DD293725A5 - PHARMACEUTICAL AGENT AND METHOD FOR THE PRODUCTION THEREOF - Google Patents

Abstract

The invention relates to a process for the preparation of a pharmaceutical agent with slow release of p-aminosalicylate as a tuberculostatic agent, consisting of a strongly basic anion exchanger with benzyltrimethylammonium groups, loaded with p-aminosalicylate. The molar amount of p-aminosalicylate may be 50 to about 150% relative to the quaternary ammonium groups. The pharmaceutical agent is prepared by loading the anion exchanger in a batch and / or column method with a aqueous solution of p-aminosalicylate. {Therapeutic agent; p-aminosalicylate; Tuberkulostatikum; A sustained-release; Drug delivery; anion}

Description

Field of application of the invention

The invention relates to a process for the preparation of a pharmaceutical agent. The product produced according to the invention is used as Tuberkufostatsikum the 2nd row

Characteristic of the known technical solutions

It is known that the p-Aminosalicylsäurenatriumsalz is a relatively weak tuberculostatic 2nd row, which acts bacteriostatically. This is for example the monograph of K. Feller and H. Hüller, Special Clinical Pharmacology, VEB Verlag Volk and Health, Berlin 1978, page 49, forth. The p-Aminosalicylsäurenatriumsalz is indicated in all active pulmonary and extrapulmonary tuberculous diseases and must be extremely high doses and therapy must be carried out for months. It is absorbed quickly after oral administration. The elimination is very rapid by tubule secretion. However, one disadvantage of using this drug is the maintenance of an approximately constant blood level value in the therapeutic range over a long period of time. In the case of oral administration of p-aminosalicylic acid sodium salt in the form of customary tablets, dragees, etc., after about 2 hours, a maximum of active substance in the blood level is produced, which is rapidly degraded.

Object of the invention

The aim of the invention, therefore, is to eliminate the disadvantages of using p-aminosalicylic acid sodium salt or to find a process for its production which improves the use of the p-aminosalicyl sodium salt.

Explanation of the essence of the invention

The object of the invention is to produce a new form of administration of the p-aminosalicylic acid sodium salt which permits slower delivery of the active substance to the organism.

The object is achieved in that strongly basic anion exchanger containing the Benzyltrimethyfammoniumgruppieru ng as solid ions, loaded with the p-Aminosalicylsäurenatriumsalz, washed, dried and in a suitable form, e.g. Tablets, dragees, etc., for therapeutic use. Both ionic and macroporous strongly basic ion exchangers with benzyltrimethylammonium groups can be used as ion exchangers. Wofatit SBW, Wofatit SZ 30, Wofatit EA 60 (VEB Chemiekombinat Bitterfeld).

The loading is carried out according to the invention in a one- or two-stage process. The ion exchanger is contacted with a solution of the drug, optionally thereafter immobilized in a column and loaded with 1% drug solution until the drug concentration before and after the column is the same. The product is rinsed from the column, filtered, washed and dried. Thereafter, it may be converted in a known manner, with or without the addition of adjuvants, into a suitable pharmaceutical administration form, e.g. Tablet, dragees, hard gelatin capsule, etc. If the drug is administered to the stomach-dairy jar, a single dose of the active ingredient is released from the body of the ion exchanger, followed by a smaller amount over a longer period. This drug release improves the therapeutic effect. The release of the active ingredient is usually detected in vitro in vitro experiments. The charged ion exchanger is added to the apparatus by means of a 0.73% Nafriumchloride solution. This ion concentration corresponds approximately to the lo'neristärice of the artificial intestinal soft tissue according to Münzel, as described in R. Voigt> eherbuch of the pharmaceutical technology, VEB publishing house people and health, Berlin 1982, p.208. ----. - - -. --- _:. .. ^^ "^ **" "" "" "" ™ "- ^

Now, samples are taken for the purpose of determining the active substance concentration, the withdrawn volume of test liquid is replaced by fresh test liquid, etc. On the basis of the results, it can be established that the active substance remains bound to the ion exchanger for a prolonged period and is released into the environment at a slower rate.

