GB2091734A - New salts with antibiotic and mucolytic activity - Google Patents

Abstract

New salts having the formula R'<+>NH3.RCOO<->,R'NH2being a beta - lactam antibiotic and RCOOH being an aminoacid, are prepared by treating an aqueous solution of an aminoacid with the beta -lactam antibiotic. Pharmaceutical compositions based on the salts have therapeutic use in the treatment of bronchopneumopathic conditions.

Description

New salts with antibiotic and mucolytic activity This invention relates to new salts of p-iactam antibiotics. The salts of this invention are formed with sulphur aminoacids having mucolytic activity and are of formula: R1-NH3.R-COO- (I) in which R1 represents a residue of a p-lactam antibiotic RNH2 and R2 represents a residue of a mucolytic aminoacid R2COOH.

Thus R'NH3+ is for example:

derived respectively from Cefadroxil, 7-[D-(a)-amino-p-hydroxyphenylacetam ido]-3-cephem-3-methyl- 4-carboxylic acid, Amoxicillin, ie 6-[D-((t)-amino-p-hydroxyphenylacetamido]-penicillanic acid, and Cefalexin, ie 7-[D-()-aminophenylacetamido]-3-methyi-3-cephem-4-carboxylic acid.

R2C00- is for example derived from N-acetylcysteine, and is of formula

or from S-carboxylmethylcysteine, and is of formula:

or from letosteine, and is of formula:

or from thiopronine, N-(2-mercaptopropionyl)glycine.

More generally the aminoacid employed in this invention can be one of the recognized sulphur aminoacids, or a derivative thereof, or another sulphur-containing acid having an amino function, or a derivative thereof, provided it has mucolytic activity.

This invention also provides pharmaceutical compositions with antibacterial and bronchosecretolytic activity which contain a salt of general formula (I). The treatment of infections of the respiratory system in man constitutes one of the most important uses of p-lactam antibiotics, in particular of ampicillins and oral cephalosporins.

In acute and chronic infections of the bronchopulmonary system, mucolytic drugs in the form of sulphur aminoacids are used, capable of providing a fluidising action and of modifying the components of bronchial secretion after oral administration.

It has now been unexpectedly found that salification between the various free amino groups of the alpha-phenylglycine or alpha-p-hydroxyphenylglycine side chains of the wide spectrum semisynthetic penicillins ampicillin and amoxicillin and of the cephalosporins cefalexin and cefadroxil, and the carboxyl groups of sulphur aminoacids with mucolytic action such as S-carboxymethylcysteine, N-acetylcysteine, letosteine and thiopronine, leads to stable products which are well definable chemically and possess surprising pharmacological and therapeutic properties.

In this respect, the salts of the present invention combine a wide spectrum antibacterial action with a fluidising action on the bronchial secretion, and are therefore able effectively to oppose the two main pathological components (the infective component and bronchial hypersecretion) of a large number of affections of the human respiratory system, because of the synergic and complementary interactions which arise between the antibiotic cationic component and the mucolytic anionic component.

The salts also have particularly favourable pharmacolcinetic properties, with an increased oral absorption which enables higher antibiotic concentrations to be obtained in the blood and also in the pulmonary tissue.

The salts of the present invention typically comprise equimolar proportions which give rise to therapeutically effective weight ratios of the two components which are compatible and tolerated by man. They are therefore suitable for formulation into oral pharmaceutical forms such as syrups, capsules, tablets and granulates, and into forms for parental and local (aerosol) administration, this latter method of administration being particularly effective in the human treatment of the aforesaid diseases of the respiratory system.

Some of the preferred salts are: cefadroxil N-acetylcysteinate amoxicillin S-carboxymethylcysteinate cefalexin N-acetyicysteinate Some characteristics of the salt ceiadroxil N-acetylcrysteinaLe are given hereinafter in comparison with cefadroxil: hematic levels (mcg/ml) in the dog after oral administration by the cross-over method with a dose equivalent to 25 mg/kg of cefadroxil.

Time Cefadroxil (hours) Cefadroxil N-acetylcysteinate 0.5 3.9 5.4 1 9.1 14.1 2 22.1 25.9 4 12.8 13.5 6 5.8 6.8 Concentration (mcg/ml) in the pulmonary parenchyma after oral administration of a dose equivalent to 100 mg/kg of cefadroxil in the rat: Time Cefadroxil (hours) Cefadroxil N-acetylcysteinate 0.5 8.4 11.2 1 11 13.7 2 6.4 9.7 4 4.2 5.6 6. 2.2 2.84 Geometrical means of the Minimum Inhibiting Concentrations (M.l.C., mcg/ml) for 20 Gram-positive strains and 20 Gram-negative strains: Gram-positive Gram-negative Cefadroxil 5.38 7.57 Cefadroxil N-acetylcysteinate 3.25 9.01 The salts according to the present invention can be prepared by adding an equimolecular quantity of -lactam antibiotic to a solution of the sulphur aminoacid. Usually, the mixture is stirred until dissolving is complete, possible using heating to a temperature of between 30 and 700C.The salt can be finally separated out by adding suitable solvents miscible with water (alcohols, acetone, dioxane etc) or by simply cooling and seeding, the salt then being filtered off. The salt solution can also be conveniently lyophilised.

