CS265492B1 - Polymeric medicine with cytostatic effect and method of production thereof - Google Patents

Abstract

The solution relates to polymeric drug preparation with protracted cytostatic effect. Polymerni drug with protracted cytostatic the effect consists of a low molecular weight cytostatics such as methotrexate encapsulated or immobilized on a polyoxypropylene glycol-based polyurethane support o mol. weight 1 500 to 2,000 and mixtures of isomers 2,4 and 2,6-toluene diisocyanate (35:65%) in molar ratio 3: 1. The way it is produced lies in that is a prepolymer consisting of polyoxypropylene glycol o mol. weight 1,500 up to 2000 and toluene diisocyanate is heated with a cytostatic, such as methotrexate, at 30-40 ° C in the presence distilled water and 2,4,6-tris- (dimethylaminomethyl) phenol as accelerators.

Description

The invention relates to a polymeric medicinal product with a protracted cytostatic effect and to a process for its preparation.

In medicine, biologically (pharmacologically) active compounds immobilized on a polymeric carrier find increasing use.

Methods are known for immobilizing biologically active compounds by synthesizing their water-insoluble derivatives to prolong the biological effect or to obtain a local effect of the compounds. Thus, polyurethane compositions containing proteolytic ferment (AO USSR No. 1 036 027) and antibiotic (AO USSR No. 1 005 431) were prepared.

Although biologically active compounds are widely used as cytostatics, methods of immobilizing them on polyurethane carriers are not known.

It is an object of the present invention to provide water-insoluble derivatives of a cytostatic immobilized on a polymeric carrier which, inter alia, exhibit therapeutic properties in relation to brain glioblastoma. These polymers can achieve widespread use in experimental biology and medicine (neurosurgery) by creating a high drug concentration immediately in the tumor zone, thereby enabling a massive local cytostatic effect to be achieved.

Methotrexate, a structural analogue and a folic acid antagonist, can preferably be used as a cytostatic agent. The effect of methotrexate inhibits the activity of the folate reductase enzyme and disrupts the conversion of folic acid to tetrahydrofolic acid, which is involved in purine exchange and cell reproduction. (Formula I shows folic acid, Formula II methotrexate).

Methotrexate is widely used in neurosurgery to treat glioblastoma. However, in order to achieve an antitumor effect, it is necessary to introduce it intravenously in a considerable amount since the blood-encephalic barrier makes it very difficult to transport the cytostatic to the site of the malignant formation. This causes a number of severe complications when using the drug. (Progression in Experimental Tumor Research, Vol. 27-28, Brain Tumor Biology, Brain Tumor Therapy, Carger, 1984).

The method of complex therapy of malignant CNS tumors includes the most radical surgery depending on the tumor localization, peroperative local and general chemotherapy, postoperative chemotherapy, immunotherapy and radiation if possible. For peroperative topical chemotherapy, Methotrexate (MTX) was first applied to the resection cavity in a gelaspone coil. However, this method has the disadvantage of a relatively rapid disappearance of MTX from the site of administration. We were therefore looking for the possibility of binding MTX to the organism harmless substance, which would gradually release the cytostatic and thus ensure its sufficient concentration in the resection area for at least two doubling phases.

We have found that a polyurethane carrier in the structure of which the cytostatic is both chemically bound and as a filler can be used to prepare a formulation with a sustained and protracted cytostatic effect.

SUMMARY OF THE INVENTION The present invention provides a polymeric drug with a protracted cytostatic effect, consisting of a low molecular weight cytostatic, e.g. weight of 1,500 to 2,000; and a mixture of 2,4 and 2,6-toluene diisocyanate (35:65%) isomers in a 3: 1 molar ratio.

The process for the preparation of the polymeric medicinal product according to the invention is characterized in that it is a prepolymer consisting of polyoxypropylene glycol with a mole percent. weight of 1,500 to 2,000 and toluene diisocyanate is heated with a cytostatic such as methotrexate to a temperature of 30-40 ° C in the presence of distilled water and 2,4,6-tris (dimethylaminomethyl) phenol as an accelerator.

The polymer composition according to the invention can be used in various forms depending on the type of application.