The advantage of the method according to the invention consists precisely in the described slow release of the active ingredient from the ion exchange backbone into the environment, so that a more uniform concentration over a longer period can be achieved than is the case with the usual dosage form.

The process according to the invention will be explained by way of examples.

embodiments

example 1

1.1. Loading the ion exchanger

5 g of strongly basic ion exchanger with benzyltriethylammonium groups Wofatit SZ 30 and 1 g of p-aminosalicylic acid sodium salt are weighed in and mixed with 200 ml of water. After 24 hours, the product is filtered off. The supernatant solution is analyzed by UV spectrophotometry at a wavelength of 275 nm. From the decrease in the active ingredient concentration, the amount of the drug adopted by the exchanger was calculated. The filtered product was immobilized in a glass column and loaded with 1% drug solution until the eluate had the same drug concentration (UV spectrometry). From the sum of the amounts of drug bound in the first and second loading processes, the total amount per gram (dry resin) was determined. This was 790 mg per 1 g dry resin (5.20 mmol / g).

1.2. release test

500 mg of the aspirated product were weighed, sewn into a Perlon bag, placed in a beaker, with 100 ml of test liquid (0.73% NaCl solution), heated to 37 ⁰ C and moved by a magnetic stirrer at 400 rev / min. From the test liquid 50 ml per hour are removed and replaced by the appropriate amount of test solution. The samples taken are diluted with borate buffer pH 8.6 and measured by UV spectrometry.

The amount of drug Q _{1 released} per hour from the loaded ion exchanger was calculated according to K. Münzel, as described in the Deutsche Apotheker-Zeitung, Vol. 104, 1964, p. 844:

Q ₁ = R, -% *

Where R is the average amount of drug present in 100 ml of test fluid. This is calculated according to R ₁ = E, FV-100

with E = extinction (UV spectroscopy) F = calibration factor V = dilution

The total amount of drug G delivered up to time t represents the sum of the Q values: G = Q, + Q ₂ + ... Q,

Similarly, for release, a citric acid / phosphate buffer of greater ionic strength was prepared (pH 4.0) as follows:

Solution A: Citric acid 21.008 g was made up to 11 with water in a volumetric flask; ί

Solution B: disodium hydrogen phosphate 2 H ₂ O 35.62g was made up to 11 with water in a volumetric flask. j

614.5 ml of solution A and 385.5 ml of solution B were mixed and, as described in Experiment 1.2, above, to release the |

Drug used. '!

1.3. Release result j

The after 1.2. In NaCI solution, after 1 h, 63% of the existing |

Amount of drug released, after 8 h 89% in citric acid phosphate buffer 60% were released after 1 h, 96% after 8 h. j

Example 2!

Analogously to Example 1, 5 g of strongly basic ion exchangers with benzyltrimethylammonium groups Wofatit SBW were then loaded with sodium p-aminosalicylic acid salt. The test revealed that per 1 g dry resin 841.6 mg (5.53 mmol) of drug were taken up.

The release test was performed only with NaCl solution. There was a release after 1 h of 62% and after 8 h of 98%.

Example 3

Analogously to Example 1, 5 g of strongly basic ion exchangers with benzyltrimethylammonium groups Wofatit EA 60 *

loaded with p-aminosalicylic acid sodium salt. The test showed that per 1 g of dry resin 903 mg (5.14 mmol) of drug [

been recorded. ·

The release tests were performed with NaCl solution and citric acid / phosphate buffer. The NaCl solution gave

a release after 1 h of 65% and after 8h of 95%. With the buffer mixture a release to 1 of 58% and after

8 h of 87%.

Claims (2)

1. A process for the preparation of a pharmaceutical agent with slow release of the active ingredient p-Aminosalicylat, characterized in that a strongly basic anion exchanger is reacted with predominantly quaternary Benzyltrirnethylarnmoniumgruppen with an aqueous solution of p-Aminosaicylatin, optionally with 1% aqueous p-Aminosalicylatlösung loaded by column method, washed, dried and incorporated in a known manner in pharmaceutical formulations. 2. A process for the preparation of a pharmaceutical composition according to claim 1, characterized in that the molar content of p-Aminosaficylat with respect to the molar Festionenkonzentration 50 to T50%.