HRP920832A2 - Device for the release of nitro-glycirine on the skin, methods of manufacture and use - Google Patents

Description

The invention relates to a device for the regulated application or release of nitroglycerin on human or animal skin, preferably in the form of a patch, with a support layer impermeable to nitroglycerin, contact adhesive, a single or multi-part reservoir, a tank, which contains nitroglycerin evenly or irregularly distributed, and optionally one detachable protective layer impermeable to nitroglycerin, to the procedures for its production, as well as to its application.

Nitroglycerin patches are already known. Production of nitroglycerin patches is problematic, since nitroglycerin is explosive and its evaporation must be avoided.

It is recommended to work at temperatures as low as possible, especially at ambient temperature, and often a layer of contact adhesive, which contains nitroglycerin, is produced from a solution. The known therapeutic systems produced in this way, in the form of patches, for applying or releasing nitroglycerin, which is administered through the skin, could fulfill the therapeutic requirements, but were complicated and expensive to manufacture.

DE-OS 32 22 800 (ALZA) describes a nitroglycerin patch, wherein the matrix, which contains nitroglycerin, is formed from a non-sticky, viscous mass that can be obtained at ambient temperature by thickening a solution of nitroglycerin with some rheological agent. US Patent No. 3,742,951 (CIBA-GEIGY), as well as German Patent No. 33 15 272 and DE-OS 33 15 245 (LOHMANN/SCHWARZ) describe simply constructed nicotine patches with contact adhesive matrix materials obtained from solution at temperature environment. It is also known from DE-OS 36 42 931 (CIBA-GEIGY) that multi-part containers, nitroglycerin containers, are used.

The use of solvents in the production of the contact adhesive layer is disadvantageous, however, for several reasons. Solvent preparation requires at least one more stage in production, which is quite complicated. It requires high technical costs and additional handling costs, while for medical purposes, an extremely clean and therefore expensive solvent must be used to dissolve the glue or its starting materials, in order to ensure that there are no residues in the skin delivery system. Another problem is to ensure that there is no solvent in the patch, which requires the use of expensive drying units and vacuum devices. Additional costs are incurred due to the collection and separation of solvents to prevent environmental pollution. The next danger is the flammability 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.

Accordingly, the problem of the present invention is to avoid the aforementioned disadvantages of known devices and processes.

This problem, according to the invention, is solved by a device for applying nitroglycerin to the skin, where the nitroglycerin tank is made using a hot-melt contact adhesive with a processing temperature between 40 and 80°C, preferably between 40 and 60°C, and especially recommended between 40 and 55 °C.

Nitroglycerin in the hot-melt contact adhesive can be adsorbed on a carrier, such as lactose, or it can be used by dissolving in one of the components of the hot-melt contact adhesive.

The invention also relates to the process for the production of the device according to the invention for the continuous or partial application of melted contact adhesive containing nitroglycerin which is released at a temperature of the contact adhesive between 40 and 80°C, preferably 40 and 60°C, and especially recommended between 45 and 55°C, on one protective layer of material, and, if desired, on some carrier.

Due to the fact that in the production of the nitroglycerin tank at low temperatures it is possible to work without solvents, there are significant material savings, faster production without drying stages that require a lot of time and without polluting the environment, which, among other things, leads to a significantly cheaper product with the use of a harmless production process.

The term hot-melt contact adhesive means any contact adhesive that is sufficiently liquid when heated to be able to be applied without problems at a temperature above about 40°C.

As hot-melt contact adhesive, all adhesives known to experts can be used, which are, among others, 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 610281 810, EP-OS 131 460 (EXXON), EP-OS 234 856 (EXXON), EP-OS 185 992 (EASTMAN KODAK), as well as in US Patents 36 99 963 and 4 358 557 (EASTMAN KODAK) and these known solutions are specifically referred to in order to avoid repetition .

