SI9010033A - Process for preparing of a superficial therapeutic system containing antineoplastic agent, particularly 5-fluoro uracil - Google Patents

Abstract

The invention refers to the procedure for the production of the superficial therapeutic system which consists of an impermeable back layer, a matrix that contains the active substance and of a re-detachable protective layer. It is marked in the way that the following components of the matrix a. antineoplastic active substance, b. self-adhesive polyacrylate, c. water absorber and possibly d. non-adhesive hydrophile polyacrylate, e. softener and/or accelerator of the penetration are homogeneously mixed, possibly with dissolving in a solvent. The homogeneous mixture is applied to the impermeable back layer, the solvent is possibly removed and then the layer of the matrix is covered with the protective layer.

Description

PROCEDURE FOR MAKING A SURFACE THERAPY SYSTEM WITH THE CONTENT OF ANTINEOPLASTIC ACTIVE MATERIAL, ESPECIALLY 5-FLUORURACIL

FIELD OF THE INVENTION

The invention belongs to the field of liquid necessities, secondary to the field of chemistry, and specifically relates to the development of a system for the surface administration of drugs, ie. of the pharmaceutical form for topical administration. The indications according to MPK are A 61 L 15/44, A 61 K 31 / 5o5, A 61 K 15/16 and A .61 K 9 / 7o.

Technical problem

The technical problem is how to get a system for surface drug delivery, which is achieved by making a matrix based on polymer acrylates in which the active substance is mixed and the matrix is placed between two layers of polymeric materials, one of which is resinous and the other serves as a protective layer, thereby achieving delivering the drug evenly at the point of administration.

The state of the art

Cytostatic and / or cytotoxically active substances in medical therapy play a role, in the case of thorne, in regulating interventions in the overgrowth of the cell. Therefore, they are the most widely used in the treatment of melignant tumors.

But topically, they are also used to treat threatening diseases such as psoriasis, warts of viral origin, karatosis, Morbus Bowen, and near-surface basaliomen. Successful therapy requires high local concentrations of the active substance without having to take into account the side effects resulting from the systematic chemotherapy of malignant tumors that can

- 2 doses * discontinuation of therapy and, rarely, also leading to fatalities · Zg local use in commerce can be swept, which as 5-fluorutscil (Ef £ udix and Effluderm, both by HS $ fmann Le Roche) AG).

5-Fluorourecil is a part of liquid entimetsbolites and is specifically the antimetabolite of pyrimidine ·

Clinical experience with this scrotal metric keo local cytostatics is already appreciated. 25 years. It is appreciated especially for its medical and cosmetic results (Goette, D.K », J.AM.AGAD.DERMATOL: 4: 655 649 1981).

But applications in the form of sweep the name of the disadvantage, which is difficult, if not impossible, that certain areas of the skin for the entire duration of treatment, which can extend over several weeks supply, on the one hand enough, or on the other hand not overdose active substances »

This drawback has also been noted and has led to the application system described in US-PS 5,734,097 * consisting of a self-adhesive, flat surface of the formulation containing the active substance, which is provided on one side with an impermeable carrier film for the active substances and excipients. on the other hand, with a removable foil having the same properties8,8li which can be removed before use.

Due to the same background, US-PS 5,789,071 should be viewed, in which the polyurethanes are taken k80 inert carrier material for the ective 5-fluorine ...... uracil .............. ..... .. — .....- ........................ ..........- Description Solving a technical problem is exemplified Performing both a listing and a brief description of the image plans

Pronelezsk does not relate, however, beyond the superficial terpia system with 8ntineopl88tive tertiary metrics, not readily 5-fluoroureciloo: in practical terms ·

During treatment with cytostatically and cytotoxically active substances, cells with enhanced® activity of division divide the gradual barrier from normally dividing cells. It is desirable, and this successful treatment, the result required, that in the field of application, an increased extinction of the divisible cells is achieved. This increased cell death is accompanied by seductive processes, which are again associated with the secretion of the wound secretion. · This increased secretion of the wound secretion makes it difficult now to maintain a certain area of the skin for a longer period of time under occlusion conditions, without the system losing its adhesion to the skin. This problem, as a prediction of the leaked self-adhesive edge of the system containing the active ingredient part, should not be deployed as optimal, since they increase the total surface area of the system and therefore make it difficult to apply especially in the area of linden.