In the polymerized state it has a consistency of harder rubber, does not form sharp edges, which is particularly advantageous for neurosurgery. It breaks down in the tissue through fermentative hydrolysis and cellular activity, and grows through fibrosis tissue. An important factor is that there is no accumulation of degradation products of the body's polyurethane - these products are, moreover, not toxic. It does not aggressively affect neurons or blood vessels. Another advantage is the autosterility and haemostasis ability.

The invention is further illustrated by the following examples without being limited thereto.

In the examples, a prepolymer consisting of 15 wt. parts by weight of polyoxypropylene glycol of 1 500 and 5 wt. % of toluene diisocyanate (35:65% mixture of 2,4 and 2,6 isomer).

Example 1 a d 1 to 6

Place the prepolymer portion in the glass vial to which methotrexate dissolved in a minimum amount of distilled water is added. The mixture was stirred vigorously for 10 minutes at 30-40 ° C.

Then 2,4,6-tris (dimethylaminomethyl) phenol (UP 606/2) was added to the reaction mixture, stirred for 1 minute and poured onto a Teflon pad. After solidification, the polyurethane is dried at 70 ° C and a pressure of 1 to 2 mm Hg to constant weight.

The extracts are summarized in Table 1

Tabulkal

Weight (g)

Examples Methotrexate Water 2,4,6-tris (dimethylaminomethyl) phenol) Předpolyme: 1 0.1 0.1 0.2 10.0 2 0.2 0.2 0.2 10.0 3 0.3 0.3 0.2 10.0 4 0.5 0.5 0.2 10.0 5 0.7 0.7 0.2 10.0 6 - 0.7 0.2 10.0

Example 7

Preparation of polyurethane as a material for endoprostheses

10 g of prepolymer are placed in a glass vial and 0.2 g of methotrexate dissolved in 0.2 ml of distilled water is added. The reaction mixture was stirred vigorously at 30 ° C for 10 minutes. Then 0.2 ml of 2,4,6-tris (dimethylaminoethyl) phenol is added, the mixture is stirred for 1 minute and poured onto polished teflon. Curing takes 3 hours. The polyurethane is obtained in the form of a sponge-like light yellow mass.

Example 8

Preparation of polyurethane as a filling material for filling pathological cavities.

10 g of freshly prepared prepolymer are placed in a glass vial, the prepolymer is dried for 2 hours at 20-30 ° C and a pressure of 1.33-2.66 Pa, after which the vial is sealed.

0.2 g of methotrexate is dissolved in 0.2 ml of distilled water and treated with 0.5 ml of 2,4,6-tris (dimethylaminomethyl) phenol. The mixture is placed in a glass vial, which is then sealed.

Before use, both ampoules are opened and the contents are poured into a syringe fitted with a catheter at the end. The reaction mixture is stirred in a syringe and a plunger is introduced into the syringe. The catheter is introduced into a cavity from which exudate has been removed, if present, and the reaction mixture is then poured into the cavity. The required amount of reaction mixture to be introduced into the cavity for hermetization is determined by the particular conditions. The solidification rate of the reaction mixture in the present example is 3 to 5 minutes, due to the considerable moisture content of the body's tissues.

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Example9 *

AND

Preparation of polyurethane as a medical adhesive!

10 g of freshly prepared prepolymer are placed in a glass vial, the prepolymer is dried for 2 hours at 20-30 ° C and a pressure of 1.33-2.66 Pa, after which the ampoules are sealed.

Methotrexate 0.2 is dissolved in 0.2 ml distilled water and treated with 0.5 ml 2,4,6-tris (dimethylaminomethyl) phenol. The mixture is sealed into glass ampoules.

If necessary, the ampoules are opened and the contents are poured into a glass container. The contents of the two ampoules are combined, mixed with the glass rod for 1 to 2 minutes, and then applied to the surface of the tissues to be stuck together. The surfaces are pressed together and left pressed for 3 to 5 minutes.