The base polymers can be, for example, polyamides, polyesters, polycaprolactams, polycaprolactones, ethylene-vinyl acetate (EVA) copolymers, ethylene-ethylacrylate (EEA) copolymers, polyvinyl ethers, polyacrylate esters, polyvinyl acetals, polyvinyl acetates, styrene-butadiene block polymers, block polymers isoprene, polyurethanes, ethylcellulose, cellulose acetate-butyrate, synthetic rubbers, (for example neoprene rubber), polyisobutylene, butyl rubber, acrylonitrile-butadiene copolymers, epoxy resins, melamine resins, phenol-formaldehyde resins and resorcinol-formaldehyde resins, and can also use the following resins for modification: hydrogenated rosin, polymerized rosin, acids of dimerized acids, disproportionated rosin, methyl esters of rosin, hydrogenated glycerin esters of rosin, methyl esters of saturated rosin, pental esters, triethylene glycol esters of saturated rosin, glycerin esters, ditriolesters and pentaesters of resin acids, pentalester polymers early rosin, pentalesters of dimerized rosin, glycerine esters of dimerized rosin, esters of maleic acid or phenolic modified rosin, aromatic and aliphatic carbon-hydrogen resins, hydrogenated resins, polyterpene resins, modified terpene resins, waxes, low molecular weight polyethylene and polypropylene, and alkyl styrene copolymers . If desired, plasticizers such as fatty acid esters, phosphoric acid esters, phthalic acid esters or epoxy plasticizers can be added to these resins. Stabilizers such as tocopherol, substituted phenols, hydroquinones, pyrocatechols, aromatic amines and, if desired, fillers such as, for example, titanium dioxide, magnesium oxide, zinc oxide and silicon dioxide can also be mixed.

The shaping of the components of the device, which has a hot-melt contact adhesive with a processing temperature between 40 and 80°C, can be done by extrusion, pouring, roller application, spatula application, spraying or printing.

The workability limit for hot melt 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, either by decomposition, reaction or partial melting, a cooled substrate can be used. Cooling can be done by known procedures, such as introducing cold inert gases or contact with a cooled surface.

The fusible contact adhesive can be applied in the form of a layer, or on individual surfaces in accordance with a certain pattern, or pattern, on a protective layer or on a covering material.

Typical compositions for hot-melt contact adhesives that are used are made of polymers in the amount of 10 to 100% by weight, preferably from 20 to 80%, most suitable from 20 to 50% by weight, between 10 to 80% by weight, preferably from 20 to 50 % by weight of plasticizers, between 10 and 80% by weight, preferably 15 and 60% by weight of tackifying agents, optionally from 0.1 to 5% by weight of antiaging agents and from 0 to 70% by weight of fillers, where the sum of the components , i.e. their percentages, always equal to 100%.

It is preferable that the hot melt contact adhesive contains from 10 to 50% by weight of styrene-isoprene-styrene synthetic rubber, which can be obtained commercially under the name CARIFLEX TR 1107, from the company SHELL, between 10 and 80% by weight of saturated alcohol, which is commercially available under the name ABITOL (HERCULES), between 10 and 80% by weight of hydrocarbon resin, for example HERCULES C (HERCULES), between 1 and 40% by weight of esters of vegetable fatty acids, for example MIGLYOL 812 (DYNAMIT NOBEL), and optionally up to 5% by weight of agents anti-aging, such as hydroquinoma, etc., as well as up to 70% of fillers by weight.

In another preferred embodiment of the invention, the hot melt contact adhesive has from 10 to 50% by weight polycarpolactones, for example CAPA 650 (INTEROX), between 10 and 80% saturated alcohol, for example ABITOL (HERCULES), between 10 and 80% by weight ABITOL -a (HERCULES), between 10 and 80% by weight of a single hydrocarbon resin, for example HERCULES C (HERCULES), between 1 and 40% by weight of esters of vegetable fatty acids, such as MIGLYOL 812 (DYNAMIT NOBEL), and, if desired, up to 5% by weight of antiaging agents, as well as up to 70% of fillers.

Suitably, the hot melt contact adhesive has from 10 to 50% by weight of polyethylene vinyl acetate, such as EVATANE 28-25 (ATOCHEM), between 10 and 80% by weight of saturated alcohol, for example ABITOL (HERCULES), between 10 and 80% by weight of some hydrocarbon resins, such as HERCULES 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 of antiaging agents, such as hydroquinone, etc. and up to 70% fillers by weight.

A suitable contact adhesive may contain from 10 to 50% by weight of polyurethanes, such as LUPHEN P 1110 (BASF), between 10 and 80% by weight of saturated alcohol, such as ABITOL (HERCULES), between 10 and 80% by weight of hydrocarbon resin, for example, HERCULES C (HERCULES), between 1 and 40% by weight of vegetable fatty acid esters, such as MIGLYOL 812 (DYNAMIT NOBEL), and optionally, up to 5% by weight of antiaging agents, as well as up to 70% by weight of fillers.