The following examples further illustrate the invention, but without limiting it.

EXAMPLE 1 Preparation of cefadroxil N-acetylcysteinate Cefadroxil (72.7 g, 0.2 moles) was added in portions to a stirred solution of N-acetylcysteinate (32.6 g, 0.2 moles) in water (1.5 litres). Dissolution was observed until about one half the necessary quantity had been added, and therefore when addition had been completed the turbid solution was heated to 700C (complete dissolution). The solution was cooled to 400C, treated with a little decolourising charcoal, filtered (colourless solution) and the filter washed with a little cold water, after which lyophilisation was carried out.

About 95 g of white product was obtained, its analytical characteristics being as follows:- M.W: 526 I.R. (KBr) cam~': 2600 (wide), 1760, 1690, 1630 (shoulder), 1610 N.M.R. (D20): 2.0 (3H,s); 2.1 (3H,s,CH30); 2.9 (2H,s,CH2SH); 3.5 (2H,dd,CH2S); 4.8 (DOH); 5.1 (1 H,d,C6H); 5.4 (1 H,s,CH-NH2); 5.8 (1 H,d,C7H); 7,0-7.6 (4H,dd, aromatic).

Elementary analysis confirms the formula.

Chemico-physical determinations confirm the saline structure of the product.

EXAMPLE 2 Preparation of cefalexin N-acetylcysteinate Cefalexin (191 g, 0.55 moles) was added slowly to a stirred solution of N-acetylcysteinate (89.65 g, 0.55 moles) in water (6 litres). The mixture was heated to 450C until dissolving was complete, then cooled to 300 C, filtered, and the filtrate solution lyophilised. 266.5 g of cefalexin N-acetylcysteinate was obtained, with the following characteristics: MW: 510 I.R. (KBr) cm-1: 2600, 1760, 1690, 1630, 1610 Elementary analysis confirms the formula.

Stability of the salts according to the invention, already mentioned above, is documented by way of example by the following comparison of the salt cefadroxil N-acetylcysteinate with cefadroxil. The stability of the salt in solution was followed by HPLC in a 10% solution at 230C.

Time (h) Residual titre (%) 0 100 0.5 99.9 1 99.8 2 98.3 3 98 4 97.5 5 96.4 Formulations according to the invention can be administered with a carrier in pharmaceutical formulations suitable, for instance, for oral, parenteral and aerosol administration. Some non-limiting formulation examples are given.

Solid oral pharmaceutical form Two-colour rigid gelatin capsules, or tablets, can be prepared containing a quantity of cefadroxil Nacetylcysteinate equivalent to 500 mg of anhydrous acid cefadroxil and to 225 mg of Nacetylcysteinate, together with inert excipients such as magnesium stearate, talc, polyvinylpyrrolidone, titanium dioxide, colloidal silica, starch, sucrose, mannitol, lactose, microcrystalline cellulose and colouring. 3-4 capsules or tablets per day can be advantageously used in human therapy.

Liquid oral pharmaceutical form An extemporaneous dry syrup having the following composition can be advantageously used in human therapy: Cefadroxil N-acetylcysteinate 4.35 g Sugar, flavouring, colouring and stabilisers sufficient to make up to 40.00 g The syrup is made up to a volume of 60 ml with distilled water. The dose is 2-3 spoonfuls a day.

Effervescent granulate An effervescent granulate in sachets having the following composition per sachet can be advantageously used in human therapy: Cefadroxil N-acetylsteinate 725 mg Sodium bicarbonate 350 mg Sweetening, flavouring and colouring excipients sufficient to make up to 3 mg The dose varies from 2 to 4 sachets per day dissolved in 20-50 ml of water.

Injectable or aerosol pharmaceutical form A pharmaceutical composition can be advantageously used in human therapy which is suitable both for parental administration and for atomisation as an aerosol. The pharmaceutical form is constituted by-sterile bottles containing cefadroxil N-acetylsteinate in a quantity for example of 435 mg, 725 mg or 1.45 g, with an accompanying solvent phial containing 2 to 5 ml of non-pyrogenic sterile doubly distilled water and suitable buffer agents so as to maintain the pH between 6 wind 8. The dose is 2-3 intramuscular injections per day or 1-2 aerosol applications per day.

Claims (8)

1. A salt of the general formula: + (I) R-NH3.R-COO- in which R' represents a residue of a p-iactam antibiotic RNH2 and R2 represents a residue of an aminoacid of formula R2COOH.

2. A salt according to claim 1, wherein RNH2 is Cefadroxil, Amoxicillin, or Cefalexin.

3. A salt according to claim 1 or 2, wherein R2COOH is N-acetylcysteine, S carboxylmethylcysteine, letosteine, or thiopronine.

4. The salt formed between equimolar quantities of N-acetylcysteine and cefadroxil.

5. The salt formed between equimolar quantities of N-acetylcysteine and cefalexin.

6. The salt formed between equimolar quantities of letosteine and cefadroxil.

7. A process for preparing a compound as claimed in any preceding claim, characterised by reacting the p-iactam antibiotic with the aminoacid in an aqueous environment.

8. A pharmaceutical composition with antibacterial and mucolytic activity, characterised by one or more salts as claimed in any of claims 1 to 6 as an active principle.