SI8811663A - Device for the application of nitroglycerine on the skin, procedures for its production and its use - Google Patents

Abstract

The present invention relates to a device for controlled application or release of nitroglycerin to human or animal skin, preferably in the form of a patch a nitroglycerin impermeable backing layer with one or multiple partial containers containing contact adhesive and one or more partial containers containing evenly or unevenly distributed nitroglycerin, and to a given case the removable protective layer is impermeable to nitroglycerin, the container being made using v hot fusible contact adhesive with temperature processing from 40 to 80 degrees Celsius, preferably from 40 to 60 degrees Celsius and especially preferably 40 degrees Celsius up to 45 degrees Celsius, the process for its manufacture, and use of the device for therapeutic purposes in human medicine and veterinary medicine.

Description

NITROGLYCERIN LEATHER DEVICE, PROCEDURES FOR PRODUCING THE SAME AND USING THE SAME

The invention relates to a device for the regulated application or discharge of nitroglycerin to human or animal skin, preferably in the form of a patch, with a carrier layer impermeable to nitroglycerin, a contact adhesive, a single or multi-part tank, container containing nitroglycerin evenly or irregularly arranged , and optionally barley detachable protective layer impermeable to nitroglycerin, to processes for its production, as well as to its application.

Nitroglycerin patches are already known. The production of nitroglycerin patches is problematic, as nitroglycerin is eco-explosive and its evaporation must be avoided.

It is advisable to operate at the lowest possible temperatures, especially at ambient temperatures, and often a layer of contact adhesive containing nitroglycerin is produced from the solution. The well-known therapeutic systems, such as patches, for the administration or discharge of nitroglycerin administered through the skin, could meet the therapeutic requirements but were complicated and expensive to manufacture.

U-DE-OS 32 22 800 (ALZA) discloses one nitroglycerin patch, wherein a matrix containing nitroglycerin is formed from a non-sticky, viscous mass: obtainable at ambient temperature by thickening a single solution of nitroglycerine and some rheological agent. U.S. Patent Nos. 3,742,951 (CIBA-GEIGY), as well as German patent documents 33 15,272 and DL-OS 33 15,245 (LOHMANN / SCHV7ARZ) describe simply constructed nicotine patches with a material, or having contact glue matrices. obtained from solution at ambient temperature ;. It is also known from DE-OS 36 42 931 (CIEA-GEIGY) that multi-tank, nitroglycerin tanks are used.

The use of solvents in the manufacture of a contact adhesive layer is incomplete, however, for several reasons. Preparation of the solution requires at least one more stage in production, which is more complicated. It requires high technical costs and additional handling costs, while extremely clean, and therefore expensive, solutions to dissolve the adhesive or its starting materials must be used for medical purposes, to ensure that there is no residue in the skin insertion system . Another problem is to ensure that there is no solvent in the patch, which requires the use of expensive drying units and vacuum generators. Additional costs are incurred by collecting and separating solvents to prevent environmental contamination. Another danger is the solubility of the solvent, especially in the case of the explosive active substance in question. Most solvents are also harmful to the human body, so complicated protective measures must be taken to protect personnel.

According to the invention, the object of the present invention is to avoid the aforementioned disadvantages of known devices and processes.

This problem is, according to the invention, solved by a device for applying nitroglycerin to the skin, wherein the nitroglycerin container is made by using a soluble contact-g adhesive with a treatment temperature of; between 40 and 80 ° C, preferably 40 and 60 ° C, and especially between 40 and 55 ° C.

Nitroglycerin in a soluble contact adhesive may be adhered to on a carrier such as lactose or may be dissolved in one of the components of the so-called contact adhesive.

The invention also relates to a process for the manufacture of a device according to the invention for the continuous or partial non-melted dissolving of> g of nitroglycerin-containing soluble contact adhesive discharged and at a temperature of soluble contact adhesive between 40 and 80 ° C, preferably 40 and 60 ° C. and particularly preferably between 45 and 55 ° C, on a carrier and, if desired, for application of a coating material.

