EP0391898A1 - Fusidic acid useful in the treatment of aids - Google Patents

Abstract

Fusidic acid and some of its analogues are useful in the profilactic and / or therapeutic treatment of complexes associated with AIDS and fully developed AIDS. Pharmaceutical compositions containing these active ingredients and methods for their preparation are described.

Description

Fusidic acid useful in the treatment of AIDS

The present invention relates to the use of fusidic acid and certain fusidic acid analogues, i.e. those described in US Patent Nos. 4,060,606, 4,100,276, 4,162,259, 4,315,004, 4,119,717 and in W. von Daehne, W.O. Godtfredsen, and P.R. Rasmussen: "Structure-Activity Relationships in Fusidic Acid-Type Antibiotics", Advances in Applied Microbiology, Volume 25, pp. 95-146 (1979) (in the following referred to as "Analogues") and their pharmaceutically acceptable salts and in vivo hydrolyzable esters in the prophylaxis and treatment of ARC (AIDS-related complex) and full-blown AIDS (acquired immune deficiency syndrome). In particular, the present invention relates to the use of fusidic acid and its analogues and their pharmaceutically acceptable salts and in vivo hydrolyzable esters for the manufacture of a medicament fo r the prophylactic or therapeutic treatment of ARC and AIDS. The present invention also relates to a pharmaceutical composition for the prophylaxis in HIV antibody positive subjects or treatment of patients suffering from ARC and AIDS, which comprises fusidic acid or one of its analogues, or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof, together with pharmaceutically acceptable, non-toxic excipients. Furthermore, the present invention is directed to a method for prophylaxis in HIV-antibody positive persons, or for the treatment of patients suffering from ARC or AIDS, which comprises administering to said subjects fusidic acid or one of its analogues, or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof.

Fusidic acid is a narrow spectrum antibiotic having the following structure I

It is formed by fermentation of the fungus Fusidium coccineum and isolated in the form of the free acid or a salt (see, for example, US Patent No. 3,072,531 and GB Patent No. 930,786; W. von Daehne, S. Jahnsen, I. Kirk, R. Larsen, and H. Lorck: Fusidic Acid: Properties, Biosynthesis and Fermentation in "Biotechnology of Industrial Antibiotics", ED. E.J. Vandamme, Marcel Decker, New York, 1984, pages 427 to 449; and W.O. Godtfredsen: Fusidic acid and some related antibiotics. Dissertation 1967, University of Copenhagen).

Since its introduction in 1962, fusidic acid has been used extensively both systemically and topically in the treatment of bacterial infections, in particular, staphylococcal infections. It has only weak activity against gram negative bacilli and fungi. At usual therapeutic doses (up to 3 g/day) it is essentially non-toxic. In order to control the emergence of fusidic acid-resistant mutants and/or to synergistically potentiate its anti-bacterial activity, fusidic acid is often used in combination with penicillins or other antibiotics (see, for instance, L.P. Garrod, H.P. Lambert, F. O'Grady, and P.M. Waterworth, "Antibiotic and Chemotherapy", Fifth Edition, Churchill Livingstone, 1981 pages 220 to 225; and EP-A-217 580).

As examples of fusidic acid analogues forming part of the present invention mention may be made of the following series of compounds: A) Compounds of the general formula II, as disclosed in US Patent No. 4,060,606,

in which Q₁ and Q₂ stand for the group or oxygen, A represents oxygen or sulphur or a sulphinyl radical, and R₁ stands for a straight or branched alkyl radical having from 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the known isomers of pentyl, hexyl, heptyl and octyl, such alkyl radicals being optionally substituted with halogen atoms or hydroxy, alkyloxy, aralkyloxy, aryloxy, alkanoyloxy, aralkanoyloxy, aroyloxy, sulfhydryl, alkylthio, aralkylthio, arylthio, alkanoylthio, aroylthio, azido, nitro, cyano, thiocyano, hydroxycarbonyl, alkyloxycarbonyl, aryloxycarbonyl, amino, alkylamino, dialkylamino, arylamino, alkanoylamino, and aroylamino groups; R₁ can further be an alkenyl or alkynyl radical having from 2 to 6 carbon atoms, such as allyl, crotyl or propargyl, a cycloalkyl radical having from 3 to 7 carbon atoms in the alicyclic ring, such as cyclop ropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or the mono- or dihalo, lower alkyl, lower alkoxy or hydroxy substituted analogues, an aralkyl, heterocyclylalkyl or aryl radical, such as benzyl, phenylethyl, phenyl or furfuryl, these radicals being optionally substituted with halogen, nitro, lower alkyl, hydroxy or alkoxy radicals; R₁ can also be a heterocyclic radical having 5 or 6 ring atoms and containing oxygen, sulphur or nitrogen atoms, such as 2- or 3-pyrrolyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-pyrazolyl, imidazolyl e.g. 1-methyl-2-imidazolyl, triazolyl e.g. 5-methyl-1,2,4- triazol-3-yl, tetrazolyl e.g. 1-methyl-1H-tetrazol-5-yl, thiazolyl, thiadiazolyl e.g. 5-methyl-1,3,4-thiadiazol-2-yl.