Example 10

Monitoring of polyurethanes with respect to methotrexate elution rate

Tracking method

In vitro comparative experiments were performed to determine the release rate of the cytostatic from polyurethane. Methotrexate concentration was determined by ultraviolet spectrophotometric method based on the relationship between absorbance and concentration

A = .c.d where A is the absorbance specif specific absorbency (extinction coefficient) d thickness of the measured layer (cuvette).

The absorbance values of variously concentrated methotrexate solutions were determined from the maximum height at 310 nm ( ^and 31q), from which the absorbance at 500 nm was subtracted.

In these experiments, the release rate of methotrexate from polyurethane (curve IV) was compared with three different pole structures (2-hydroxyethyl methacrylate) (curves I, II, III). the results are shown in Fig. 1.

Figure 2 shows the release rate of the cytostatic from the surface of the polymer 2 over time (Q = mg / cm). Again, polyurethane and three different pole structures (2-hydroxyethyl methacrylate) (HEMA) were used in the experiments.

Curve 1 - 80 % HEMA + solvent + MTX Curve 2 - 50 % HEMA + solvent + MTX Curve 3 - 70 % HEMA + solvent + MTX (sponge)

Curve 4 - polyurethane

Example 11

Cytostatic release rate from the preparation: Methotrexate content in cerebrospinal fluid t

A spectrophotometric method was also used to determine the cytostatic release from the seal in in vivo experiments. 8% trichloroacetic acid was used to remove the protein component from the cerebrospinal fluid, followed by centrifugation. The resulting clear solution above the precipitate was aspirated and measured at 500-240 nm against a reference aqueous solution of trichloroacetic acid of the same concentration. The results are summarized in Table 1.

Table 1

Patient no. Subscription interval after implantation (h) ^(A 310 to ^A 500 ^ ' ^A O MTX concentration (MTX = methotrexate) (mg / 100 ml) 1 40 2.50 14.7 120 0.007 0 2 48 0.147 0.86 72 0,031 0.18 96 0.159 0.94 120 0,080 0.47 144 0 0 3 96 0.157 0.92 120 0,098 0.58 144 0.195 1.15 192 0.030 0.15 288 0.105 0.61 4 24 0.166 0.98 48 0 0

Table 1 shows that since the first methotrexate collection, the monotone concentration has been decreasing at least and after 288 hours (the longest collection) MTX is still detected in cerebrospinal fluid. Of course, the distance between the seal placement and the ventricular system, the size of the seal-brain interface, the resorption rate of the urine and, last but not least, the total amount of urine in each individual patient play a role in determining MTX.

It is known that with standard administration of methotrexate by the method of lumbar puncture, this disappears from the wet system in approximately three days. Our results show the presence of cytostatic agent in the urine after 12 days.

The polymeric drug in the form of a seal was applied 16 times, always with glioblastomas verified by rapid peroperative biopsy, postoperative histology, or clear relapses.

Examples of use:

Patient - woman, over 50 years old

Intracerebral hematoma at the depth of the right frontal lobe with collateral malaria and susp. an infiltrating tumor, while performing surgery, removing hematoma, stopping bleeding with staples, coagulating with hydrogen peroxide and 40 4 glucose, a Gelaspon with a seal containing a preparation containing 50 mg methotrexate was inserted into the cavity.

Woman, 40 years old

Paraventricular TU front, and pariet. obl. 1. sin

After partial resection of the tumor extending to the basal ganglia and corpus cellosa, a spherical preparation containing 100 mg methotrexate was inserted into the resection cavity.

Claims (2)

CLAIMS 1. Polymeric medicinal product with a protracted cytostatic action consisting of a low-molecular-weight cytostatic, for example methotrexate encapsulated or immobilized on a polyoxypropylene glycol polyurethane carrier with a mole. weight of 1,500 to 2,000; and a 35:65 mixture of 2,4: 2,6-toluene diisocyanate isomers in a 3: 1 molar ratio. 2. A process for the preparation of a polymeric medicinal product according to claim 1, characterized in that the prepolymer consists of polyoxypropylene glycol of mol. weight of 1,500 to 2,000 and toluene diisocyanate is heated with a cytostatic such as methotrexate to a temperature of 30 to 40 ° C in the presence of distilled water and 2,4,6-tris (dimethylaminomethyl) phenol as an accelerator.