Another process according to the invention comprises the steps of continuous or irreducible application of molten soluble contact adhesive containing nitioglycerin discharged at a temperature of soluble contact adhesive between 40 and 80 ° C, preferably 40 and 60 C, especially preferably between 40 and 55 C. to one protective layer of material, and, if desired, to a carrier.

Due to the fact that it is possible to produce nitroglycerin tanks at low temperatures. without solvents, considerable material savings, faster production with no drying phases that require a great deal of time and no pollution of the environment, which, among other things, lead to a much cheaper product using a harmless manufacturing process.

The term soluble contact adhesive means any contact adhesive that is appropriately liquid when heated so that it can be applied easily at temperatures above about 40 ° C.

Any adhesives known in the art can be used as soluble contact adhesives, which are described, inter alia, in DE-OS 15 94 268 (SUN CIL CO.), DE-OS 24 13 979 (E.I.

DU PONT EE NEMOURS), DE-CS 24 35 863 (DYNAMIT NOBEL AG), DE-OS 28 00 302 (CIEA GEICY), EP-A-104 005 (PERSONAL PRODUCTS CO.),

JP 6104 2583 and JP 61 281 8 ': 0, EP-OS 131 460 (E), EP-OS 234 856 (E), EP-CS 185 992 (EASTMAN KODAK), as well as in U.S. Patent Nos. 36 99 963 and 4 358 557 (EASTMAN CODE) and these known solutions are specifically invoked to avoid embezzlement.

Primary polymers may be formed, for example, by polyamides, polyesters, polycaprolactams, polycaprolactones, ethylene-vinyl acetate (EVA) copolymers, ethylene-ethylcrylate (EEAJ) copolymers, p-lyacrylate esters, polyvinylacetates, polyvinyl acetates, polyvinylacetates , block polymers of isoprene, polyurethanes, ethylcellulose, cellulose acetate-botirate, synthetic rubbers (for example neoprene rubber), polyisobutylene, butyl rubber, copolymers of acrylonitrile butadiene, epoxy resins, melamine resins, phencl-formaldehyde, phenol-formaldehyde resins, and the following resins may also be used for modification: hydrogenated rosin yum, polymerized rosin yum, dynerised acid salts, d: proportional rosin yum, methyl esters rosin jumps, hydrogenated glycerin esters of rosin hydrochloride, methylogonium methyl ester , pentyl esters, triethylene glycols of hydrogenated rosin, j um, glycerin and esters, ditriol esters and pentaesters acid pitch resin, pentyl ester polymers, pentesters of dimerized rosin, glycerine, esters of dimerized rosin, esters of maleic acid, or phenolic modified rosin, bolds of aromatic and aliphatic hydrocarbons, resins of aromatic and aliphatic carbon, low molecular weight waxes, polyethylene and polypropylene and alkyl styrene copolymers. These resins can be optionally added to plasticizers such as, for example, fatty acid esters, phosphoric acid esters, phthalic acid esters, polyesters, fatty acid esters, citric acid esters or epoxy. plasticizers. Stabilizers such as tocopherol, substituted phenols, hydroquinones, pyrocatechols, aromatic amines and, optionally, butterflies, such as, for example, titanium dioxide, magnesium oxide, zinc oxide and silica, can also be mixed.

The formation of the components of a device having a soluble contact adhesive with a treatment temperature between 40 and 80 ° C can be done by extrusion, pouring, ordering by roller, spatula, spray or printing.

The crucible value for the machinability of zc-floating contact adhesive in many of these processes is a viscosity of about 80,000 Pa.

If the substrate to which the adhesive is applied, as a component of the device, can be damaged by the temperature of the hot-applied adhesive, cold decomposition may be used, due to its decomposition, reaction or partial melting. Hlader.it can be made by an acquaintance. steps such as supplying cold inert gases or contacting a cooling surface.

Soluble contact adhesive can be applied as a layer, or on individual surfaces in accordance with a predefined pattern or pattern, on a protective layer or on a covering material.