The dotted line between C-24 and C-25 indicates that the carbon atoms in question are connected with either a double bond or a single bond.

B) Compounds of the general formula III , as disclosed in US Patent Nos . 4 ,100 , 276 , 4 ,162 ,259 , and 4 ,315 , 004

in which Q₁ and Q₂ stand for the group or oxygen, A'represents oxygen or sulphur, and R'₁ stands for a straight or branched alkyl radical having from 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the known isomers of pentyl, hexyl, heptyl, octyl, and dodecyl, such alkyl radicals being optionally substituted with halogen atoms or hydroxy, alkyloxy, aralkyloxy, aryloxy, alkanoyloxy, aralkanoyloxy, aroyloxy, sulfhydryl, alkylthio, aralkylthio, arylthio, alkanoylthio, aroylthio, azido, nitro, cyano, thiocyano, hydroxycarbonyl, alkyloxycarbonyl, aryloxycarbonyl, amino. alkylamino, dialkylamino, arylamino, alkanoylamino, and aroylamino groups; R'₁ can further be an alkenyl or alkynyl radical having from 3 to 6 carbon atoms, such as allyl, crotyl or propargyl, a cycloalkyl radical having from 3 to 7 carbon atoms in the alicyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or the mono- or dihalo, lower alkyl, lower alkoxy or hydroxy substituted analogues, an aralkyl or aryl radical, such as benzyl, phenylethyl, phenyl, furfuryl or naphthyl, optionally substituted with halogen, lower alkyl, hydroxy or alkoxy radicals; R'₁ can also be a heterocyclic radical having 5 or 6 ring atoms and containing oxygen, sulphur or nitrogen atoms, such as 2- or 3-pyrrolyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-pyrazolyl, imidazolyl e.g. 1-methyl-2-imidazolyl, triazolyl e.g. 5-methyl-1,2,4-triazol-3-yl, tetrazolyl e.g. 1-methyl-1H-tetrazol-5-yl, thiazolyl, thiadiazolyl e.g. 5-methyl-1,3,4-thiadiazol-2-yl.

The dotted line between C-24 and C-25 indicates that the carbon atoms in question are connected by either a double bond or a single bond, and the asterix at C-20 indicates that the compounds exist in two diastereomeric forms which both are part of the invention

C) Compounds of the general formula IV, as disclosed in US Patent No. 4,119,717

in which Q'₁ represents oxygen or one of the groupings Z being a hydroxy group, a halogen atom, an alkylsulfonyloxy or arylsulfonyloxy group, such as methanesulfonyloxy or p-toluenesulfonyloxy, an azido or a nitro group Q₂ is oxygen or the grouping and R₁ stands for a straight or branched alkyl radical having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, iso- propyl, butyl, isobutyl, tert-butyl or the known isomers of pentyl and hexyl, a phenyl or a heterocyclyl radical having 5 or 6 ring atoms and containing nitrogen, oxygen and/or sulfur atoms, these radicals being optionally substituted with halogen, nitro, lower alkyl or lower alkoxy radicals.

The dotted line betwen C-24 and C-25 indicates that the carbon atoms in question are connected by either a double bond or a single bond. Where not otherwise stated the term "lower" indicates a carbon atom content of 1 to 4.

