MXPA99006051A - Extremely flexible plaster acting dermally or transdermally, and method for producing same - Google Patents

Abstract

The invention relates to a method for producing an extremelyflexible dermally or transdermally acting plaster with an adhesive matrix layer containing an active ingredient, which has, on the side facing the skin, a removable protective layer. Said method is characterized in that the matrix layer is not covered on the side facing away from the skin but that its open surface is not made adhesive.

Description

SUMMARIZED FLEXIBLE EMPLOYMENT OF DERMAL OR TRANSDERMAL ACTION AND PROCEDURE FOR PREPARATION The present invention relates to an extremely flexible plaster of dermal or transdermal effect for the controlled release of active substances through human or animal skin, composed of a contact adherent matrix layer containing the active substance (s). , which on the face remote from the skin lacks adhesion properties by contact, as well as a procedure for its preparation. The plasters for the controlled release of active substances through human or animal skin are well known and have been widely described as transdermal therapeutic systems (TTS) or "Transdermal Delivery Systems" (TDS). In general, it is distinguished in these systems, according to their structure and the class of release of the active substance, between the so-called plasters of bags or deposits and the so-called matrix plasters. In the first case, these plasters are composed of a bag or flat sachet containing the active substance, whose face away from the skin is impermeable and whose face facing the skin fulfills the function of control membrane, and which for its Adhesion on the skin is coated with an adhesive.

Due to its complicated structure, the manufacture of these plasters is very complex since the different components are prepared separately and then they have to be combined to form a system. On the other hand, the characteristics of use are impaired due to the thickness that the plaster must necessarily have. In the bag system there is also the risk of so-called "Drug Dumping", ie the sudden total release of the active substance into the skin due to the destruction of the membrane or the bag. EP 0 235 563 describes e.g. a transdermal therapeutic system or poultice of this kind for the combined application of estrogens and progestins. From US 4 624 665 therapeutic systems or plasters are known which contain the active substance in microencapsulated form in the reservoir. The tank is embedded between a back layer and a membrane. The edge surrounding the poultice is provided with a contact adhesive. The structure and manufacture of these plasters are very complicated since it is necessary to microencapsulate the active substance / a and to distribute it homogeneously to embed it next between the back layer and the membrane. It is also necessary that the plaster has a flange that adheres on the skin and also has to be covered with a protective layer. Matrix systems or matrix plasters are generally composed of a waterproof backing layer for the active substance, away from the skin and an adherent layer in which the active substance is distributed. To protect the adherent layer, it has an anti-adhesive protection sheet that must be removed before application. In DE-OS 20 06 969, e.g. a system of this type in which contraceptive substances are incorporated in the adhesive components or in the adhesive film. From this memory it is deduced that the adhesive film can be an acrylate. In the known systems of bag, tank or matrix or in the plasters, the necessary thickness is disadvantageous, which is conditioned by the manufacturing process and which undesirably harms the flexibility. The flexibility of the system or poultice has a direct effect on its characteristics of use, since the comfort of use increases when the thickness decreases, and is reduced by increasing the thickness. The object of the present invention is to describe a process for the production of a highly flexible poultice, endowed with a desirable wearing comfort, with a dermal or transdermal action, in which a separate back layer is totally renounced and which therefore results more thin and flexible, and that due to the lower complexity in its manufacture gives rise to a cheaper alternative to existing systems.

This problem is solved by a method according to the characteristics of the main claim. Surprisingly it has been seen that these plasters also adhere more safely and for a longer time on the skin thanks to their greater flexibility. Due to its relatively smaller thickness and its greater flexibility, the plaster object of the invention is suitable, unlike conventional systems or plasters, to also apply it permanently in difficult places of the body, e.g. in the area of the ear, in the genital area or in the fingernails of the fingers or toes. A preferred and exemplary embodiment of a plaster object according to the invention has the following structure: It is composed of a support layer, a matrix containing the active substance with a contact adherent part and a surface without contact adhesion, as well as a layer of protection detached. To apply the plaster according to the invention, the protective layer is removed and the plaster is applied by the support layer on the application point in such a way that the face with contact adhesion faces towards the skin, and then the layer is removed of face support that has no contact adhesion.