Typical compositions for soluble contact adhesives used are made of polymers in an amount of 10 to 100% by weight, preferably 20 to 80%, most preferably 20 to 50% by weight,

J

-5 between 10 and 80% by weight, preferably 2 to 50% by weight of plasticizers, between 10 and 80% by weight, preferably 15 to 60% by weight of adhesive, optionally 0.1 to 5% by weight of anti-aging agents and 0 up to 70% by weight of the fillers, with the sum of the components, i. their percentages, always equal to 100.

Preferably, the soluble contact adhesive contains up to 50% by weight of styrene-isoprene-styrene synthetic rubber, commercially available under the name CARIFLFX TR 1107, SPELI, between 10 and 80% by weight of hydrogenated alcohol, commercially available under the name ABITOL (HERCULES), between 10 and 80% by weight of hydrocarbon resin, for example HERCURES C (HERCULES), between 1 and 40% by weight of vegetable fatty acid esters, for example MIGLVOL 812 (ΕΥΝΑΜΙΤ NOBEL), and optionally up to 5% by weight aging, such as hydroquinone, etc., as well as up to 70% by weight. fillers.

In another preferred embodiment of the invention, the soluble contact adhesive has 10 to 50% by weight polycaprolactone, for example, CAPA 650 (INTEROI), between 10 and 80% hydrogenated alcohol, for example AEI1CL (HERCULES), between 10 and 80% by weight ABITOL— a (HERCULES), between 10 and 80% by weight of one hydrocarbon resin, for example HERCURES C (HERCULES), between 1 and 40% by weight of e. old vegetable fats, such as MIGLYOL 812 (DYNAMIT NOBEL), and, if desired , up to 5% by weight anti-aging agents as well as up to 70% by weight fillers.

It may be advantageous for the soluble contact adhesive to have 10 to 50% by weight polyethylene vinyl acetate, such as EVATANE 28-25 (ATOCHEM), between 10 and 80% by weight hydrogenated alcohol, for example ABITOL (HERCULES), between 10 and 80% mass of some hydrocarbon resins, such as HERCURES C (HERCULES), between 1 and 40% by weight of vegetable fatty acid esters, for example M1GLYOL 812 (DYNARIT NOBEL), and optionally up to 5% by weight anti-aging agents, such as hydroquinone, etc. , and up to 70? mass fillers.

One suitable soluble contact adhesive may contain 10 to 50% by weight of polyurethanes, such as I-UPHEN P 1110 (BASF.), Between 10 and 80% by weight of hydrogenated alcohol, such as ABITOL (HERCULES), between 10 and 80% hydrocarbon resin masses, for example HERCURES C / HERCULES), between 1 and 40% by weight of 6 fatty acid esters, such as MIGLYOL 812 (DYNAEJT NOBEI.), and optionally up to 5% by weight anti-aging agents, and up to 70¾ masffth fillers.

It is also possible that the soluble contact adhesive contains 10 to 50% by weight of polyamides, such as EURELON 930 (SCHERING), between 10 and 80% by weight of hydrogenated alcohol, such as ABITOL (HERCULES), between 1 and 40% by weight of esters vegetable fatty acids, for example MIGLYOL 812 (DYNAMIT NOBEL), and optionally up to 5% by weight anti-aging agents as well as up to 70% by weight fillers.

It is also possible to use a tapestry contact adhesive with 10 to 50% by weight of epoxy, for example EUREPOK 7001 (SCHERING), between 10 and 80% by weight of hydrogenated alcohol, such as ABITOL (HERCULES), between 10 and 80% by weight of hydrocarbon resin , such as HERCURES C (HERCULES), between 1 and 40% by weight of vegetable fatty acid esters, for example MIGLYOL 812 (DYNAMIT NOBEL), and optionally up to 5% by weight anti-aging agents such as hydroquinone, etc., and up to 70% by weight of fillers.

Another soluble contact adhesive that can be used in the manufacture of a system for introducing substances through the skin has 10 to 50% by weight of polyisobutene with a sticky, rubbery consistency, such as OPPANOL B 50 (BASF), between 10 and 80% by weight of hydrogenated alcohol. for example ABITOL (HERCULES), between 10 and 80% by weight of hydrocarbon resin, for example HERCURES C (HERCULES), between 1 and 40% by weight of esters of vegetable fats, for example MIGLVOL 812 DYNAM.IT NOBEL), and optionally up to 5 % anti-aging agent as well as up to 70% by weight fillers.