Unless otherwise indicated herein, the alkyl groups preferably contain 1 to 4 carbon atoms, the alkanoyl groups preferably contain 1 (or 2) to 7 carbon atoms and preferred, aryl radicals are phenyl and naphthyl. The preferred aralkyl, alkoxy, aralkyloxy, aryloxy, alkanoyloxy, aralkanoyloxy, aroyloxy, alkylthio, aralkylthio, arylthio, alkanoylthio, aroylthio, alkoxycarbonyl, aryloxycarbonyl, alkylamino, dialkylamino, arylamino, alkanoylamino, aroylamino radicals etc. are derived from the above preferred alkyl, aryl and alkanoyl groups. All of these groups may be straight- chain or branched radicals.

Although fusidic acid and a few related compounds have been shown to have some in vitro activity against certain viruses such as Coxsackie virus A21, and rhinovirus (see, for example, Br. J. Pharm. Chemother., 1967, 31, pageg 210 to

220), it has never been possible to demonstrate a clinical effect of fusidic acid or any of its analogues in viral diseases. It has now suprisingly been found that fusidic acid and the fusidic acid analogues described above as well as the pharmaceutically acceptable salts and in vivo hydrolyzable esters thereof have a clinical effect against ARC and AIDS caused by the retrovirus HIV (human immunodeficiency virus).

Patients suffering from ARC or AIDS are susceptible to a number of opportunistic infections which are difficult to treat with usual antimicrobial therapy since the immune system of such patients is damaged and, therefore, does not assist in the elimination of the pathogens. A special problem with such patients is the presence of intracellular microorganisms which cannot be reached by many of the known antibiotics, such as β-lactam antibiotics and aminoglycosides.

Since it is known that fusidic acid can penetrate phagocytic cells and kill introcellular bacteria, fusidic acid sodium salt was administered to AIDS patients with

opportunistic infections in the hope that it might assist other antibiotics in combatting these infections. It was, unexpectedly, found that, when fusidic acid was added to the therapeutic regimen of AIDS patients, it caused a remarkable improvement of their general condition which cannot be explained exclusively by the well-known antibacterial effect of the antibiotic. The present invention is based on this unexpected finding.

In view of these favourable clinical results, fusidic acid and its analogues were tested in vitro against human immunodificiency virus (HIV) which is the etiologic agent of AIDS.

HIV binds to a specific and selective subset of T-lymphocytes called T-4 helper/inducer cells which are phenotypically defined by the presence of CD4 molecules along their surfaces. The CD4 molecule which is used by cells to recognise antigenes in association with the class I major histocompatibility complex is also the receptor for the virus. The T-4 cell has the major responsibility for orchestrating virtually all immune functions in humans and, therefore, HIV can do maximal damage to the immune system by eliminating this particular cell.

In the in vitro test for anti-HIV activity, a CD4 positive cell line was used. It was examined which concentrations of fusidic acid were necessary to prevent infection of this cell line with three different retrovirus isolates, namely, CBL-1, ARV-2 and RF.

The results showed that fusidic acid at a concentration of 50 μg/ml is able to inhibit the HIV prototype isolate CBL-1 from infecting the CD4 positive cell line and that 100 μg/ml was required to prevent infection of this cell line with the other isolates ARV-2 and RF.

Plasma concentrations of the active ingredients of the present invention exceeding 100 μg/ml can easily be attained by, for example, oral or intravenous administration of doses which are essentially non-toxic. Since it is known that fusidic acid concentrations in leucocytes and lymphocytes are 7 to 10 times higher than in the surrounding medium, it should thus be possible to inhibit HIV replication in humans with non-toxic doses (cf. A. Forsgren and A. Belahsene: "Antibiotic Accumulation in Human Polymorphonuclear Leucocytes and Lymphocytes" in Scand. J. Infect. Dis. 1985, Supp. 44, pp. 16-23).

Moreover, it has been shown that certain analogues have an in vitro effect against the retrovirus HIV (cf. Table 1).

Thus, the invention is directed to the use of fusidic acid and its analogues, and their pharmaceutically acceptable salts and in vivo hydrolyzable esters, in the manufacture of a medicament for the prophylaxis in HIV antibody positive subjects or treatment of patients suffering from ARC or AIDS. Furthermore, the invention relates to a method for the prophylactic or therapeutic treatment of ARC and AIDS, which comprises administering an effective amount of fusidic acid or one of its analogues or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof to a person in need of such treatment.

