DE2256538C2 - Probenecid salt of the pivaloyloxymethyl ester of D - (-) - α-aminobenzylpenicillin, its preparation and pharmaceutical compositions containing the same - Google Patents

Description

The invention relates to the subject matter characterized by the claims.

Mustereeid, the chemical name of which is p- (Dipropylsulfamyl) -benzoic acid is is a known compound (Merck Index, 8th Edition, page 866). The D - (-) - «- aminobenzylpenicillin pivaloyloxymethyl ester is also known (Acyloxymethyl Esters of Ampicillin, Daehne et ω al. Journal of Medicinal Chemistry, 1970, Vol. 13, No. 4, Page 607). When administered orally, this ester gives a high blood level of D - (-) - <% - aminobenzylpenicillin, also known as ampicillin. This ester is therefore used as an antibacterial agent in cases J5 where ampicillin is currently used.

The new probenecid salt of D - (-) - oc-aminobenzyI-penicillin-pivaloyloxymethyl ester according to the invention is a crystalline solid which contains 1 mol each of the probenecid and the penicillin ester. It's f *> odorless and virtually tasteless, largely insoluble in water and only slightly soluble in low molecular weight alkanols. These properties are unexpected and of considerable importance as they enable the manufacture of pharmaceutical compositions which are tastefully acceptable and therefore of considerable value in the medical field where an antibacterial agent is convenient and often preferably in the form of a liquid or chewable preparation suitable for the Patients are not uncomfortable being administered, are, allow. The previously used salts of

D - (-) - «- aminobenzylpenicillin pivaloyloxymethyl ester, especially the hydrochloride, have a bitter taste that is natural for an oral Administration, especially oral administration in the form of liquids, is disadvantageous. Even Sample oath has a bitter taste, and it is surprising that the salt made from these two compounds, each of which has a bitter taste on its own, is practically tasteless.

In the method according to the invention the penicillin compound is preferably in the form of a Mineral acid addition salt, in particular a hydrohalide such as the hydrochloride or hydrobromide, used. The probing oath is preferably in the form of the sodium or potassium salt or the Ammonium salt used. According to a preferred embodiment of the method according to The invention is thus the D - (-) - «- aminobenzylpenicillin pivaloy] oxymethyl ester and the sample oath is used in the form of inorganic salts, so that at Completion of the reaction, an inorganic salt which is soluble in the reaction medium is obtained as the second reaction product. The probenecid salt of the D - (-) - «- aminobenzylpenicilin-pivaloyIoxymethyl-ester is expediently in a very pure state by direct crystallization from the reaction mixture separated while the other reaction product remains in solution. For example, if potassium probenecid and D - (-) - «- AminobenzylpeniciIlin-pivaloyIoxy-

methyl ester hydrochloride in a low molecular weight Alkanol are reacted with one another, the desired probenecid salt of D - (-) - a-aminobenzylpenicillin pivaloyloxymethyl ester crystallizes, while the second product, potassium chloride, remains in solution

Although essentially equimolar amounts of the two reactants are generally used for the preparation of the new compound, one of the two reactants can also be used in a molar excess if this appears to be desirable for any reason. The process is preferably carried out in a polar organic solvent in which the starting materials are soluble but the desired antibacterial salt according to the invention is insoluble. Suitable solvents are the low molecular weight alkanols, such as methanol, ethanol, propanol or isopropanol. However, other organic solvents which meet the above requirements for dissolving power can of course also be used. For best results, the presence of water in the solvent must be kept as low as possible. Usually the reactants are mixed with one another at temperatures from about 15 to 50 ^° C. and preferably at about room temperature in such amounts that the resulting solution is saturated or nearly saturated at each reactant, and the desired crystalline product is obtained by cooling such a solution. Crystallization temperatures of about -10 to about + 10 ° C. are appropriate, but can of course vary, as is known to the person skilled in the art.

