aplyhanolate, allyiisothiocyanate ethinazone, benzoyl peroxide, benzyl alcohol, bisabolol, bisnorephedrine, butacetoluid, benactyzin, camphor, cholecaldferol, chlorohydrate, clemastine, chlorobutanol, capsaidn, cydopentamine, clobutinol, chamazulin, dimethocaine, codeine, chlorine , diethylethane, divinylethane, dexchloropheniramine, dinoprostone, dixyrazine, ephedrine, ethosuximide, enallylpropymal, emylcamate, erythrolethetranitrate, emetin, enflurane, eucalyptol, etofenamate, ethylmorphan, guanyl, fentanyl, fentanyl hexyl resorcin, isoamine filtrate, isosorbide dinitrate, ibuprofen, iodine, iodoform, isoaminil, lidocaine, lopiri n, levamisole, methadone, methyprylon, methylphenidate, mephenesine, methylphedrine, medastine, methopromazine, mesuximide, nicethamide, norpseudoephedrine, menthol, methoxyflurane, methylpentinol, methixen, misoprostol, oxytetracoline, oxyprenoline, oxyprenoline, oxyprenoline , piperazine, pivazide, phensuximide, procaine, phenindamine, promethazine, pentetrazole, profenamine, perazine, phenol, pethidine, pilocarpine, prenylamine, phenoxybenzamine, resoquine, scopolamine, salicylic acid esters, spartein, trichlorethylene, 30 trichlorethylene, 30 trichlorethylene tranylcypromine, tri-methanion, tybamate, thymol, thioridazine, valproic acid, verapamil and, further, to those skilled in the art, usual active substances which can be absorbed through the skin and mucous membranes. Of course, this list is not exhaustive. 1

Typical compositions of useful hot melt adhesives are such

I DK 175442 B1 I

I I

I which is prepared from between 10 and 100% by weight, preferably 20 to 80% by weight and I

In particular, 20 to 50% by weight of polymer, between 10 and 80% by weight, preferably 15 to 1

In 60% by weight plasticizer; between 10 and 80% by weight, preferably 15 to 1

In 60% by weight adhesive; optionally 0.1 to 5% by weight of aging protective I

5, and optionally 0 to 70% by weight of filler, the sum of the percentage of I

In the constituents are 100. I

It is preferred that the hot melt adhesive contains up to 10 to 50% by weight of styrene

In isoprene-styrene synthetic rubber, for example, which is commercially available under the designation I

I 10 CARIFLEX TR 1107 from SHELL; between 10 and 80% by weight of a hydrogenated alcohol

hol, which can be obtained, for example, under the designation ABITOL from HERCULES: between 10 and 1

In 80% by weight of a hydrocarbon resin, for example the resin HERCURES C from I

In HERCULES, between 1 and 40% by weight of an ester of a plant fatty acid, e.g.

I MIGLYOL 812 from DYNAMIT NOBEL and optionally up to 5% by weight of aging protection I

In solvent, such as hydroquinone, etc., and up to 70% by weight of filler. IN

In a further preferred embodiment of the invention, the melt contains

In the adhesive up to 10 to 50% by weight of a polycaprolactone, for example CAPA 650 I

I from INTEROX; between 10 and 80% by weight of a hydrogenated alcohol, for example I

I 20 ABITOL from HERCULES; between 10 and 80% by weight of a hydrocarbon resin, I

For example, in HERCURES C from HERCULES; between 1 and 40% by weight of an ester of an I

In plant fatty acid such as MIGLYOL 812 from DYNAMIT NOBEL and optionally up to 5 I

By weight% of age-protecting agent, and up to 70% by weight of filler. IN

I It may also be preferred that the hot melt adhesive contains up to 10 to 1

In 50% by weight polyethylene vinyl acetate, such as EVATANE 28-25 from ATOCHEM, between I

In 10 and 80% by weight of a hydrogenated alcohol, for example ABITOL from HERCULES, I

In between 10 and 80% by weight of a hydrocarbon resin, for example resin I

I HERCURES C from HERCULES; between 1 and 40% by weight of an ester of a plant I

In 30 fatty acids, for example, MIGLYOL 812 from DYNAMIT NOBEL and optionally until I