Also, the invention relates to a pharmaceutical composition for the prophylaxis in HIV antibody positive subjects or treatment of patients. suffering from ARC and AIDS, which comprises fusidic acid or one of its analogues, or a pharmaceutically acceptable salts or in vivo hydrolyzable ester thereof, together with pharmaceutically acceptable, non-toxic excipients.

The pharmaceutical compositions of the present invention are, generally, prepared by bringing the active ingredient (fusidic acid or one of its analogues or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof) into association with one or more pharmaceutically acceptable non-toxic excipients.

Specific examples of pharmaceutically acceptable salts are salts of fusidic acid with alkali metals, alkaline earth metals, amines and alkanolamines; for instance, the water-soluble sodium, potassium, ammonium, triethylamine, piperidine, morpholine, cyclohexylamine, monoethanolamine and diethanolamine salts and the slightly water-soluble calcium, magnesium, sym-dibenzylethylenediamine, benzyl-β-phenyl- -ethylamine and procaine salts. Other suitable salts are, for instance, those with pyrrolidine, piperazine, guanidine, methylamine, ethylamine, benzylamine or similar unsubstituted or substituted amines, furthermore, quaternary amines such as choline and its derivatives,and salts with basic antibiotics such as aminoglycosides and ansamycines such as rifampicin. Specific examples of in vivo hydrolyzable ester groups are: alkanoyloxymethyl with from 3 to 8 carbon atoms, 1-(alkanoyloxy) ethyl with from 4 to 9 carbon atoms, alkoxycarbonyloxy-methyl with from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)-ethyl with from 4 to 7 carbon atoms, and α-aminoalkanoyloxy-methyl with from 2 to 6 carbon atoms. Other preferred esters are lactonyl esters, e.g. 3-phthalidyl, 4-crotonolactonyl or γ-butyrolacton-4-yl esters.

Also within the scope of the invention are methoxy- methyl, cyanomethyl, or mono- or dialkyl substituted amino- alkyl esters, e.g. 3-dimethylaminoethyl, 2-diethylaminoethyl, or 3-dimethylaminopropyl esters.

A pharmaceutically acceptable excipient is to be broadly understood to include any carrier, diluent, filler, binder or other substance such as an inert pharmaceutical additive to facilitate formulation that is acceptable for administration to a human patient from a toxicity viewpoint and that will not substantially interfere with the administration of the active compound.

Depending on the intended mode of administration, the compositions may be in the form of solid, semi-solid or liquid dosage forms such as, for example, tablets, capsules, sterile powders for reconstitution before parenteral administration, suppositories, pills, liquids, suspensions or the like, preferably in unit dosage forms suitable for single administration of precise dosages. Such unit dosage forms preferably contain the active ingredient in an amount of from 0.025 g to 1 g per dosage unit. For solid compositions, conventional non-toxic solid excipients include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate and the like. The active ingredient as defined above may be formulated as suppositories using, for example, polyalkylene glycols, for example, propylene glycol, as the carrier. Liquid pharmaceutically administerable compositions, can, for example, be prepared by dissolving, dispersing etc., an active compound as defined above and optional pharmaceutical adjuvants in a carrier such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art, for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 15th Edition, 1975.

For oral administration fast disintegrating formulations are preferred in order to avoid any local irritation which might be caused by fusidic acid at the dosages employed. A particularly preferred formulation of this type is a film-coated tablet which comprises the following components:

Active ingredient 40 to 60 wt.%

Crospovidone 5 to 20 wt.%

Auxiliary agents ad 100 wt.%

(e.g., fillers, such as lactose and microcrystalline cellulose; binders, such as gelatine and polyvinylpyrrolidone; glidants such as silica; lubricants, such as talc and magnesium stearate; disintegrants, preservatives; flavouring agents etc.)

The film coating, for instance, consists of hydroxy- propylmethylcellulose and may contain a colouring agent such as titanium dioxide. The film-coated tablets is fast disintegrating and shows good bioavailability without any local irritation.

Administration of the active ingredients according to the present invention and of the pharmaceutical compositions described above, can be via any of the accepted modes of administration for antiviral agents. These methods include oral, parenteral, and otherwise systemic administration. Parenteral administration is generally characterized by intravenous injection or infusion.

The amount of active ingredient administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration and the judgement of the prescribing physician. The daily dosage, however, usually varies from 5 to 75 mg/kg body weight, preferably 10 to 50 mg/kg body weight, and may, for instance, be given orally in one or more, preferably one to three doses per day or continuously as infusion.