The probenecid salt of D - (-) - <x-aminobenzylpenicillin pivaloyloxymethyl ester can be used as an antibacterial agent in pharmaceutical agents. When such agents are administered, a higher blood levels of the antibacterial agent (measured as ampicillin) that is retained longer than if mineral acid salts of D - (-) - «- aminobenzylpenicillin pivaloyloxymethyl ester, in particular the hydrochloride, administered in the same way, achieved. This long-term effect is an essential one Beneficial especially when treating bacterial infections that are difficult to control. aside from that the salt according to the invention has the advantage that it is tasteless, while other D - (-) - «- aminobenzylpenicillin pivaloyloxymethyl ester salts have a bitter taste. So the new salt is of great value for oral preparation too administering agents, such as liquid suspensions or drops or solid preparations, for example chewing tablets or pills. The absence of taste is natural with pharmaceutical agents in the form of capsules or coated tablets in which the D - (-) - «- aminobenzylpenicillin pivaloyloxymethyl ester not with the

oral mucous membrane comes into contact, less significantly than with solid or liquid preparations which appeal to the patient's sense of taste.

The pharmaceutically acceptable agents according to the invention can be any of those for oral administration common forms, for example the form of tablets, capsules and liquids of the above specified type. In addition to the antibacterial agent according to the invention, these agents can include the ι ο additives, fillers and diluents commonly used in this field contain and can also suitable flavors, granulating agents, Contains sweeteners, suspending agents, hardeners and emulsifiers.

Solid agents according to the invention may be in the form of unit doses, which are preferably each about 100 to 1000 mg of probenecid-D - (-) - a-aminobenzylpenicillin pivaloyloxymethyl ester included. Liquid funds, such as suspensions or Dispersions, preferably contain the salt according to the invention in an amount of about 25 to 300 mg / ml and especially about 50 mg / ml to about 150 mg / ml. For the production of liquid funds, im in general, preferably first a dry powder, which shortly before its use to a liquid dosage can be processed, manufactured, of course, can be made both in solid and in liquid means lower concentrations of the antibacterial agent! used what, however does not bring any particular advantage. Concentrations higher than those specified above can also be used can be used, the upper limits generally deriving from pharmaceutical processability and tolerance. If the salt according to of the invention because of its taste benefits must be used at the higher concentrations it is ensured that the means remain comfortable for the patient.

Aqueous forms of such agents that are acceptable in terms of taste are, for example:

component

No. I. No. 2

Probenecid salt of D - (-) - a-aminobenzyl- 270 mg penicillin pivaloyloxymethyl ester

Food color red No. 2 0.70 mg

Anti-foam emulsion (silicone emulsion) 0.15 mg

Cherry Flavor T 20.0 mg

Cane sugar powder 3.00 mg

540 mg

0.70 mg

0.15 mg

20.0 mg

3.00 mg

The coloring agent and about half of the cane sugar are used to produce such suspensions mixed together and passed through a sieve with a mesh size of 0.25 mm Silicone emulsion and the rest of the cane sugar are mixed with each other and also through a Sieve with a mesh size of 0.25 mm. Both mixtures are a mixture of the remaining ingredients including the antibacterial agent added, and the product thus obtained is mixed thoroughly and passed through a sieve with a mesh size of 0.18 mm. That so The dry powder obtained is processed into an aqueous suspension by adding 5 ml of water.

For example, a chewable tablet contains the following ingredients:

Components

a dispersion of the Acacia in water, and the moist product is passed through a sieve with a clear Mesh size of 2.0 mm passed and dried. This product is then passed through a Grind sieve with a mesh size of 1.2 mm and with the saccharin sodium, the the dried flavor and the magnesium stearate mixed together. The mixture thus obtained becomes to Compressed tablets The process is carried out with such quantities of the constituents that 1000 Tablets are obtained.