To eliminate the surface adhesive strength of the layers with contact adhesion, all the methods that modify the structure of the surface can be used, a) by altering the molecular bond of the contact adhesion system on the surface itself 1. modifying the state of aggregation - liquid / crystalline (thermal influence) liquid = crystalline adhesion = non-adherent 2. by crosslinking the parts of the polymer molecule that determine the adhesive strength, chemically by means of crosslinking agents or by means of radiation, b) modifying the structure of the surface by means of additional substances to create a new boundary surface towards the outside, being able to be used as additional substances: 1. Solid particles with a particle size of the order of 0.5 -20 μm, having a spherical or scale shape. Examples which may be mentioned are starch flours or layered silicates such as bentonite or mica. The important thing is the pulverulent configuration of these particles that facilitate their uniform application. 2. Liquid media, which after application a) physically forms a liquid, semi-solid or solid film - (eg silicone oil, greases, aqueous dispersions of acrylate or polymer solutions), b) by cross-linking chemistry form a new boundary surface. The contact adhesion matrix layer may be composed of polymers such as hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, copolymerized 60:40 vinylpyrrolidone-vinylacetate, ethylcellulose, copolymers of the ester of acrylic and methacrylic acid with trimethylammonium methacrylate, copolymerized dimethylaminomethacrylic acid and neutral esters of methacrylic acid, shellac, cellulose acetalphthalate, hydroxypropylmethylcellulose phthalate, polymerized methacrylic acid and esters of methacrylic acid, polymerized 70:30 acrylic acid ethyl ester methacrylic acid methyl ester, copolymerized 50:50 ethacrylic acid methyl acrylic acid ester, gelatin, polyvinylacetate, methacrylate, acrylate dispersions, polyether-polyamide block copolymer, copolymer polyethylene-methylmethacrylate block, polyurethanes, polyester block copolymer, polyisobutylene-styrene-styrene copolymer, styrene-butadiene-styrene-isoprene copolymer, ethylene-vinyl acetate copolymer, polyamide nitrocellulose as well as other lacquer-forming products or known films for technicians containing at least one reactive polymer terminal group. The addition of plasticizers is necessarily given to the extent of the flexibility required for the film. To complete the crosslinking film, other substances can be added or applied, such as: acrylmodified and / or methacrylmodified polysiloxanes with a high content of unipolar methyl groups containing at least one reactive terminal acrylic and / or methacrylic acid group, in addition monofunctional, bifunctional and trifunctional acrylic or methacrylic acid esters. It is also possible to use vinyl or epoxy compounds containing perfluoroalyl or perfluoroalkenyl groups, or epoxypolysiloxanes. Especially suitable for powder additives are SiO 2, zinc stearate, mica, bismuth oxychloride, titanium dioxide, magnesium oxide, talcum, magnesium stearate and other metal salts of acid grades, as well as triglycerides and pigments. of color used especially in decorative c -. In this regard it should be noted that the face away from the skin of the adherent matrix layer containing the active substance can also be deactivated e.g. after its application on the skin by foreign substances in powder applied by the upper face. With regard to the present invention, the term "active substance" means organic and inorganic chemical substances that can leave the elements of the device object of the invention that contain them, thus causing the desired therapeutic or cosmetic effect. Within the fields of application of the plaster object of the invention, human and veterinary medicine as well as the application in plants have special importance. The active substances to be released serve mainly for dermal treatment of local diseases of the skin, for the intradermal and transdermal treatment of diseases as well as for the treatment of wounds or the care of the skin in cosmetic preparations. For the dermal treatment of local skin diseases local anesthetics, local antibiotics, antiseptics, antifungals, antihistamines and anti-irritant drugs, keratolytics and caustic drugs, virustics, antiscabies, spheroids as well as various substances for the treatment of acne, psoriasis, photodermatosis or pre-cancer. Among the active substances having intradermal application are included e.g. spheroidal and non-steroidal anti-rheumatics, local anesthetics, substances that promote blood supply or vasoprotectors and vasoconstrictors for the treatment of vascular diseases as well as active substances that influence subcutaneous fat tissue processes. Among the active substances of transdermal application, e.g. analgesics, antiarrhythmics, narcotics and their antagonists, neuroleptics, hormones or hormone substitutes, antidepressants, tranquilizers, hypnotics, psychostimulants, anti-Parkinson products, ganglioblockers, sympathomimetics, alpha-sympatholytics, beta-sympatholytics, anti-sigmatotonic, anti-asthmatics, antiemetics, appetite reducers, diuretics or active substances for weight loss, etc. The preferred active substances are spheroids such as estradiol, estriol, progesterone, noretistesterone, norethindrone, levonorgestrel and its derivatives as well as ethinodioldiacetate, norgestamate, gestadene, desogestrel, demegestrone, promegestrone testosterone, hydrocortisones and their derivatives; nitroso compounds such as amyl nitrate, nitroglycerin, isosorbidine nitrate; amine compounds such as nicotine, chlorphenylamine, terfenadine and triprolidine; oxicam derivatives such as piroxicam; mucopolysaccharidases such as thiomucases, opioids such as buprenorphine, morphine, fentanyl and their salts, derivatives or analogs, naloxon, codeine, dihydroergotamine, lysergic acid derivatives, pizotiline, salbutamol, terbutalin; prostaglandins such as those of the PGA, PGB, PGE and PGF series, e.g. misoprostol and enprostil, omeprazole, imipramine; benzamides such as metoclopramine and scopolamine; peptides and growth factors such as EGF, TGF, PDGF etc .; somatoestatin; clonidine, dihydropyridines such as nifedipine, nitrendipine, verapamil, diltiazem, ephedrine, propanolol, metoprolol, spironolactone; thiazides such as hydrochloric thiazide and flunarizine. For the treatment of wounds hemosesthetic substances and substances for cleaning wounds are used as e.g. Enimes, antiseptics, disinfectants and antibiotics, analgesic products and anesthetic materials as well as active substances that facilitate the healing of wounds to excite granulation, to induce the formation of vessels or to promote epithelization. On the other hand, the plaster can also be used for the treatment of wounds for the release of estradiol, also on chronic wounds, e.g. ulcer cruris. In a preferred embodiment for interdental application of active substances, the contact adherent layer contains a eutectic mixture of local anesthetic, lidocaine and prilocaine. By this mixture of active substances can be achieved, both in the case of prior intradermal analgesia e.g. to vein punctures as well as in the treatment of rheumatoid arthritis, an effect that can not be achieved with the active substances and combination of active substances commonly used, from the group of topical anesthetics. In another preferred embodiment of the poultice of the invention, the film layer contains plant preparations such as e.g. extracts or tinctures. These can be used for the treatment of local skin diseases, such as e.g. oak bark extract, walnut bark extract, arnica flower tincture, hammamelis bark extract, carmel extract, pansy extract, thyme extract or sage extract for treatment of damaged or damaged skin, such as e.g. hypericone tincture, tincture of rudbeckia lacinata, extract of camomile flowers or tincture of calendula flowers as well as for the care of married and damaged skin, such as e.g. extract of birch leaves, nettle extract, custard extract, symphitum officinalis tincture, horsetail extract or aloe vera extract. The plant preparations can also be released from the film layer for the intradermal treatment of diseases, such as e.g. the extracts of horse chestnut and rusco for veins disease, or the extracts and tinctures of arnica, calendula and capsicu for contusions, dislocations or bruises. The plant preparations in the system object of the invention can also be used for transdermal therapy, thus e.g. Ginsen extract in senile ailments, tincture of valerian, melissa extract and hops to calm in case of overexcitation, sleep and stress alterations, cola and tea extracts to achieve a stimulating effect or hawthorn extract to stabilize circulation . Another special form of execution refers to the use of the plaster object of the invention as a support for narcotics, psychotropic drugs and products for the treatment of Alzheimer's disease and senile dementia. These powerful medicines require a system that has guaranteed support characteristics over several days. The following example serves to clarify the manufacture of a poultice according to the invention. The solution of a contact adhesive mass containing the active substance, Composed of Active substance 5.0 g Methacrylic acid copolymer 5.0 g Dimethyl phthalate 0.25 g Ethyl acetate 79.75 g Spreads on a 100 μm thick siliconized polyester sheet (protective layer) and dries at about 80 ° C. After the drying process, the laminate that has been obtained passes through a spray tunnel where magnesium stearate powder is sprayed onto the surface of the adhesive layer by contact (matrix). Magnesium stearate powder that is not adhered to the surface of the matrix layer is removed by a polishing cylinder. The surface of the matrix that has undergone this treatment is covered with a sheet of polyester silica gel 30 μm thick (support layer). From the laminate thus obtained composed of the protective layer, the polymer matrix sprayed with powder and the support layer are punched out by activating transdermal therapeutic plasters using known methods.