It is advantageous to combine the treatment with the active ingredient of the present invention with other therapy such as antibacterial, antitubercular, antifungal, antiparasitic, antiviral, and/or immunomodulating drugs. The combined treatment can take place by administration of the drugs individually or in fixed combinations.

As examples of antibacterial drugs used in such combined treatment, mention may be made of β-lactam antibiotics such as:

(i) penicillins and their prodrugs, for example benzylpenicillin, phenoxymethylpenicillin, methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, ampicillin, epicillin, amoxicillin, hetacillin, pivampicillin, bacampicillin, talampicillin lenampicillin, carbenicillin, carfecillin, carindacillin, ticarcillin, azlocillin, mezlocillin. piperacillin, apalcillin, aspoxicillin, sulbenicillin, temocillin, formidacillin (BRL 36650), mecillinam (amdinocillin), pivmecillinam, bacmecillinam, augmentin, and sultamicillin; (ii) cephalosporins and their prodrugs, for example cephaloglycin, cephalothin, cephaloridine, cefazolin, cefsulodin, cefalexin, cephradine, cefamandole, cefonicid, cefotiam, cefuroxime, cefuroxime axetil, cefotaxime, ceftizoxime, cefodizime, ceftriaxone, cefmenoxime, ceftazidime, cefoperazone, cefpinazole, cefpiramide, cefpirome, cefminox, cefuzonam, cefepime (BMY 28142), cefachlor, cefadroxil, cefroxadine, cefixime, cefetamet, ceftetrame, cefteram pivoxil, SCH 39720 (7432-S), cefoxitin, cefmetazole, cefotetan, cefbuperazone, moxalactam, and flomoxef (6315-S);

(iii) monobactams and their prodrugs, for example azthreonam, carumonam, tigemonam, and pirazmonam; and (iv) carbapenems and penems and their prodrugs, for example imipenem, FCE 22101, SCH 29482, and SCH 38343; tetracycline antibiotics such as tetracycline, chlorotetracycline, oxytetracyline, rolitetracycline, demeclocycline, lymecycline, methacycline, clomocycline, cloxycycline, and minocycline; macrolide and lincosamide antibiotics such as erythromycin and its esters, oleandomycin, josamycin, rosaramycin, spiramycin, roxithromycin, lincomycin, and clindamycin; ansamvcin antihiotics such as rifamycin, rifampicin, and rifabutin; qninolone antibiotics such as nalidixic acid, norfloxacin, ofloxacin, ciprofloxacin, enoxacin, fleroxacin, difloxacin, pirfloxacin, and pefloxacin; aminoglycoside antihiotics such as gentamycin, kanamycin, tobramycin, dibekacin, abikamycin, streptomycin, amikacin, spectinomycin, butyrosin, sissomycin, framycetin, and neomycin; diaminopyrimidines such trimethoprim and tetroxaprim; sulphonamides such as sulphamethizole, sulphadiazine, sulphadimetoxine, sulphamethoxypyridazine, and phthalyl- sulphathiazole; as well as other antibiotics such as chloramphenicol, olymyxin, deptomycin (LY 146032), novobiocin, vancomycin, teichoplanin, and fosfomycin. As examples of antifungal drugs to be used in such combined treatment, mention may be made of amphothericin B, nystatin, griseofulvin, flucytosine, miconazole, clotrimazole, econazole, and ketoconazole.

As examples of antiparasitic drugs to be used in such combined treatment, mention may be made of metronidazole, tinidazole, chloroquine, levamisole, and pentamidine.

As examples of antitnhercular drugs to be used in such combined treatment, mention may be made of isoniazide, ethambutol, p-aminosalicylic acid, pyrazinamide, and dapsone. As examples of antiviral drugs to be used in such combined treatment, mentioned may be made of acyclovir, amphotericin B methyl ester, glycyrrhizin, ribavirin, amantidine, foscarnet, ganciclovir, eflornithine, and desciclovir. As examples of immunomodulators to be used in such treatment, mention may be made of α-interferon, β-interferon, cyclosporin, interleukin 2, isoprinosine, krestin, lentinan, muramyl tripeptide, and penicillamine.

