Use of fosfomycin pharmaceutically acceptable salts as a topical cicatrizer

Abstract: Phosphomycin and pharmaceutically acceptable salts thereof topically used as cicatrizing agents.

Description: With the term cicatrization, the complex of events is meant the object of which is the healing of the breach of tissue continuity and that ends-up with the formation of a scar, by cicatrizing agent being therefore meant a substance that promotes or accelerates the healing wounds. The cicatrizers are a therapeutical class to which substances of various nature belong, such as protective substances, that is substances that are in a measure of forming films suitable for providing a shelter for the wound without thereby occluding it, for example polyvinyl alcohol (FR-A-2566270) and certain synthetic polymers (GB 2060381), anti-congestive agents, such as chondroitin sulfate B (EP 097625), anti-inflammatory agents, such as glycirrhetinic acid and its derivatives (GB 2122893) and the extract of arnica (FR-A-2504009), methabolism activators, such as coenzyme Q10 (US-A-4654373), the biostimulines, retinol and its salts (EP 038246) , somatotropin and its derivatives and co-factors (WO-A-8800207), vasodilatory agents, such as nicotinic acid, acetylcholine and benzylimidazoline, disinfectants and antibiotics. The above-mentioned substances have actually a cicatrization adjuvant action, but do not directly take part in the mechanisms that are in charge of repairing the tissues, and among them the antibiotics known for this use essentially have the function of preventing the wound, lacking its normal natural defences, from being infected. Fosfomycin, i.e. (-)cis-(1,2-epoxypropyl)phosphonic acid, is an antibiotic described in US patent U.S.-A-3914231 and is used in the therapeutical field as a systemic antibacterial agent since it is active against both gram-positive and gram-negative bacteria. Arch. Derm. Forsch., 1973, 246, p. 27-34 and Drugs Exp. Clin. Res., 1981,7(2), p. 109-113 only refer to the topical use of fosfomycin as an antibiotic, with no reference to cicatrization parameters, i.e. angiogenesis, granulation tissue formation, connective tissue regeneration and the like. It has now been surprisingly discovered that fosfomycin pharmaceutically acceptable salts develop an outstanding, absolutely unexpected cicatrizing activity when administered by a topical route. Such a novel therapeutical activity can in no way be related to the known antibiotic properties of the drug, but it is certainly related to an unexpected biochemical action that fosfomycin salts exhibit in an evident and surprising way. The object of the present invention is therefore the use of a fosfomycin pharmaceutically acceptable salt for the preparation of a medicament for use as a cicatrizing agent. An especially preferred salt of fosfomycin is the sodium salt. The concentration of fosfomycin salt in the medicament to be applied onto the wound can range from 100% to about 0.5%, the higher the drug concentration, the greater being the effectiveness of the medicament, the fact being thereby to be kept in mind that, even if the medicament contains 100% fosfomycin, it gives rise to no side-effects at a topical level or a systemic level. Fosfomycin salts, preferably the sodium salt, are topically applied in form of a dusting powder, but also in such pharmaceutical forms as lotions, gels, ointments, cremes, tablets for topical use, sprays, impregnated gauzes, sponges of a suitable material, such as fibrinogen. To the formulation there can obviously be added further substances, such as antimycotic, antiviral, antipruriginous agents, absorbent substances, deodorizers, emollients, vitamins, amino-acids, either of natural or synthetic origin. Experimental studies carried out to the purpose of ascertaining the precise cicatrizing activity of fosfomycin have demonstrated that the drug stimulates the hemostasis, with a consequent reduction of inflammation, performs a precise function in angiogenesis, i.e. the regeneration of the blood vessels, displays a chemotactic action on the monocytes and fibroblasts, thereby providing a support for the fibroblastic proliferation and the granulation tissue. In particular, its action gives rise to an in situ increase of plasmatic fibronectin and of the number of macrophages that produce tissue fibronectin, fibronectin being a glycoprotein that is deeply involved in chemotaxis phenomena, opsonizations and methabolic processes concerning the connective tissue. This novel activity of fosfomycin is therefore surprising not only in view of its well known antibiotic characteristics, but also because no one of the so-called cicatrizing drugs previously used ever exhibited an