Finally, it is advisable to use a polyester-based soluble contact adhesive containing between 10 and 80% by weight of carbonated alcohol, for example ABITOL (HERCULES), between 10 and 80% by weight of hydrocarbon resin, for example HERCURES C (HERCULES ), between 1 and 40¾ fatty acid esters of vegetable fats, for example MIGLYOL 812 (DYNAMIT NOBELj, and optionally up to 5% anti-aging agent as well as up to 70% by weight fillers

The device according to the invention may dc " contain one or more nitroglycerin containers, in which the nitroglycerin is at a higher concentration than in a layer of soluble contact adhesive containing the active substance, so that evening doses of nitroglycerin can be processed, leaving the device in use for a long time before it has to be replaced. A typical construction is shown in uDE-CS 36 29 304 (LOHMANN). Preferred constructs of the invention are given in the sub-claims, which are specifically mentioned.

The production of the solution required to produce the device according to the invention is by known methods. During the treatment of nitroglycerin as explosive and volatile matter, the following measures during processing are appropriate:

A) Working with as low a temperature as possible,

B) Raise the external pressure on the backwash,

C) Saturation of the vapor chamber above the nitroglycerin solution in the vapor state and operation in a hermetically sealed system, and

D) Work with a minimal content of nitroglycerin in the solution.

It is normal to operate in a closed system in order to avoid unregulated evaporation of nitroglycerin and eventual collection of explosive quantities of it in cold areas of the plant, such as, for example, a gas exhaust system.

Other features and advantages described herein with reference to the accompanying drawings, wherein:

Figure 1 shows, schematically, a cross-section of a device according to the invention with a nitroglycerin container.

Figure 2 shows, schematically, a section through the following device according to the invention with a nitroglycerin container.

Figure 3 shows, schematically, a cross-section of another embodiment of the device according to the invention without a container for the active substance

Figure 1 shows one preferred embodiment of the device according to the invention as a skin-acting system for applying nitroglycerin to the skin. It has a soluble contact adhesive 12, permeable to nitroglycerin, a container 14 of nitroglycerin, in which the concentration of nitroglycerin is higher than that of a soluble contact flap 12, and to a nitroglycerin impermeable carrier layer 10 on which a container 14 of nitroglycerin is mounted. The device adheres to the skin 18.

Nitroglycerin moves continuously at a predetermined speed through a soluble contact adhesive into the skin 18. A reduction in the amount of nitroglycerin is compensated by the influx of nitroglycerin from the nitroglycerin container, 14, so that it is tc> k forward.

Λ- From a certain period of time, a predetermined equilibrium concentration of nitroglycerin in the soluble contact adhesive 12 is established, which ensures the release of constant amounts of nitroglycerin onto the skin 18.

Figure 2 shows another preferred embodiment of the device according to the invention, wherein the nitroglycerin container 14 is surrounded on all sides by a soluble contact adhesive 12. This embodiment is particularly suitable if a large contact surface between the nitroglycerin container and the soluble contact adhesive is desired, if wants rapid release of nitroglycerin into said adhesive.

Figure 3 shows another simple embodiment of the device according to the invention, on the pier a soluble contact adhesive 12 containing nitroglycerin is applied to the nitroglycerin impermeable carrier material 10 such that the material comprises adhesive 12 on three sides, the device is glued to the skin 18, so that contact with the entire surface is ensured over the entire surface of the application, and the transfer of nitroglycerin from the soluble contact adhesive is carried out over one constant surface at one constant speed.

Hereinafter, an improved process for the manufacture of a nitroglycerin skin-acting system will be described according to the invention. First, a mixture of the components of the soluble contact adhesive with nitroglycerin is prepared. This mixture is brought to the treatment temperature and is not transferred from the melt to some support material. Further processing, such as the application of some adhesive-treated protective layer, is carried out in a conventional manner. Nitroglycerin can be incorporated into a soluble contact adhesive or in a solution, preferably dissolved in one of the adhesive components, or on a carrier such as lactose.