In a surprising way, it has now been discovered that this task can be solved by making the polymeric carrier of the active substance polar and by adding an additional so-called " water absorber "

The object of the invention is to provide a process for making a surface terepitic system, consisting of an impermeable backing layer, a metric containing an active metric, and a re-separable protective layer ©, characterized in that the following components of the matrix

e. antineoplastic active substances b · Shell-stick polysacrylate c · Water absorber, _________ _______________________ ___________ and in the case of d, non-adhesive hydrophilic polyacrylate,

e. omekšiveč and / or ubrziveč penetration homogeneous izmešaju u detom case rsstveranjem u restvaraču, the homogeneous mixture is applied to nepropusni last layer in dstom case removed rastvareČ and operations rigid the layer of the matrix covers the zestitnim layer · _ι Keo re & etivno polerni semolepljivi base polymer primenjuje the poliekrilet , since these adhesive pliers in the medical area did not have multiple application possibilities and a larger keel was well tolerated to the skin. Keo undeniably suitable was the semi-skeletal adhesive Durotek 280-2516 by Netionel Sterch.

Non-stick keo pore polyacrylates, which have certain contents of the following free half-sniffs: hydroxy, carboxyl, emino, quaternary emmonium, etc. #

For this purpose, it is not feasible to apply, for example, the RShm-Pherme polyurethanes of Eudregit, as they have been widely used in tabletting technology and can be considered physiologically indisputable. The chemical marking of Eudregit RL 100 is extremely good. k80 copolymer of acrylic acid and methacrylic acid ester s8 with a certain content of quaternary emmonium groups keo not pr · 1,2-propendiol ·

Water absorbers are offered to the market for a large number of products of fae escapes of natural and synthetic polymers, Κθ ₀ suitable ebsorbers of water do not escape non-crosslinked, previously neutralized polyacrylic acids. The best results are achieved with the product of Aquekeep 10 SH, by Seitetsu Kegeku. On the basis of their transverse networking, the liquid absorbers are usually not homogeneously restrained in the metrixflesters, but they do not have the necessary cohesion and adhesive bonding of the metric in the required amount.

The backing layer may consist of a radiant or non-volatile meter and be fitted with one or two layers. Substances that can be used for their manufacture are polymeric substances, k80 not e.g. polyethylene, polypropylene, polyvinyl chloride, polyethylene terephtelet and polyemide. Even metal foils, such as aluminum foils, sealed or coated layers of polymer coating, can also be used. The prefabricated embodiment is 10 in thick polyethylene terephthalate foil, which is coated with aluminum on the bar metrics and after application to the outside side, the colored side is colored with skin®.

The detachable protective layer, which is in contact with the saraole-adhesive compound and is removed prior to application, consists, for example, of the same materials as they are used to make the backing layer, presumably rendered detachable, e.g., silicone® rite. Other cdopable protective layers are, for example, of tetrafluoroethylene " paper " cellophane and the like.

The system of the present invention shows a cross-sectional view of figure 1, a click 2 shows an increase in the water intake of the acrylic adhesive by the addition of Eudragit-RL 100 and Aquakeep-10 SH. curve 1 shows practically negligible water intake of the purity of the acrylate adhesive, Knive 2 a slight increase in the additives® Eudragit-e RL 100 and curve 5 a grammatical increase with the inflow of Aquakeep 10 SH. _v

Curve 5 is basically the following formulation of metrics, which is obtained after solvent removal, which has also been shown to be well activated in the clinical trial:?:

7910 g of shelves; il-: glue (Durotek 280-2pl6, from National Sterch) 1980 g of copolymers from acrylic and methacrylic esters; saliva with certain quaternary ammonium® group holders (Eudregit aL 100, Rohra-Lherra ?!)

500 g Quaternary Neutralized Pc Acrylic Acid Water Absorber (Aauakeep 10 OH, Oeitetsu Kagi)

1040 g of 1,2-propanediol 85 g of 5-fluorourecils p

; ovr; Inner masses: 11.5 g / ® '.

r-ivoj 2 and 1 is basically the same formulation and same vegetable? asa all- about Apue'-cQ: .- a 10 .Rl resp. without AO.uekuep IG :, Ιϊ i ... vdv cit-e RL

10 (the ver sions were performed ηε 32 ° G were demineroized with water and absorbed with <

of water determined gravimetrically.

As in Example 3, the in vitro release of the samples on the anger formulation was assumed to be 85 mg tg / cra. The false curves indicate the flow of keck is typical of matrix systems.