In 5% by weight of age-protecting agent, such as hydroquinone etc., and up to 1

In 70% by weight filler. IN

A suitable hot melt adhesive may contain up to 10 to 50% by weight of polyurethane; IN

In 35 such as LUPHEN P 1110 from BASF; between 10 and 80% by weight of an I

9 DK 175442 B1 hydrogenated alcohol, for example ABITOL from HERCULES; between 10 and 80% by weight of a hydrocarbon resin, for example, the HERCURES C resin from HERCULES; between 1 and 40% by weight of an ester of a plant fatty acid, for example MIGLYOL 812 from DYNAMIT NOBEL and optionally up to 5% by weight of aging protection agent, and up to 70% by weight of filler.

It is also possible that the hot melt adhesive contains up to 10 to 50% by weight polyamide, such as EURELON 930 from SCHERING; between 10 and 80% by weight of a hydrogenated alcohol, for example ABITOL from HERCULES; between 10 and 80% by weight of a hydrocarbon resin, for example the HERCURES C resin from HERCULES; between 1 and 40% by weight of an ester of a plant fatty acid, for example, MIGLYOL 812 from DYNAMIT NOBEL and optionally up to 5% by weight of aging protection agent, and up to 70% by weight of filler.

A melt adhesive with 10 to 50% by weight epoxide can also be used, for example EUREPOX 7001 from SCHERING; between 10 and 80% by weight of a hydrogenated alcohol, for example ABITOL from HERCULES; between 10 and 80% by weight of a hydrocarbon resin, for example, the HERCURES C resin from HERCULES; between 1 and 40% by weight of an ester of a plant fatty acid, for example, MIGLYOL 812 from DYNAMIT 20 NOBEL and optionally up to 5% by weight of antifouling agent such as hydroquinone etc., and up to 70% by weight of filler.

A further useful melt adhesive! for the preparation of transdermal systems according to the invention contains up to 10 to 50% by weight polyisobutene with 25 sticky rubbery consistency, such as OPPANOL B 50 from BASF, between 10 and 80% by weight of a hydrogenated alcohol, eg ABITOL from HERCULES, between 10 and 80 wt% of a hydrocarbon resin, for example the resin HERCURES C from HERCULES, between 1 and 40 wt% of an ester of a plant fatty acid, for example MIGLYOL 812 from DYNAMIT NOBEL and optionally up to 5 wt% 30 antifouling agent and up to 70 wt% filler.

Finally, it is preferred to use polyester-based melt adhesives containing, for example, between 10 and 80% by weight of a hydrogenated alcohol, e.g., ABITOL from HERCULES, between 10 and 80% by weight of a hydrocarbon resin, e.g., the HERCURES C resin from HERCULES, between 1 and

I DK 175442 B1 I

I 10 I

In 40% by weight of an ester of a plant fatty acid, for example MIGLYOL 812 from DYNAMIT I

In NOBEL and optionally up to 5% by weight of anti-aging agent, and up to I

In 70% by weight filler. IN

Devices according to the invention may further have one or more fabric depots, in one

In which (s) the substance is present at a higher concentration than in the melt adhesive layer I

With active substance, you can work with higher doses of the substance and thereby

In the device can remain at the application site for a long time before it needs to be replaced. IN

Typical designs can be found, for example, in DE-OS 36 29 304.0. Preferred designs

The invention according to the invention is set out in the dependent claims to which reference is made. IN

Further features and advantages of the invention subsequently become

As explained in the accompanying drawing. IN

I 15 This shows: I

In FIG. 1 is a schematic section through the layers of a device according to I

In the invention with a fabric depot. IN

In FIG. 2 is a schematic section through a further device according to I

In the invention with an active substance depot, and I

In FIG. 3 is a schematic section through a further embodiment of I

In the device according to the invention without a dust deposit. IN

In FIG. 1 is a device according to the invention, depicted here as a patchy, I

In an active substance transdermal therapeutic system. It has a melt adhesive layer 12, an I

In the deposit of active substance 14, in which the active substance is present in at least one higher concentration

In centration than in the melt adhesive layer, like a carrier 10 which does not allow active I

In the substance to penetrate, on which the repository of active substance 14 lies, and which is I