According to another example of a unit dose, tablets, each 0.540 g on the Probenecid salt of D - (-) - «- aminobenzylpenicillin pivaloyloxymethyl ester are made as follows:

mg per tablet Ingredients g

Probenecid salt of D - (-) - a- 270-1080 Aminolienyl penicillin pivaloyloxymethyl ester Mannitol 750 Sodium saccharine 4-5 Acacia 50-80 Dried Flavor SlofT 10-25 Magnesium stearate 30-50

55

60

To make such a tablet, the probenecid salt and mannitol are passed through a sieve with a clear mesh size of 0.84 mm and 15 Minutes mixed together. The mixture is with

Probenecid salt of D - (-) - e-aminobenzyl- 540

penicillin pivaloyloxymethyl ester

Lactose 55

Polyvinyl pyrrolidone 7

Cornstarch 50

Talc 25

Magnesium stearate 3

The pivaloyloxymethyl ester and the lactose are passed through a sieve with a mesh size of 0.84 mm passed and mixed for 15 minutes The mixture is mixed with a solution of polyvinylpyr-

rolidon moistened in 95% ethanol. Pie damp The mass is passed through a sieve with a mesh size of 2.0 mm and then at 38 ° C dried. After the alcohol has evaporated, the granules are broken up on a sieve with a mesh size of 1.2 mm and mixed with the corn starch, the talc and the magnesium stearate mixed. The granulate becomes tablets weighing 0.68 g each compressed, and there are 1000 tablets, each 0.540 g containing the probenecid salt.

Examples of capsules containing the compound according to the invention are:

Components

Capsule # 1

Capsule no

Probenecid salt of D - (-) - a-aminobenzyl- 270 mg peniculin pivaloyloxymethyl ester

Microcrystalline cellulose
Modified food starch
Magnesium stearate USP

The ingredients, with the exception of the magnesium stearate, are passed through a sieve with a mesh size of 0.84 mm and then mixed with one another for 15 minutes. The magnesium stearate is passed through a sieve with a mesh size of 2 ^r > 0.15 mm and added to the other ingredients, and the whole mixture is mixed for 15 minutes. The product is then filled into capsules in the usual manner

The invention is illustrated by the following examples J < > further illustrated.

example 1

A solution of 325 mg of potassium probenecid in 5 ml of methanol is added at room temperature to a solution of 504 mg of D - (-) - a-aminobenzylpenicillin pivaloyloxymethyl ester hydrochloride in 10 ml of methanol. The solution thus obtained is ^{cooled to about -5 ° C. for} 2 hours with stirring, during which time the probenecid salt of the D - (-) - «- aminobenzylpenicil-4-lin-pivaloyloxymethyl ester crystallizes. The mixture is filtered and the crystalline sample oath is washed with distilled water and dried at about 30 ° C.

540 mg

14 mg 28.5 mg 14 mg 28.5 mg 2 mg 3 mg 300 mg 600 mg Example 2

A mixture of 85.5 g of sample oath in 250 ml 114 ml of 2.63 η sodium methoxide are added to methanol. The resulting solution is under nitrogen filtered. The filtrate is, with thorough stirring, a solution of 155 g of D - (-) - «- AminobenzyIpenicillin pivaloyloxymethyl ester hydrochloride added in 700 ml of methanol, the addition being carried out at room temperature within 10 minutes Use the flask is washed with 35 ml of methanol; and the washing liquid is added to the reaction mixture. The entire mixture is then inoculated and cooled under nitrogen for 1 hour to 2 to 3 ° C and then 90 minutes to - 15 ° C, wherein the crystallization of the probenecid salt des

D - (-) - A-aminobenzylpenicillin pivaloy! Oxymethyl ester takes place. The mixture is then filtered and the solid is washed with cold methanol and then with bis water. The solid crystalline product is dried at room temperature under reduced pressure.
Fetwal 93 ° C (dec.).

Claims (1)

Claims; 1, probenecid salt of the pivaloyloxymethyl ester of D - (- J-a-aminobenzyl penicillins. Z Process for the preparation of the probenecid salt of the pivaloyloxymethyl ester of D - (-) - Ä-aminobenzylpenicillin, characterized in that an acid addition salt is used in a manner known per se of the pivaloyloxymethyl ester of D - (-) - a-amino- ίο benzylpenicillin and an alkali salt of probeness oath in a reaction medium in which the reactants soluble, but the reaction product is insoluble, brings intimate contact with one another 3. Pharmaceutical agent, characterized in that it is the probenecid salt of pivaloyloxymethyl ester of D - (-) - «- AminobenzyIpenicillin in intimate mixture with a non-toxic pharmaceutical contains acceptable carrier. 20th