DD273380A1

DD273380A1 - CARRIER FOR DRUGS WITH IMPROVED BIODEGRADABILITY BASED ON AMPICILLIN

Info

Publication number: DD273380A1
Application number: DD31720988A
Authority: DD
Inventors: Reinhard Neubert; Thomas Dittrich; Walter Fuerst
Original assignee: Univ Halle Wittenberg
Priority date: 1988-06-28
Filing date: 1988-06-28
Publication date: 1989-11-15
Also published as: DD273380B1

Abstract

Die Erfindung betrifft ein Verfahren zur Verbesserung der Bioverfuegbarkeit von Ampicillin. Erfindungsgemaess werden dem Ampicillin Alkylsulfate oder Alkylsulfonate als Carrier zugesetzt.The invention relates to a method for improving the bioavailability of ampicillin. According to the invention, alkyl sulfates or alkyl sulfonates are added to the ampicillin as a carrier.

Description

Object of the invention

Ziel der Erfindung ist eine Arzneiform von Ampicillin mit verbesserten pharmakokinetischen Parametern, wie absolute Bioverfügbarkiet und mittlere Verweildauer im im Organismus.The aim of the invention is a drug form of ampicillin with improved pharmacokinetic parameters, such as absolute Bioverfügbarkiet and average residence time in the organism.

Darling of the essence of the invention The invention had the object of finding a suitable carrier for the ampicillin, with the help of the Bioavailability is decisively improved. According to the invention are alkyl sulfates or sulfonates with a Alkyl chain length of 10 to 20 alone or in combination with conventional excipients for the preparation of pharmaceutical preparations of the Ampicillins used with improved bioavailability and mean residence time. Alkyl sulfonates, but especially Alkylsulfa'o are synthetic - in contrast to the previously used aromatic Sulfonic acids - easier to prepare and have much better properties in vitro (see Example 1) than aromatic ones Sulfonic acids. embodiments example 1

1.1. In vitro Membrantransport1.1. In vitro membrane transport

In vitro membrane transport was investigated using the apparatus of Fürst and Neubert (Pharmazie 35, 106 [1980]).

Variantevariant Konzentrationconcentration Flux des AmpicillinsFlux of ampicillin SS ηη (mmol"¹)(mmol " ¹ ) nrr.olcrrr'min"¹)nrr.olcrrr'min " ¹ ) (%)(%) Ampicillinampicillin 11 0,1300.130 19,619.6 66 Ampicillin +Ampicillin + 11 0,1800,180 18,818.8 33 Naphthalensulfonatnaphthalenesulfonate Ampicillin +Ampicillin + 11 0,1700,170 20,120.1 33 HeptansulionatHeptansulionat Ampicillin +Ampicillin + 11 2,052.05 15,915.9 66 Dodecylsulfatdodecyl sulfate DK = pH 2,4DK = pH 2.4 Ampicillin +Ampicillin + 11 0,070.07 22,922.9 88th Dodecylsulfatdodecyl sulfate DK = pH 8,0DK = pH 8.0

Es zeigte sich, daß der Membrantransport des Ampicillins durch Laurylalkohol-Kollodium-Membranen vom Dodecylsulfat um den Faktor 15,8 gesteigert wird. Dabei handelt es sich um einen spezifischen Effekt, da bei pH 8,0 im Donatorkompartiment (DK) - dort liegt die Aminogruppe des Ampicillins nicht dissoziiert vor- keine Carrierwirkung des Dodecylsulfates beobachtet wurde.It was shown that the membrane transport of the ampicillin is increased by a factor of 15.8 by lauryl alcohol-collodium membranes of the dodecyl sulfate. This is a specific effect since at pH 8.0 in the donor compartment (DK) - where the amino group of the ampicillin is not dissociated - no carrier effect of the dodecyl sulfate was observed.

1.2. In vitro Resorption1.2. In vitro absorption

These studies were performed with a resorption model (Pharmazie 37, 571 (1982)). Variant half transport time (h) S (%) N Ampicillin 50 mg 36.1 21.2 5 Bacampicillin 50mg 1.75 19.7 4 Ampicillin 50 mg + 2.07 18.5 5 Dodecylsulfate 34 mg

Eo zeigte sich, daß in vitro die Resorption des Amiciiiins durch Zugabe von Dodecyisuifat beträchtlich gesteigert wird. Die Steigerung liegt ebenso hoch wie die des Bacampiciliins, das jedoch synthetisch weitaus komplizierter herstellbar ist.Eo showed that in vitro the absorption of amicillin is considerably increased by the addition of dodecylsulfate. The increase is as high as that of bacampicillin, which is synthetically much more complicated to produce.

Claims

Carrier for drugs with improved ampicillin-based bioavailability, characterized by alkyl sulfates or sulfonates with a chain length N of 10 to 20.

Field of application of the invention

The invention relates to a carrier for drugs based on ampicillin, which are used as antibiotics.

Characteristic of the known solutions

Heretofore, derivatives of the drug ampicillin, which is very hydrophilic and thus poorly absorbable, such as bacampicillin and pivampicillin, which are more lipophilic, have been used to improve absorption (US 3697507 and US 3956279). Furthermore, aromatic sulfonic acids, such as. For example, tetrahydronaphthalene sulfonic acid (US 3534035), 3,7-di-tert-butylnaphthalene-1,5-disulfonic acid (BP 1548775), sulfanilic acid and aminonaphthalene sulfonic acid (US 3278525), Nonylbenzensulfonsäuro, p-toluenesulfonic acid, p-Cymensulfonsäure, 2-naphthalenesulfonic acid (BG 639025), Guajacolsulfonsäure (FR 2439784) and Aminonaphthalenedisulfonsäure (FR 1502761) used. These acids, in the sense of a carrier, improve the bioavailability of the hydrophilic drug ampicillin.

2-Naphthalenesulfonic acid, like aromatic sulfonic acids in general, only slightly affects the transport of ampicillin in vitro.

The alkylsalicylic acids (DD 246029) also used as carriers for hydrophilic drugs can not be used for ampicillin, since they dissociate only to a small percentage in the pH range of 2.0-4.0, which is suitable for carrier-influencing available. In addition, the solubility of the alkylsalicylic acids in this pH range is very low, so that it is necessary to find a specific carrier for certain drugs, since there is no universal carrier substance *.