In the adhesive to the skin 18. The active substance now migrates continuously and with predetermined I

At a speed through the skin 18, whereby the content of active substance in the layer 12 decreases. IN

The reduction of active substance is compensated by the outflow of active substance from I

In the repository 14, so that for a predetermined period of time, a balance equilibrium prevails

In the center of the active substance in the melt adhesive layer 12, whereby an I

In constant amount of active substance to the skin 18. I

I 35 I

11 DK 175442 B1 In fig. 2 is a further preferred embodiment of the device according to the invention, in which an active substance depot 14 is surrounded on all sides by the melt-adhesive layer. This embodiment is particularly suitable when a large contact surface is desired between the active substance deposit and the melt adhesive layer to obtain a rapid release of active substance into the melt adhesive layer.

In FIG. 3, a further simple embodiment of a device according to the invention is shown, in which an active substance-containing melt adhesive layer 12 is placed on a covering layer 10 impermeable to active substance 10 such that the covering layer material 10 covers the melt adhesive layer on three sides. . It is adhered to the skin at the free hot-melt adhesive so that a total surface contact is guaranteed throughout the application time, and the transition of active substance to the skin occurs over a constant surface at a constant rate.

In the following, the improved preparation of a device according to the invention is described.

First, a mixture of the components of the hot melt adhesive is prepared with the substance to be administered. This mixture is brought to processing temperature and then placed in a molten state on a support material. Further processing such as the application of a removable protective material is carried out in the usual manner.

Claims (11)

Apparatus for dispensing substances from melt adhesives having a uniform or H uniform distribution of substances, characterized in that there is a melt adhesive / substance mixture or in a solution of the substance in the melt adhesive, where the melt adhesive has a processing temperature of 40 ° C and 80 ° C, preferably between 40 ° C and 60 ° C and, more preferably, between 40 ° C and 55 ° C. IN Device according to claim 1, characterized in that the melt adhesive containing the substance (s) to be released is present as one or more layers. IN Device according to claim 1 or 2, characterized in that the melt adhesive is provided with a carrier which is permeable or impervious to the substance (s) to be delivered. IN Device according to any one of claims 1-3, characterized in that the melt adhesive is made from styrene-isoprene-styrene block polymers, polycaprolactones, ethylene-vinyl acetate copolymers, polyurethane, polyepoxides, polyisobutene, polyvinyl ethers, optionally by the addition H of plasticizers, adhesives, fillers, anti-aging and / or thixotropic agents. Device according to claim 4, characterized in that the melt adhesive is made of between 10 and 1 80% by weight, preferably 20-80% by weight, and most preferably 20-50% by weight polymer, between 1 and. In 80 wt%, preferably 1-60 wt% plasticizer; between 10 and 80 wt.%, preferably 15-60 wt.% of adhesive, optionally 0.1-5 wt.% of anti-aging agent and optionally 0-70 wt.% filler, the sum of the percentages of H constituents being 100. H Device according to any one of claims 1-5, H characterized in that it has a removable protective layer. I Ί i i i DK 175442 B1 12 j Process for the preparation of a device according to any one of claims 1-6, characterized in that a molten mixture of hot melt adhesive and the substance to be delivered is continuously or discontinuously applied to a carrier at a temperature of the mixture pi. between 40 ° C and 80 ° C, preferably 40-60 ° C and especially 45-55 ° C, and optionally a protective layer material is applied. Process for the manufacture of a device according to any one of claims 1-6, 10, characterized in that a molten mixture of hot melt adhesive and the substance to be dispensed is applied continuously or discontinuously to a protective layer material at a temperature of the mixture of between 40 ° C and 80 ° C, preferably 40-60 ° C and especially preferably 45-55 ° 0, and optionally a carrier material is applied. Process according to claim 7 or 8, characterized in that the manufacture of the components of the device, which comprises melt adhesive with a processing temperature of between 40 ° C and 80 ° C, is effected by extrusion, casting, kiss-roll coating, smearing, spraying. or by a printing method. 20 Use of the device according to any one of claims 1-6 in human or veterinary medicine, diagnostics or cosmetics. Use according to claim 10 of the device for delivering temperature sensitive and / or volatile substances. 1