The release was performed with the help of a Rotsting Bottle at 32 ° C using saline as the middle of the freezer, and the concentration of the active meter was measured photoroetrically to form samples.

Ka sistGmims of the same metric formulation, bread geometry and p size

1,13 cm 'clinical trials were performed on 8 patients with ectinic kerstosis index and in all cases after the application of 6 »7 systems the success of the therapy could be recorded. Changes to the system took place for 2 to 3 days.

No Fig. 4 shows the absorption of 5-fluorourecils from the system, as it is delineated by the remnants of the active meter in the wearing systems.

on average (calculated from the trial of not 8 psiets and 6 systems per patient) absorbed 69.5% or. 65.8 ₍ ug crushed 91.8 pg of 5-fluorourecile during the course of wearing the 2 or 3 day system. This corresponds to the average absorbance of prifcl · 56 ΡΓ w -fluorourecile per ci. T ntu, cr nu ή system. as a matter of urgency, the order of the effective meter should be secured with the exception of systematic secondary migration.

-Eke once more niche ·· recapitulate the particular advantages of the invention:

a. safe therapeutic action with minimal absorption of the active substance

b. short shaking treatment

c. active meters are sharply attached to the surface of the cell to be treated

d. high capacity water absorption today

e. phototoxic reactions are prevented by the conditions

f. good cosmetic results

Mr Rücker significantly improved the patient experience with the required administration only every 2-5 days of the new system (sweep 2 x daily).

Example

The procedure is for nribl. 100 nf 5-fluorourecil poizr: 'in ;. whom therapeutic; systems

4,552 g of a 40% (g / gjf) solution of the copolymer ester of acrylic and methacrylic acid ester is quenched by the content of quaternary ammonium groups (Eudragit RL 100, Rohm P ^ arsa) in methylethyl ketone added with stirring at 16,697.8 g £ 2% Of (g / g) solution of polyacrylate adhesive & Durotek 280-2516, from National Starch), 456 g of water-based sorption based on quaternary neutralized pgliskrylic acid (j $ quakeep 10 SH, by Seitetsu Kegeku, particle size «w = 125 ^ um ) and finally added a solution of 75 g of 5-fluorouracil in 2.755 g of 1,2-propendiol.

This mass is not greased with 100 p thick aluminum and siliconized polyester film, but after removal of the solvent, a surface mass of about 115 g / m is obtained. · This film is covered by t

with 10 fl thick polyester foil and cut and cut into desired size pieces.

A Citation on the Best Way to Economically Use a Found Find

The best way to commercially use the claimed invention, which was known to the applicant at the time of filing this patent application, is by way of the description, and in the example, and of the construction as shown in the drawings.

Claims (6)

PATENT APPLICATIONS A method for producing a surface therapeutic system comprising an antineoplastic active substance, in particular 5-fluoruracil, consisting of an impermeable backing layer, an active matrix-containing material and a re-removable protective layer, characterized in that the matrix components such as the antineoplastic active substance are polyacrylate, aqueous absorber, non-adhesive hydrophilic polyacrylate and softener and / or penetration enhancer dissolve in the solvent and stir homogeneously, homogeneous mixture is applied to the impermeable layer to remove the solvent and a protective layer is applied to the matrix. The method of claim 1, wherein the antineoplastic active substance is 5-fluorouracil. The method according to claim 1 or 2, characterized in that the matrix consists of at least 50%, preferably 65-75% self-adhesive polyacrylate, 0-48.8, preferably 0-35%, and particularly preferably 15-25% of non-adhesive hydrophilic polyacrylate, 0-20%, preferably 5-15%, and especially preferably 5-10% of plasticizer or penetration enhancer, 1-15%, preferably 1-10%, and particularly preferably 4-5% of the aqueous absorber and 0.2-5%, preferably 0.3-1% and especially preferably 0.6-0.9% of 5-fluorouracil. Process according to one of Claims 1 or 2, characterized in that it is a plasticizer or a plasticizer. 1,2-propanediol penetration enhancer. Method according to one of Claims 1 or 2, characterized in that the system is cut into pieces of circular shape 0.5 - 3 cm in diameter, preferably 1 - 2 cm, especially preferably 1 -1.2 cm, by applying the re-removable protective layer. Method according to one of Claims 1 or 2, characterized in that the system is cut into pieces of rectangular surface of 1 - 200 cm ³ , preferably 1 - 50 cm ³ , especially preferably 2 - 20 cm ³ , by applying a protective film.