It is also possible for the fusible contact adhesive to contain from 10 to 50% by weight of polyamides, such as EUROLON 930 (SCHERING), between 10 and 80% by weight of saturated alcohol, such as ABITOL (HERCULES), between 1 and 40% by weight of vegetable esters. fats, for example MIGLYOL 812 (DYNAMIT NOBEL), and optionally, up to 5% by weight of antiaging agents, 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 epoxies, for example, EUROPOX 7001 (SCHERING), between 10 and 80% by weight of saturated alcohol, such as ABITOL (HERCULES), between 10 and 80% by weight of hydrocarbon resin, such as HERCULES C (HERCULES), between 1 and 40% by weight of vegetable fatty acid esters, for example, MIGLYOL 912 (DYNAMIT NOBEL) and, if desired, 5% by weight of antiaging agents such as hydroquinone, etc. as well as up to 70% by weight of fillers.

Another hot melt contact adhesive, which can be used in the manufacture of transdermal delivery systems, has from 10 to 50% by weight of polyisobutenes with a tacky, gummy consistency, such as OPPANOL B 50 (BASF), between 10 and 80% by weight of saturated of alcohol, for example, ABITOL (HERCULES), between 10 and 80% by weight of a hydrocarbon resin, for example, HERCULES C (HERCULES), between 1 and 40% by weight of vegetable fatty acid esters, for example, MIGLYOL 812 (DYNAMIT NOBEL) and if desired, up to 5% of anti-aging agents, as well as up to 70% of fillers by weight.

Finally, it is recommended to use a hot-melt contact adhesive with a polyester base, and containing between 10 and 80% by weight of saturated alcohol, for example, ABITOL (HERCULES), between 10 and 80% by weight of hydrocarbon resin, for example, HERCULES C (HERCULES), between 1 and 40% by weight of esters of vegetable fatty acids, for example, MIGLYOL 812 (DYNAMIT NOBEL) and, if desired, up to 5% of antiaging agents, as well as up to 70% by weight of fillers.

The device according to the invention can contain one or more containers for nitroglycerin, in which nitroglycerin is found in a higher concentration than in the layer of soluble contact adhesive containing the active substance, so that larger doses of nitroglycerin can be processed, and thus the device can remain in use for a longer time before than it must be replaced. A typical construction is shown in DE-OS 36 29 304 (LOHMANN). Recommended constructions of the invention are given in the subclaims, in which they are specifically mentioned.

The production of the solution, required for the production of the device according to the invention, takes place using known procedures. During the processing of nitroglycerin as an explosive and volatile substance, the following measures are suitable during the processing:

a) work at temperatures as low as possible,

b) raise the external pressure by known measures,

c) saturation of the steam chamber above the solution with nitroglycerin in a vapor state and works in a hermetically sealed system, and

d) work with a minimum proportion of nitroglycerin in the solution.

It is normal to work in a closed system, in order to avoid uncontrolled evaporation of nitroglycerin and possible collection of explosive amounts of it in cold areas of the plant, such as, for example, the exhaust gas system.

Other properties and advantages are described in the following text with reference to the attached drawings, whereby:

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

- figure 2 shows, schematically, a section through the following device according to the invention with a nitroglycerin tank

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

The picture shows one recommended embodiment of the device according to the invention in the form of a system for acting through the skin, for applying nitroglycerin to the skin. It has a fusible contact adhesive 12, permeable to nitroglycerin, a nitroglycerin container 14, in which the nitroglycerin concentration is higher than in the fusible contact adhesive 12, and a nitroglycerin impermeable carrier layer 10 on which the nitroglycerin container 14 is placed. The device sticks to the skin 18.

Nitroglycerin continuously moves at a predetermined speed through the hot-melt contact adhesive into the skin 18. The decrease in the amount of nitroglycerin is compensated by the inflow of nitroglycerin from the nitroglycerin tank 14, so that during a predetermined period of time a predetermined equilibrium concentration of nitroglycerin is established in the hot-melt contact adhesive 12, which ensures the release of constant amounts of nitroglycerin on the skin 18.

Figure 2 shows another recommended embodiment of the device according to the invention, in which the nitroglycerin container 14 is surrounded on all sides by a hot-melt contact adhesive 12. This design is particularly suitable if a large contact surface is desired between the nitroglycerin container and the hot-melt contact adhesive, if a quick release of nitroglycerin into the mentioned glue.

Figure 3 shows another simple version of the device according to the invention, on which a fusible contact adhesive 12 containing nitroglycerin is applied to a support material 10 impermeable to nitroglycerin, so that this material includes the adhesive 12 with three sides, the device is glued to the skin 18, so that contact is ensured with the entire surface 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.