The following is a typical case history of an AIDS patient treated with fusidic acids

The patient, a 58 year old male with a past history of hepatitis (HBsAG positive) and recurrent seborrhoic dermatitis, was well until 1984 when he consulted a physician since he was suffering lethargy, fever and weight loss. Upon examination he was found to have generalised lymphadenopathy. He was found to be HIV positive by ELISA and Western blot with a normal T helper lymphocyte count but was allergic to non-specific mitogens. He remained stable with no further deterioration until 1986 when he suffered further weight loss and diarrhoea. Gastro-enterological investigations revealed atrophic gastritis, B12 malabsorption, candidial esophagitis as well as Entamoeba coli, Entamoeba hartmannii, Endolimax nana, Iodamoeba bfltschlii and Ascaris lumbricoides in the stool. Mycobacterium hominis was grown from both the stool and the flood following the detection of acid fast bacilli in a lymph node biopsy. The patient was given isoniazid, ethambutol and rifampicin as well as antiparasitic and local antifungal therapy. After six weeks of treatment there was no improvement with respect to his symptoms and he continued to lose weight (16 kg since admission).

At this time, fusidic acid sodium salt (500 mg three times a day orally) was added to his regimen. Two weeks following commencement he became afebrile, began to put on weight and was able to undergo a transurethral prostectomy, following which he returned to work and has been well since. Two months later he had increased his weight by 10 kg.

The following examples serve to illustrate the present invention but should not be construed as narrowing it or limiting its scope in any way.

EXAMPLE 1 Capsule Sodium fusidate 250 g

Polyvidone 10 g

Magnesium stearate 5 g

Moisten the sodium fusidate with a solution of polyvidone in ethanol/methylenechloride (1:9) and dry the granulate at 35°C. Sieve the granulate through a 0.6 mm sieve, mix with magnesium stearate. Fill the granulate in hard gelatine capsules No. 0 using a fill weight of 265 mg yielding approx. 1000 capsules.

EXAMPLE 2 Tablet

Sodium fusidate 200 g

Polyvidone 10 g Crospovidone 50 g Lactose 210 g

Talc 25 g

Magnesium stearate 5 g Moisten the sodium fusidate with a solution of polyvidone in ethanol/methylenechloride (1:9) and dry the granulate at 35ºC. Sieve the granulate through a 1 mm sieve and mix with Crospovidone, lactose, talc and magnesium stearate. Press 1000 tablets of 500 mg each, using a tablet press equipped with 12 mm circular punches.

EXAMPLE 3 Tablet Sodium fusidate 250 g

Polyvidone 12. 5 g

Crospovidone 50 g

Talc 36 g

Colloidal silica 5 g Microcrystalline cellulose 72 g

Lactose 72 g

Gelatine 0. 4 g

Magnesium stearate 2 g

Hydroxypropylmethylcellulose 8 g Titanium dioxide 0.5 g

Moisten the sodium fusidate with a solution of polyvidone in ethanol/methylenechloride (1:9) and dry the granulate at 35ºC. Sieve the granulate through a 1 mm sieve. Granulate the lactose with gelatine dissolved in water, dry at 60°C and sieve the granulate through a 1 mm sieve. Mix the granulates with the Crospovidone, talc, silica, cellulose and magnesium stearate. Press 1000 tablets of 500 mg each using a tablet press equipped with 7.8 x 16 mm oval punches. Film-coat the tablets in a fluid-bed coater with a solution prepared from hydroxypropylmethylcellulose and titanium dioxide in equal parts of ethanol and water.

EXAMPLE 4 Injectable solution

A solution for intravenous injection is prepared by dissolving the following dry substance in the solvent prior to use :

Dry substance

Sodium fusidate 1000 g Dry-fill 1 g of sodium fusidate aseptically in each sterile vial and close with a rubber stopper and an aluminium cap.

Solvent Citric acid 20 g

Sodium phosphate 390 g

Water for injection up to 20 litres

Dissolve the citric acid and sodium phosphate in water for injection.

Filter the solution through a 0.2 μm membrane filter and fill 20 ml into each vial. Close the vials with rubber stoppers and aluminium caps. Finally, sterilize the solution by autoclaving at 121°C for 15 minutes.

EXAMPLE 5 Injectable solution

A solution for intravenous injection is prepared by dissolving the following dry substance in the solvent prior to use:

Dry substance Sodium 16-deacetoxy-16β-acetyl- thiofusidate (VD1460 sodium) 1040 g

Dry-fill 1.04 g of VD1460 sodium aseptically in each sterile vial and close with a rubber stopper and an aluminium cap.