intervention at this level, that can be considered as one of the main stages of the cicatrization phenomenon. In view of the above, fosfomycin pharmaceutically acceptable salts, can be used in the treatment of traumatic lesions, with loss of substance, surgery wounds with delayed cicatrization or dehiscence of the suture, fibropathic ulcers, mammal abscesses, sacrococcigeal abscesses, burns. A complete healing has been observed in all the cases treated with fosfomycin salts, including the cases that would usually have required surgery. To confirm that the therapeutical cicatrizing action of fosfomycin can in no way be related to its antibiotic activity, experimental work has been carried out also with known antibiotics for the topical application, such as neomicin, bacitracin, sulfadiazine, either alone or in association. None of the comparison antibiotics tested has shown an activity that may be compared with that of fosfomycin, which, used alone, is able of inducing a complete cicatrization of wounds. Clinical experimentation examples will now be provided that better illustrate the cicatrizing activity of fosfomycin and provide a comparison with antibiotics known in the field. Test example 1 Thirty patients with surgery wounds arising from operations of various severity and kind, and that had not healed up within the usual time, or that had dehiscence of part of the suture with the consequent formation of a suppuration pouch, have been subjected, after regular drainage of the purulent mass, to the daily application of pure sodium phosphomycin in the form of a sterile powder. The drug has been dusted directly on to the wound in a homogeneous distribution covering the whole of the injured area and kept in place with a sterile gauze protection. After a two days therapy, all the treated wounds clearly exhibited the typical improvement signs of the cicatrization process, namely with a lively proliferation of the granulation tissue. The clinical healing has been noted for all the wounds of various kind within seven days of therapy with sodium fosfomycin alone, topically applied. Test example 2 Fifty cases of wounds with loss of substance caused by various traumas have been randomly divided into two groups, only providing for equally dividing between the two groups wounds of a similar severity. The wounds of both groups were cleansed daily with sterile water. The wounds of the first group of 25 cases were treated by homogeneously and completely dusting them with a commercially available product containing as the active ingredients neomicin sulfate (3300 IU), bacitracin zinc (250 IU), L-cysteine (2 mg), DL-threonine (1 mg), glycine (10 mg). Said treatment was repeated twice a day, always removing the sterile covering, according to the directions for use supplied with said composition. The clinical healing of the wounds of this group has been noted between the 7th and 25th treatment day. The wounds of the second group of 25 cases were treated with pure, sterile sodium fosfomycin, carefully providing for the whole wound to be homogeneously covered with the drug, which in turn was kept in place by means of a sterile gauze. The clinical healing has been noted between the 3rd and the 10th day of treatment. No other topical or sistemic therapy has been carried out contemporaneously. The following examples are non limiting drug formulations examples. Formulation example 1 100% fosfomycin dusting powder Sodium fosfomycin, sterile 5 g Formulation example 2 Dusting powder comprising: Sodium fosfomycin, sterile 0,5 g Kaolin bolus alba, sterile 99 g Formulation example 3 Preparation for recombination lotion comprising: Sodium fosfomycin, sterile 0,5 g Distilled water, sterile 30 ml The drug is introduced into a membrane stopper closing a 30 ml ampule filled with sterile distilled water. At the moment of use, a light pressure is applied to the stopper, thereby causing the powder contained therein to be mixed with water, and the resulting solution is used for the treatment. Formulation example 4 Dressed gauze. Each gauze is impregnated with fosfomycin dissolved in a suitable amount of propylene glycol. Formulation example 5 Ointment: 100 g of ointment contain Fosfomycin 10 g Yellow vaseline 75 g Lanolin anhydrous 3 g Wool wax 2 g Light mineral oil 10 g

Claims: Use of a fosfomycin pharmaceutically acceptagle salt for the preparation of a medicament for use as a cicatrizing agent.

Inventors: RAPISARDA NUNZIO, RAPISARDA, NUNZIO
Applicants: FRANCIA FARMA, PIGNATARO SALVATORE, RAPISARDA NUNZIO, FRANCIA FARMACEUTICI INDUSTRIA FARMACO BIOLOGICA S.R.L., PIGNATARO, SALVATORE, RAPISARDA, NUNZIO
Application year: 1991
Main classification: A61K31
IPC codes: A61K31, A61P31, A61P43, A61P17