DE1792447B2 - ORAL CYTOSTATIC AGENT - Google Patents

Description

The invention relates to an orally applicable, cytostatic agent containing a cytosine arabinoside base as an active ingredient, which is characterized in that it consists of at least one layer

(a) a pharmaceutically suitable acrylic acid derivative or methacrylic acid derivative containing acid groups with a molecular weight between 100,000 and 150,000 or

(b) a pharmaceutically acceptable cellulose acetate phthalate

is covered.

The invention relates in particular to those agents which are in the form of coated tablets.

Among these agents are in turn to be emphasized those which have one or more coating layers of polymeric derivatives of acrylic acid, preferably of acrylic acid derivatives, which Have acid groups, a molecular weight of these derivatives of about 135,000 being particularly has proven beneficial. There are such polymeric acrylic acid derivatives of the type mentioned preferred, which dissolve at a pH of 7 to 8, with corresponding mixtures of two or several derivatives of acrylic acid can be used. The acid number of the polymers mentioned is z. B. - based on the dry weight - at a value iwischen 20 and 50, advantageously between 23 and 43.

The invention also relates to those agents of the composition mentioned in which the polymer consists of cellulose acetate phthalate.

The cytostatic, immunosuppressive and antiviral effects of cytosine arabinoside with parenteral use is known. The use form according to the invention, as defined at the outset, is against it new and led to an unforeseeable beneficial effect. The expert in this field had to be expect that an oral form of administration would lead to no or only an insufficient effect. This is z. B. from the publication of the research fto laboratories of the pharmaceutical company »The Upjohn Company ”, Kalamozoo, Michigan, USA, dated June 15, 1968“ Cytarabine ”(Arabinofuranosyl Cytosine; U-19 920) »Antileukemic Agent«, in which it expressly states on page 5: »Cytarabine is not oral (15 effective."

The surprising success of the agents according to the invention is also particularly clear that a Oral application of the same amount of active ingredient in cytosine arabinoside base in the form of gelatin capsules did not lead to success.

It was surprising and not obvious that the basic active ingredient cytosine arabinoside was carried out by Coating with the acidic polymer does not react and does not lose its effectiveness and still orally is effective.

Oral administration of cytostatics for tumors of the intestinal tract in the already inoperable Stage is a general method of medicine. An oral derivative of 5-fluorouracil has recently been used (FTORAFUR) also very widespread in advanced tumors of the gastrointestinal tract applied. Despite the existing tumors, the drug is still being resorbed Gastrointestinal tract instead.

The agents according to the invention can be used in particular in the disease states such as those in the following Publications are described, used v / erden: S. Witte and D. M. Goldenberg, »Die Medical World «, 18, 1838-1840 (Ϊ967),» First clinical experience with the antimetabolite cytosine arabinoside in the chemotherapy of hemoblastosis and related diseases "; D. S. Fischer, E. P. Cassidy and A. D. Welch, "Biochem. Pharmacol., 1966, Vol. 15, pp. 1013-1022, "Immunosuppression by pyrimidine nucleoside analogs «.

Example t

Production of 1000 coated tablets

100 g cytosine arabinoside base,
35 g microcrystalline cellulose,
40 g corn starch,
5 g magnesium stearate

are mixed. The cores contain about 30 to 40 jobs with a solution of acidic groups Methacrylate-based polymers in isopropanol. In particular, two different polymers the following formula is used:

CH ₃
-C-CF
C = O
OH

CH ₃
-C-CF
C = O

OR

CH ₃

-C-CF
C = O
0 "H ⁺

CH ₃

C = O
OR

The two polymers, which are designated as A and B, have the following characteristics:

Polymer
A.

Polymer B

Dry matter 13.75% 13.75%

Security number 292 178

mg / KOII / g dry matter

Density Djü 0.845 0.845

Refractive index ιή? 1.39 1.39

Aceionhallige lacquers ntf !, 385 1,385

These two polymers are used in a mixing ratio of 1: 1.

Such polymers generally have a dry substance content from 13.0 to 14.5% by weight.

Polymer A dissolves rapidly at pH 7.0, and polymer B dissolves rapidly at pH 7.0 pH 8.0.

Talc is sprinkled between each application.

Instead of the above methacrylic acid polymer, the following can be used in the same way Use cellulose acetate phthalate solution:

12.0 g cellulose acetate phthalate,

3.0 g dibutyl phthalate,

67.5 g ethyl acetate,

67.5 g of isopropanol.

After applying the excess, the coated tablets in the usual way with the help of sugar syrup and coating powder to a total weight of 315 mg coated.

Example 2
Clinical trials

Seven male patients between the ages of 50 and 70 years with inoperable tumors of the esophagus, of the stomach, colon and rectum received daily doses of 400 to 600 mg of cytosine arabinoside base over 5 to 8 days (approx. 5 to 10 mg / kg / day). The active ingredient was produced in the form of coated tablets according to example 1 of this application, spread over the whole day, applied. With regard to the im Literature reported fact that certain neoplastic conditions result from changes in the bone marrow are accompanied, aspirations from the sternal medulla were performed in all patients, namely one day before the start and on the day following the first course of treatment. The bone marrow smears were stained using the May-Grunwald-Giemsa technique.

Due to the known fact that cytosine arabinoside causes the rapid formation of megaloblastosis with IV application (R. W. T a 11 e y and V. R.

ίο Vaitkevicius, Blood, 21, 352 [1963]) could it can be assumed that the occurrence of such a change after oral administration of the Active ingredient - regardless of any directly demonstrable anti-tumor effects - a there had to be a clear indication of sufficient absorption in this application.

Results

Megaloblastosis was observed in the bone marrow of all treated patients. These with parenteral treatment with cytosine arabinoside typical bone marrow changes shows that the Substance is absorbed from the intestine after oral administration and indicates the usefulness of an oral form of cytosine arabinoside base in the treatment of certain neoplastic diseases. The concerned Bone marrow changes became apparent from about the 6th day after starting treatment with a Daily dose of 500 mg observed. Any gastrointestinal side effects (nausea, vomiting, Nausea) did not occur in any case.

Claims (2)

Patent claims: 1. Orally applicable, cytostatic agent with a content of cytosine arabinoside base as active ingredient, characterized in that it is made up of at least one layer (a) a pharmaceutically suitable acrylic acid derivative or methacrylic acid derivative containing acid groups with a molecular weight ι ο between 100,000 and 150,000 or (b) a pharmaceutically acceptable cellulose acetate phthalate is covered. 2. Means according to claim 1, characterized in that it is in the form of a tablet.