Solvent

Citric acid 20 g

Sodium phosphate 390 g Water for injection up to 20 litres

Dissolve the citric acid and sodium phosphate in water for injection and fill 20 ml in each vial. Close the vials with rubber stoppers and aluminium caps. Finally sterilize the solution by autoclaving at 121ºC for 15 minutes.

EXAMPLE 6

Capsule

Sodium 16-deacetoxy-16β-benzoyl- thiofusidate (VD1546 sodium) 250 g

Corn starch 25 g

Polyvidone 8 g

Magnesium stearate 5 g

Mix the VD1546 sodium with the corn starch and moisten the powder with a solution of polyvidone in ethanol and deionized water, equal parts.

Dry the granulate at 40°C, pass it through a 0.6 mm sieve and mix with the magnesium stearate. Fill the granulate in hard gelatin capsules no.0 using a fill weight of 288 mg, yielding app. 1000 capsules.

EXAMPLE 7

Tablet

3α,11α-dihydroxy-16β-isopropyl- thiofusida-13(17),24-dien-21-oic acid (PR1089) 400 g

Corn starch 200 g Methylcellulose 15 cps 30 g

Crospovidone 30 g

Magnesium stearate 5 g

Talc 30 g Silicon dioxide 5 g

Mix PR1089 and the corn starch.

Moisten the powder with an aqueous solution of the methylcellulose and dry the granulate at 50°C.

Sieve the granulate through a 1 mm sieve and mix with crospovidone, magnesium stearate, talc and silicon dioxide. Press 1000 tablets of each 700 mg using a tablet press equipped with 13.5 mm circular punches.

EXAMPLE 8

Tablet

Fusidic acid 250 g Rifampicin 300 g

Corn starch 50 g

Methylcellulose 15 cps 15 g

Corn starch 30 g

Microcrystalline cellulose 70 g Talc 35 g

Magnesium stearate 5 g

Mix fusidic acid, rifampicin with the corn starch and moisture the powder with methylcellulose dissolved in deionized water. Dry the moist mass at 45°C and sieve the granulate through a 1.2 mm sieve.

Mix the granulate with corn starch, microcrystalline cellulose, talc and magnesium stearate.

Press 1000 tablets of each 755 mg using a tablet press equipped with 10 x 18 mm oval punches.

Claims

1. A pharmaceutical composition for the prophylaxis and treatment of AIDS-related complex and full-blown AIDS, which comprises an effective amount of at least one compound selected from the group consisting of:

a) fusidic acid and its pharmaceutically acceptable salts and in vivo hydrolyzable esters;

b) a compound of the general formula II

in which Q₁ and Q₂ stand for the group or oxygen, A represents oxygen or sulphur or a sulphinyl radical, and R₁ stands for a straight or branched alkyl radical having from 1 to 8 carbon atoms, such alkyl radicals being optionally substituted with one or more halogen atoms or hydroxy, alkoxy, aralkyloxy, aryloxy, alkanoyloxy, aralkanoyloxy, aroyloxy, sulfhydryl, alkylthio, aralkylthio, arylthio, alkanoylthio, aroylthio, azido, nitro, cyano, thiocyano, hydroxycarbonyl, alkyloxycarbonyl, aryloxycarbonyl, amino," alkylamino, dialkylamino, arylamino, alkanoylamino, and aroylamino groups; R₁ can further be an alkenyl or alkynyl radical having from 2 to 6 carbon atoms, a cycloalkyl radical having from 3 to 7 carbon atoms in the alicyclic ring, or the mono- or dihalo, alkyl, alkoxy or hydroxy substituted analogues, an aralkyl, heterocyclylalkyl or aryl radical, these being optionally substituted with one or more halogen, nitro, alkyl, hydroxy or alkoxy radicals; R₁ can also be a heterocyclic radical having 5 or 6 ring atoms and containing oxygen, sulphur or nitrogen atoms; and pharmaceutically acceptable salts and in vivo hydrolyzable esters thereof;