A particular advantage of the process according to the invention is in the toe that after application of the soluble contact adhesive; for example, with the help of a large slit nozzle, the material of the carrier or the protective layer can be arranged so that evaporation of the soluble contact adhesive layer can prevent the evaporation of nitroglycerin from the freshly prepared system.

The production of the nitroglycerin patch is described as follows:

Example

15.5 g of one ethylene-vinyl acetate copolymer, such as commercially available under the name Evatane 28-25, of Atochem, is mixed with 20.4 g of hydroabietyl alcohol, commercially available under the name ABITOL, from Hercules, 30.4 g of adhesive, based on g resins of aliphatic hydrocarbons, commercially available under the name Eercures, from Hercules, as well as 3.4 g plastif icat.or based on medium chain vegetable masses (commercial is purchased under the name MIGLYOL 812 from Dynamit Nobel) and melts at 110 ° C. After cooling to 50 to 60 ° C, 26.6 g of nitroglycerin triturate and lactose (corresponding to 2.7 g of pure nitroglycerin) were added to this mixture with stirring. This mixture is then applied to silicone. Called polyester thin film, treated with aluminum vapor on one side (mass per unit area of the adhesive layer is 402 g / m) and a single aluminum coated layer is placed over it. The 2 laminates thus obtained are cut into 16 cm rectangular patches and individually packaged in sealing bags in a known manner.

It is obvious that according to the invention it is possible to manufacture other therapeutic systems that act through the skin and which contain nicotine, and to use soluble contact adhesives, so that the above examples are not intended in any way to limit the scope of protection, but merely illustrate many possible applications of soluble contact adhesives in this field.

Claims (7)

PATENT APPLICATIONS A device for the controlled application of nitroglycerin to human or animal skin, preferably in the form of a patch with a nitroglycerin impermeable layer, with a contact adhesive with one or more partial containers containing uniformly or uniformly distributed nitroglycerin, and optionally with removable protective a nitroglycerin-impermeable layer, characterized in that the container is made using hot melt contact adhesive at a treatment temperature of from 40 to 80 ° C, preferably from 40 to 60 ° C and especially preferably from 40 to 55 ° C. Device according to claim 1, characterized in that the hot melt contact adhesive is made on the basis of styrene-isoprene-styrene block of polymers, polycaprolactones, ethylene vinyl acetate copolymers, polyurethanes, polypoxides, polyisobutene, polyvinyl ethers, optionally added adhesives, plastics, fillers, anti-aging agents and thixotropic agents. Apparatus according to one of the preceding claims, characterized in that in hot melt contact adhesive is made from 10 to 100% by weight, preferably from 20 to 80% by weight, and especially preferably from 20 to 50% by weight of polymer, from 10 up to 80% by weight, preferably from 15 to 60% by weight of the plasticizing agent, from 10 to 80% by weight, preferably from 15 to 60% by weight of the adhesive, optionally from 0.1 to 5% by weight anti-aging agents and, optionally, from 0 to 70% by weight of the filler, the sum of the percentages of the components being always 100. Process for the manufacture of a device according to one of the preceding claims, characterized in that a molten hot-melt adhesive containing nitroglycerin released at a temperature of 40 to 80 ° C in hot melt adhesive is applied continuously or discontinuously, preferably from 40 to 60 ° C and especially preferably from 45 to 55 ° C, a layer of protective substance is applied to the carrier and optionally. A method for manufacturing a device according to any one of claims 1 to 3, characterized in that a molten hot-melt adhesive containing nitroglycerin released at a temperature of 40 to 80 ° C in hot melt is applied continuously or discontinuously. C, preferably from 40 to 60 ° C and especially preferably from 40 to 55 ° C, a carrier layer is applied to the protective substance layer and optionally applied. Μ A method for manufacturing a device according to any one of claims 1 to 3, characterized in that the manufacturing of the components of the device comprising in hot melt contact adhesive is carried out at a treatment temperature of 50 to 80 ° C, by extrusion, ejection, using a cylinder , with a knife, spray or compression application. Use of the device according to one of claims 1 to 3 for therapeutic purposes in human medicine and veterinary medicine.