CS223950B1 - Medicinal form of the cis-beta-4-n-pentoxybenzoyl-beta-bromacryl acid for peroral feeding - Google Patents

Description

The invention relates to a dosage form of cis-beta-4-n-pentoxybenzoyl-beta-bromoacrylic acid for oral administration, solid or liquid, with reduced gastrointestinal irritation.

AND

In the search for new cancerostatic drugs, there are occasional substances which are effective in specific pharmacological evaluation in animals but already show oral irritation to the mucosa of the gastrointestinal tract at this stage. When selecting the appropriate therapeutic dose for man, it is necessary to eliminate or minimize this unwelcome side effect in the oral form already in the first phase of the clinical trial (tolerance evaluation). In addressing such a problem, consideration should be given to the area of therapeutic effect and, if known at this stage for the gastrointestinal tract, to allow targeted resorption.

Several procedures have been described in the literature that lead to a certain solution to this problem, such as the preparation of coated tablets and enteric coated dragees that protect the gastric mucosa from irritation, so that there is no defense tissue reaction that often leads to vomiting. The substances commonly used for enteric coating are, in particular, some hydrophobic cellulose derivatives, hydrophobic waxes, hardened fats, especially in combination, acrylic acid, methacrylic acid derivatives and many others. A certain disadvantage of this process is the fact that the granulate shell breaks under pressure when the tablets are compressed.

Prolonged-acting tablets, at least 10 to 12 hours, could be used, but the dose of the active ingredient in one tablet would have to be greatly increased to produce the required blood level.

The enteric coatings for tablets or dragees allow, as mentioned above, a major resorption in the intestinal tract. By rapidly releasing a substantial amount of dose in this area, the mucosal irritant may again induce a tissue defense response, accompanied by an acceleration of peristalsis and often resulting in diarrhea. It follows that, in the case of stronger irritation of the gastric and intestinal mucosa, there is a high probability of loss of the active substance accompanied by a decrease in blood level.

In an analysis of the possible solutions to this problem with cis-beta-4-n-pentoxybenzoyl-beta-bromoacrylic acid (U.S. Patent No. 131,764), it was concluded that emphasis should be placed on retarding absorption and more uniform drug release throughout gastrointestinal tract. This can be achieved by adding physiologically harmless high molecular weight or hydrophilic substances to the dosage form, for example tablets or aqueous suspensions. Following oral administration of the formulated formulation, there will be some prolongation of resorption due to the formation of a protective film on the mucosa of the gastrointestinal tract. However, the film formed also reduces contact mucosal irritation so that the entire dose of active ingredient can be absorbed undisturbed and provide a sufficiently high blood level.

Accordingly, the present invention provides a dosage form of cis-beta-4-n-pentoxybenzoyl-beta-bromoacrylic acid for oral administration, solid or liquid, with reduced gastrointestinal irritation; this dosage form is characterized in that it comprises the addition of a substance capable of forming a protective film on the mucosa of the gastrointestinal tract, in particular a physiologically harmless hydrophilic high molecular weight gelling agent, preferably sodium alginate.

The addition of a substance of the above-mentioned properties prevents rapid local absorption and also reduces local irritation leading to undesirable reactions. A suitable amount is added already during the preparation of the granulate and finally mixed in the dry state into the granulate before compression of the tablets or during the preparation of the syrup.

Among the hydrophilic high molecular weight substances which may be considered in addition to sodium alginate are, in particular, tragacanth, pectin, polyvinylpyrrolidone, some starch modifications, some hydrophilic cellulose derivatives and similar derivatives of acrylic or methacrylic acid. The substances are used in the pharmaceutical grade in the form of dust, in some cases, such as granulation, a sol is prepared in advance.

As far as the required amount is concerned, tablets may range from 400 to 1600 mg, preferably from 800 to 1000 mg, based on 1000 mg of active ingredient, with 20 to 80 wt. 20 to 80 wt. in the form of dust in the preparation of the pulp.

In suspension syrups, the hydrophilic gelling agent can then be used in a 4 to 6-fold amount of excess active ingredient.

The invention is illustrated in the following by examples for the preparation of tablets and suspension syrup containing cis-beta-4-n-pentoxybenzoyl-beta-bromoacrylic acid.

Example 1

Preparation of cis-beta-4-n-pentoxybenzoyl-beta-bromoacrylic acid (PBBA) tablets

Composition of 1 tablet (in mg):

PBBA 125.0 lactose 34.5 sodium alginate 100.0 cornstarch 32.0 glyoetol 2.5 talc 6.0

A mixture of 125 g of disintegrated PBBA, 70 g of sodium alginate and 34.5 g of lactose is thoroughly homogenized on a walking granulator and further granulated with a binder solution containing 6 g of corn starch, 10 g of sodium alginate, 2.5 g of glycerol, 9.5 g of ethanol and 92.5 g of distilled water. The wet granulate is dried at 50 ° C in a fluidized bed. After sieving, a tablet is prepared from dry granulated material by adding 26 g corn starch, 20 g sodium alginate and 6 g talc. On a rotary tablet press, tablets having a diameter of 9 mm, a weight of 300 mg, with a disintegration time of 60 to 90 minutes are compressed.

Example 2

Preparation of suspension syrup PBBA

Ingredients 300 ml syrup:

PBBA 2.5 g sodium alginate 12.0 g bentonite type thickener 1, 2 g sorbitol 30.0 g preserved water to 300.0 ml

The disintegrated PBBA is mixed with the thickener and allowed to swell in 50 ml of canned water. Especially the whole amount of sodium alginate is swollen in 100 ml of canned water. After the two colloidal solutions were combined, sorbitol dissolved in canned water was added with vigorous stirring and the total volume was adjusted to 300 ml. Finally, the suspension is allowed to pass through a suitable homogenizer repeatedly.

Claims (2)

Claims 1. A dosage form of cis-beta-4-n-pentoxybenzoyl-beta-bromoacrylic acid for oral administration, solid or liquid, with reduced gastrointestinal irritability, characterized in that it comprises an additive capable of forming a protective film on the mucosa hydrophilic high molecular weight gelling agents. 2. The dosage form of claim 1, wherein the physiologically acceptable hydrophilic high molecular weight gelling agent is sodium alginate.