c) a compound of the general formula III

in which Q₁ and Q₂ stand for the group > or oxygen, A' represents oxygen or sulphur, and R'₁ stands for a straight or branched alkyl radical having from 1 to 12 carbon atoms, such alkyl radicals being optionally substituted with one or more halogen atoms or hydroxy, alkoxy, aralkyloxy, aryloxy, alkanoyloxy, aralkanoyloxy, aroyloxy, sulfhydryl, alkylthio, aralkylthio, arylthio, alkanoylthio, aroylthio, azido, nitro, cyano, thiocyano, hydroxycarbonyl, alkyloxycarbonyl, aryloxycarbonyl, amino, alkylamino, dialkylamino, arylamino, alkanoylamino, and aroylamino groups; R'₁ can further be an alkenyl or alkynyl radical having from 3 to 6 carbon atoms, a cycloalkyl radical having from 3 to 7 carbon atoms in the alicyclic ring, or the mono- or dihalo, alkyl, alkoxy or hydroxy substituted analogues, an aralkyl or aryl radical optionally substituted with one or more halogen, alkyl, hydroxy or alkoxy radicals; R'₁ can also be a heterocyclic radical having 5 or 6 rings atoms and containing oxygen, sulphur or nitrogen atoms; and pharmaceutically acceptable salts and in vivo hydrolyzable esters thereof; and

d) a compound of the general formula IV

in which Q '₁ represents oxygen or one of the groupings

Z being a hydroxy group, a halogen atom, an alkylsulfonyloxy or arylsulfonyloxy group, an azido or

a nitro group, Q₂ is oxygen or the grouping and

R"₁ stands for a straight or branched alkyl radical having from 1 to 6 carbon atoms, a phenyl or a heterocyclyl radical having 5 or 6 ring atoms and containing nitrogen, oxygen and/or sulphur atoms, these radicals being optionally substituted with one or more halogen, nitro, alkyl or alkoxy radicals, and pharmaceutically acceptable salts and in vivo hydrolyzable esters thereof;

as an active ingredient in association with one or more pharmaceutically acceptable non-toxic excipients.

2. A composition according to claim 1 in the form of a sterile powder for reconstitution before parenteral administration.

3. A composition according to claim 1 in the form of an aqueous suspension or solution.

4. A composition according to claim 1 in the form of a tablet or capsule.

5. A composition according to claim 4, containing a compound as defined in claim 1 in an amount of 0.025 g to 1 g per dosage unit.

6. A composition according to claim 1, containing fusidic acid or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof.

7. A composition according to claim 1, containing 16-deacetoxy-16β-acetylthiofusidic acid or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof.

8. A composition according to claim 1, containing 16-deacetoxy-16β-benzoylthiofusidic acid or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof.

9. A composition according to claim 1, containing 3α, 11α- dihydroxy-16β-isopropylthiofusida-13(17), 24-dien-21-oic acid or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof.

10. A film-coated tablet comprising the following components in the amounts indicated (based on the total weight):

Fusidic acid or pharmaceutically acceptable salt thereof 40 to 60 wt.%

Crospovidone 5 to 20 wt.% Auxiliary agents ad 100 wt.%

11. A compound as defined in claim 1 for use as active ingredient in the prophylaxis and treatment of AIDS- related complex and full-blown AIDS.

12. Fusidic acid and its pharmaceutically acceptable salts and in vivo hydrolyzable esters for use as active ingredients in the prophylaxis and treatment of AIDS- related complex and full-blown AIDS.

13. The use of a compound as defined in claim 1 as active ingredient in the manufacture of a medicament for the prophylaxis and treatment of AIDS-related conplex and full-blown AIDS.

14. A method of treating persons in risk of contracting or suffering from AID-related complex and full-blown

AIDS, which comprises administering an effective amount of a compound as defined in claim 1 as active ingredient to a person in need of such treatment.

15. A method according to claim 14 which comprises the prophylactic treatment of a person in risk of contracting AIDS-related complex and full-blown AIDS.

16. A method according to claim 14 which comprises the therapeutic treatment of a patient suffering from AIDS- related complex and full-blown AIDS.

17. A method according to claim 14 which comprises administering a compound as defined in claim 1 as active ingredient in combination with one or more antibacterial, antitubercular, antifungal, antiparasitic, antiviral and/or immunomodulating drugs.

18. A method according to claim 17 which comprises administering a compound as defined in claim 1 as active ingredient in combination with an ansamycin antibiotic such as rifampicin.