It is noted that in relation to this date, the best method known by the applicant to date, the best method known by the applicant to implement the aforementioned invention, from the manufacture of the objects to which it is intended. ref was. Having described the invention as above, the content of the following is claimed as property.

Claims (13)

R E I V I N D I C A C I O N S

1. A system containing a compound in the form of a patch formed of a layer of pressure-sensitive adhesive matrix, for controlling the release of the active compound via a removable protective layer, characterized in that on the lateral side away from the contact surface it is It gives a non-adhesive treatment.

2. A system containing a compound according to claim 1, characterized by a removable support layer that is far from the side face.

3. A system containing a compound according to claim 1 or 2, characterized by a high flexibility due to a correspondingly small thickness of the matrix layer.

4. A process for producing a system containing an active compound according to any one of claims 1-3, characterized in that the non-adhesive treatment is carried out by a chemical reaction.

5. A process according to claim 4, characterized in that the non-adhesive treatment is carried out by application of at least one foreign substance.

6. A method according to claim 4 or 5, characterized in that the chemical reaction is carried out with the aid of a radiation-induced crosslinking agent.

7. Process according to claim 5 or 6, characterized in that an extraneous substance of powdery consistency is applied.

8. Process according to claim 4 or 5, characterized in that the non-adhesive treatment is carried out by a treatment with a foreign substance of liquid consistency.

9. Process according to claim 8, characterized in that a film-forming substrate is used as the foreign substance of liquid consistency.

10. Process according to one or more of claims 4 to 9, characterized in that the foreign substance is applied by a printing process.

11. Process according to one or more of claims 4 to 10, characterized in that the foreign substance applied is exposed to irradiation with electrons. Process according to one or more of claims 4 to 11, characterized in that the methacrylic modified polysiloxane, such as the foreign substance, with a weight per unit area of 1 to 5, and preferably 2 g / m2 is applied to the face of the surface away from the contact surface, after which it is irradiated with electrons. 13. Process according to claim 12, characterized in that the irradiation is carried out completely with an acceleration voltage of 150 to 250 keV at a radiation dose of 2 Mrd.