In the following text, the procedure for the production of a system for the action of nitroglycerin through the skin, improved according to the invention, will be described. First, a mixture of the components of the hot-melt contact adhesive with nitroglycerin is prepared. This mixture is brought to the processing temperature and transferred from the solution to a support material. Further processing, such as the application of a protective layer treated with glue, is done in a conventional way. Nitroglycerin can be included in the soluble contact adhesive or in a solvent, preferably dissolved in one of the components of the adhesive, or on a carrier such as lactose.

A special advantage of the process according to the invention is that after applying the hot-melt contact adhesive, for example using a large nozzle with a slot, the material of the carrier or protective layer can be placed so that by covering the layer of hot-melt contact adhesive the evaporation of nitroglycerin from the freshly prepared system can be suppressed.

Production of nitroglycerin patch is described in the following text:

Example

15.5 g of an ethylene-vinyl acetate copolymer, such as is commercially available under the name Evatane 28-25, from the company Atochem, is mixed with 20.4 g of hydroabiethyl alcohol, which is commercially available under the name ABITOL, from the company Hercules, 30.4 g of a tackifier based on aliphatic hydrocarbon resins, which is commercially available under the name Hercules, from the Hercules company, as well as with 3.4 g of a plasticizer based on medium-chain vegetable fatty acids (commercially available under the name MIGLYOL 812 from the Dynamit company Nobel) and melts at a temperature of 110ºC. After cooling to 50 to 60°C, 26.6 g of triturate nitroglycerin and lactose (equivalent to 2.7 g of pure nitroglycerin) are added to this mixture with stirring. This mixture is then applied to a siliconized polyester thin layer, treated with aluminum vapor on one side (mass per unit area of the adhesive layer is 402 g/m2) and over this is placed an aluminum coated polyester layer. The laminate obtained in this way is cut into rectangular patches of 16 m2, and individually packed in hermetic bags in a known manner.

It is obvious that it is possible according to the invention to produce other therapeutic systems that act through the skin, and which contain nicotine, and to use fusible contact adhesives, so that the examples shown above are in no way intended to limit the scope of protection, but only to illustrate the many possible applications of fusible of contact adhesives in this area.

Claims (7)

1. Device for continuous release of nitroglycerin on human or animal skin, preferably in the form of a patch with a support layer impermeable to nitroglycerin, with contact adhesive, a single or multi-part container containing evenly or irregularly distributed nitroglycerin and, if desired, a removable protective layer impermeable to nitroglycerin, indicated by the fact that the container is produced using a soluble contact adhesive with a processing temperature of 40 to 80°C, preferably 40 to 60°C, and especially recommended from 40 to 55°C. 2. Device according to claim 1, characterized by the fact that the soluble contact layer is made on the basis of the block polymer styrene-isoprene-styrene, polycaprolactone, ethylene-vinyl acetate copolymer, polyurethane, polyepoxide, polyisobutene, polyvinyl ether, optimally with the addition of adhesive agents , plasticizers, fillers, antiaging agents and thixotropic agents. 3. Device according to one of the previous claims, characterized in that the soluble contact adhesive is produced from between 10 and 100% by mass, preferably 20 to 80% by mass, and especially preferably 20 to 50% by mass of polymers, between 10 and 80% by mass, preferably 15 and 60% by mass of agents for obtaining stickiness, optionally 0.1 to 5% by mass of agents to prevent aging and optionally 0 to 70% by mass of fillers, whereby the sum of the percentages of the components is always 100. 4. The procedure for making a device according to one of the previous requirements, indicated by the fact that melted soluble glue containing nitroglycerin is applied continuously or in places, which will be released, and at a temperature of the soluble contact glue between 40 and 80°C, preferably 40 and 60 °C, and especially recommended 45 and 55°C, on some carrier, and if desired, apply a layer of protective material. 5. The method for the production of a device according to one of the requirements from 1 to 3, indicated by the fact that melted contact adhesive containing nitroglycerin is applied continuously or in places, which is discharged at a temperature of the contact adhesive between 40 and 80°C, preferably 40 and 60°C, and especially recommended between 40 and 55°C, on the material of the protective layer, and if desired, application on one carrier. 6. The procedure for the production of a device according to one of the requirements from 1 to 3, characterized by the fact that the shaping of the components of the device, which includes a soluble contact adhesive, takes place at a processing temperature between 50 and 80°C, by extrusion, pouring, application of rollers, application with a spatula, spraying or printing. 7. Application of the device according to one of claims 1 to 3, for therapeutic purposes in human and animal medicine.