HRP930667A2 - Process for the production of top therapeutic system containing antineoplastic active substance, particularly 5-fluorouracil - Google Patents

Description

The technical field to which the invention belongs

The invention belongs to the field of current life needs, secondarily to the field of chemistry, and specifically relates to the creation of a system for the surface application of drugs, that is, a pharmaceutical form for the surface administration of a drug.

Technical problem

The technical problem is how to obtain a system for surface administration of the drug, which is achieved by making a matrix based on polymeric acrylates into which the active substance is mixed and the matrix is placed between two layers of polymeric materials, one of which is self-adhesive, and the other serves as a protective layer, which achieves a uniform release of the drug at the site of application.

State of the art

Cytostatic and/or cytotoxic active substances play a role in medical therapy, where it is a matter of regulating interventions in excessive cell growth. They have therefore found their greatest application in the therapy of malignant tumors.

But locally applied, they are also used for the treatment of threatening diseases such as psoriasis, warts of viral origin, keratosis, Bowen's disease and basal cell carcinoma close to the surface. In doing so, the high local concentrations of the active substance required for successful therapy are achieved, without having to take into account the side effects that occur during systemic chemotherapy of malignant tumors, which can force the discontinuation of therapy and very rarely have also led to deaths. Ointments containing 5-fluoroutacil as an active ingredient (Effudix and Effluderm, both from Hoffman La Roche AG) are commercially available for local use.

5-Fluorouracil is one of the so-called antimetabolites and is especially an antimetabolite of pyramidine.

Clinical experiences with this active substance as a local cytostatic have existed for approx. 25 years. It is valued especially for its medical and cosmetic results (Goette, D.K., J.AM.ACD. DERMATOL : 4 : 633 - 649 1981 ).

But receiving it in the form of an ointment has the disadvantage that it is difficult, if not impossible, to supply certain areas of the skin during the entire duration of the treatment, which can extend over several weeks, on the one hand, with a sufficient, but on the other hand, not an overdose amount of active substances. This shortcoming has also already been noted and has led to the application system described in US-PS 3,734,097. which consists 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 active substances and excipients and on the other side, with a removable film that has the same properties, but which is additionally removed before use can remove.

For the same background, one should look at US-PS 3,769,071. in which semi-urethanes are used as an inert carrier material for the active substance 5-fluorouracil.

Description of the solution to the technical problem with implementation examples and a list and brief description of the blueprint image

The invention relates to a process for producing a surface therapeutic system with an antineoplastic active substance, especially 5-fluorouracil. The task of this invention so far has been to develop a system on this basis, which has all the advantages of the previous formulations, additionally has an improvement and is confirmed in practical tests. In the course of treatment with cytostatically and cytotoxicly active substances, cells with increased dividing activity gradually become stronger and more damaging than cells that divide normally. It is desirable, and a necessary result for successful treatment, that an increased death of actively dividing cells occurs in the area of application. This increased cell death is accompanied by inflammatory processes, which are again related to the secretion of wound secretions. This increased secretion of wound secretions makes it difficult now to maintain certain areas of the skin for a long time under occlusion conditions, without the system losing its adhesion to the skin. The solution to this problem, as the prediction of the dropped self-adhesive edge of the system containing the part with the active substance, should not be considered as optimal, since they increase the total surface of the system and therefore make it difficult to apply, especially in the face area. In a surprising way, it has now been discovered that this task can be solved by making the polymer carrier of the active substance preferably polar and adding an additional so-called lead absorber.

The subject of the invention is therefore a process for the production of a surface therapeutic dressing, which consists of an impermeable back layer, a matrix that contains the active substance and a removable protective layer, which is characterized by the fact that the following components of the matrix

a. antineoplastic active substance

b. self-adhesive polyacrylate

c. water absorber

and in the given case

d. hydrophilic polyacrylate that does not stick

e. softener and/or penetration accelerator

homogeneously mixed, in the given case by dissolving in the solution, the homogeneous mixture is applied to the impermeable last layer, in the given case the solvent is removed and after that the matrix layer is covered with a protective layer.

Polyacrylate is used as a relatively polar self-adhesive base polymer, since this class of glue has found multiple application possibilities in the medical field and is known to be well tolerated by the skin. Duretak 280-2516 polyacrylate adhesive from National Starch proved to be particularly suitable.

Early polyacrylates that do not stick are those that have a certain content of the following free polar groups: hydroxy groups, carboxyl groups, amino groups, quaternary amenium groups, etc.

For this purpose, they can be well used, for example. polyacrylates of the Eudragit range of the company Rohm-Pharma, since they have found wide application in tableting technology and can be considered as physiologically safe. Eudragit RL 100, which can be chemically characterized as a polymer of esters of acrylic acid and methacrylic acid with a certain content of quaternary ammonium groups, is particularly well suited. It is characterized by the fact that it swells to a large extent independent of the pH value and thus already supports the absorption of moisture in the system.

In addition, some softening effect of additional auxiliary substances such as 1,2-propanediol is compensated. As water absorbers, a large number of products based on natural and synthetic polymers are offered on the market. Water absorbers based on slightly cross-linked, previously neutralized polyacrylic acids have proven to be suitable. The best results are achieved with the Aquakeep 10 SH product from Seitetsu Kagaku. Based on their cross-linking, such water absorbers naturally do not dissolve homogeneously in the matrix of the patch, and in the required amount, they do not have a negative effect on the cohesion and adhesive force of the matrix.

The last layer can consist of flexible or non-flexible material and be equipped with one or two layers. The substance that can be used for their production are polymeric substances, such as e.g. polyethylene, polypropylene, polyvinyl chloride, polyethylene terephthalate and polyamide. As further materials, metal foils, such as aluminum foils, alone or coated with a layer of polymer coating, can also be used. The design that is assumed is a 10 μ thick polyethylene terephthalate film, which is coated with aluminum in the middle of the matrix and after application is painted on the outside with the color of the skin.

The removable protective layer, which is in contact with the self-adhesive matsix and is removed before application, consists for example of the same materials as those used for the production of the last layer, assuming that they are made removable, such as e.g. silicone treatment. Other removable protective layers are e.g. from tetrafluoroethylene, treated paper, cellophane, etc.

The system according to the present invention is shown in Figure 1 in section. Figure 2 shows the increase in water uptake of acrylate glue with the addition of Eudragit RL 100 and Aquakeep 10 SH. Curve 1 shows the practical negligible water uptake of pure acrylate glue.

Curve 2 a slight increase with the addition of Eudragit RL 100 and curve 3 a dramatic increase with the addition of Aquakeep 10 SH.

Curve 3 is basically the following formulation of the matrix that is obtained after removing the solvent, which also proved to be very active in the clinical trial:

7910 g of polyacrylate glue (Durotak 280-2516, National Starch)

1980 g of copolymer from acrylic and methacrylic acid esters with a certain content of quaternary ammonium groups (Eudragit RL 100 from Rohm-Pharma)

500 g of water absorber based on quaternary neutralized polyacrylic acid (Aquakeep 10 SH, company Seitetsu Kagaku)

1040 g of 1,2-propanediol

85 g of 5-fluorouracil

Surface mass: 115 g/m2.

Curves 2 and 1 basically have the same formula and the same surface mass, certainly without Aquakeep 10 SH or without Aquakeep 10 SH and Eudragit RL 100.

Measurements were performed at 32oC with demineralized water and water absorption determined gravimetrically.

Figure 3 shows the in-vitro release of the sample based on the above formulation. The content of the active substance is 85 μg/cm2. The release curve shows the flow typical of matrix systems. The release was carried out using a "Rotating Bottle" device at 32°C with the use of a physiological solution of table salt as a release medium, and the concentration of the active substance was measured photometrically in the sample solutions.

With systems of the same matrix formulation, circular geometry and size of 1.13 cm2, clinical trials were performed on 8 patients with an indication of actinic keratosis, and in all cases, after the application of 6-7 systems, the success of the therapy could be noted. The system was changed every 2 to 3 days.

Figure 4 shows the absorption of 5-fluorouracil from the system, as determined by determining the remainder of the active substance in the worn systems.

On average (calculated from a trial of 8 patients and 6 systems per patient) 69.5% or. 63.8 μg rubbed 91.8 μg of 5-fluorouracil in the body of the system wear time of 2 or 3 days. This corresponds to an average absorption of approximately 30 μg of 5-fluorouracil per patient, day, and system. With this extraordinarily low absorption of the active substance, systemic side effects should be ruled out with certainty.

Let the advantages of the invention be summarized once again below:

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

b. short duration of treatment

c. the active substance is strictly limited to being applied only to the surface to be treated

d. high water absorption capacity of the system

e. phototoxic reactions are prevented by occluding conditions

f. good cosmetic results

g. significant improvement in the patient's compliance with the necessary application only every 2-3 days of the new system (ointment 2x a day)

Example

Manufacturing process for approximately 100 m2 of 5-fluorouracil surface therapy system.

4.352 g of a 40% (w/w) solution of acrylic and methacrylic acid ester copolymer with a certain content of quaternary ammonium groups (Eudragit RL 100, Rohm Pharma) in methyl ethyl ketone is added with stirring to 16.697 g of 42% (g/w) g) solution of polyacrylate glue (Durotak 280-2516, National Starch company), 436 g of water absorber based on quaternary neutralizing polyacrylic acid (Aquakeep 10 SH, solution of 75 g of 5-fluorouracil in 2,753 g of 1,2-propanediol).

This mass is spread on l00 in a thick aluminized and siliconized polyester film, so that after removing the solvent, a film with a surface mass of 115 g/m2 is obtained. This film is covered with a 10 μ thick polyester film and tied and cut into pieces of the desired size.

Claims (5)

1. Surface therapeutic system consisting of an impermeable back layer, a matrix with an active substance and a protective layer that can be removed, characterized by the fact that the matrix contains: a. 0.2 - 5%, preferably 0.3 - 1%, and particularly preferably 0.6 - 0.9% of the antineoplastic active substance b. at least 50%, preferably 65 to 75% of a polar polymer carrier of the active substance and in the form of self-adhesive polyacrylate. c. 1 to 15%, preference 1 to 10%, and a particular preference 4 to 5% absorbent-water added to the active substance, based on cross-linked, previously neutralized polyacrylic acids, and in case d. 0 to 48.8%, preference 10 to 35%, and a particular preference 15 to 25% of non-sticky hydrophilic polyacrylate, based on a copolymer of acrylic and methacrylic acid esters with the content of quaternary ammonia groups e. 0 to 20%, preferably 5 to 15%, and particularly preferably 5 to 10% of some softener or penetration accelerator 2. Surface therapeutic system according to claim 1, characterized in that the antineoplastic active substance is 5-fluorouracil. 3. Surface therapeutic system according to one of claims 1 or 2, characterized in that the softener or penetration accelerator is 1,2-propanediol. 4. The surface therapeutic system according to one of claims 1 to 3, indicated by circular geometry and a diameter of 0.5 to 3 cm, preferably 1 to 2 cm, and particularly preferably 1 to 1.2 cm. 5. Surface therapeutic system according to one of claims 1 to 3, characterized in that it is rectangular and has an area of 1 to 200 cm2, preferably 1 to 50, and particularly preferably 2 to 20 cm2 cm2