GB2232889A - Pharmaceutical composition comprising 3-(n-piperidinomethylazino)methylrifamy- cin s as active ingredient - Google Patents

Description

PHARMACEUTICAL COMPOSITION COMPRISING 3-(N-

PIPERDINOMETHYLAZIN0)METHURIFAMYCIN S AS ACTIVE INGREDIENT The present invention relates to pharmaceutical compositions comprising 3(N-piperidinomethyl-azino)methylrifamycin 5 as active ingredient.

US-A-4,447,432 and the corresponding patent applications GB-A-2,110,677 and JP-A-92682/83 (Application No. 199147/82), all in the name of the present applicants, disclose and claim azino-rifamycin compounds of formula 3 H 3 BD H 3C H 3C 3 U1 0 CH 3 NH 1 0 OS H 3 as well as the corresponding oxidized quinones. Such compounds are disclosed as having strong antibacterial activity against Gram-positive and Gram-negative bacteria and especially against Mycobacterium Tuberculosis.

It is known that rifampicin is the basic rifamycin derivative worldwide used against Mycobacterium Tuberculosis. However, many other rifamycin derivatives have been discovered and patented in the past years.

The most promising of the known rifamycin derivatives, including rifampicin, have been studied and compared with each other by Jean M. Dickinson and D.A. Mitchison of the Department of Bacteriology, Royal Postgraduate Medical School of London who have concluded that the 3-(Npiperidinomethyl-azino)methylrifamycin SV (referred to herein "FCE 22250") has the most important bactericidal activity and it is the most effective sterilizing drug having also a long half- life. Such results have been published in TUBERCLE (1987) 68, 183-193.

The outstanding biological characteristics including antibacterial activity and favourable pharmacokinetic properties of FCE 22.250 on laboratory animals are reported in THE JOURNAL OF ANTIBIOTICS, Vol. 38, No. 6, pp. 779-786, June 1985. The laboratory animals were treated by an oral route and by a parenteral route, especially intravenously, with the cited drug.

Further accurate tests carried out "in vivo" by oral administration of FCE 22250 have shown that it is unsatisfactorily absorbed. This makes it unsuitable at present for practical oral administration. Also at present, no salt or ester derivatives of FCE 22250 which may be hydrolysed in the organism after absorption are known.

This problem has been taken into very careful consideration and it has been found that the bioavailability and solubility of FCE 22250 in an environment with a pH from substantially neutral to about 1 (as it is in the gastrointestinal tract of animals) are rather low. This may explain why FCE 22250 is unsatisfactorily absorbed when it is administered by the oral route.

It has now been surprisingly discovered that the oxidized (quinone) derivative of FCE 22250, which is 3-(Npiperidinomethylazino)methylrifamycin S (referred to herein as FCE 22807) is provided with a surprisingly high solubility and enhanced bioavailability compared to its reduced paregt compound (FCE 22250). This fact leads to thebelief that FCE 22807 is easily absorbed when orally administered. it is also well known that in the organs of animals (especially in the liver) there are enzymes transforming oxidized compounds into the corresponding reduced compounds and vice-versa. It is therefore possible that FCE 22807 is wholly or partially metabolized into the parent reduced compound FCE 22250.

The title compound, 3-(N-piperidinomethyl-azino)methylrifamycin S (PCE 22807) and its synthesis are described at the end of Example 1 of US-A-4, 447,432, where the compound is identified by its MS and Rf characteristics. Nothing, however, is disclosed to suggest to one skilled in the art that the oxidized (quinone) compound FCE 22807 has enhanced solubility and bioavailability compared to its parent reduced (hydroquinone) compound FCE 22250. Furthermore, no disclosure in the prior art indicates that FCE 22807 should be selected from the numerous other available rifamycins and incorporated into a pharmaceutical composition specifically for oral administration. Indeed, the very many works carried out in many Universities and laboratories throughout the world have always made use of the reduced FCE 22250 (see also IL FARMACO, May 1985, No. 5) and never of its oxidised derivative FCE 22807.

The surprisingly good solubility and bioavailability that FCE 22807 has been found to possess therefore make it possible to prepare pharmaceutical compositions comprising 3-(N-piperidinomethyl- azino)methylrifamycin S as active ingredient, suitable for oral adminstration. The present invention accordingly provides an orally adminstrable pharmaceutical composition comprising a pharmaceutically acceptable carrier and/or diluent and, as active substance, 3-(N- piperidinomethyl-azino)methylrifamycin S.

The orally administrable pharmaceutical compositions of the invention comprise 3-(N-piperidinomethyl-azino) methylrifamycin S as active substance in association with a pharmaceutically acceptable excipient (which can be a carrier or diluent). They are suitably presented in solid or liquid form.

1 The compositions are administered orally in the form of, for example, tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions. The dosage of the active ingredient depends on the age, weight and conditions of the patient, and is chosen to yield the desired activity without causing adve::se side-effects. For example, a typical effective dosage for an adult human is in the range of about 0.001 to 0. 25 ng/kg per day, preferably from 0.01 to 0.25 mg/kg per day. The compositions of the invention are therefore typically presented in unit dosage form comprising from 10 to 200 mg of active substance.

The oral formulations of the pharmaceutical compositions of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form. The said pharmaceutical preparations may be manufactured in any known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.

Solid oral forms may comprise, together with the active ingredient, diluents, e.g., lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate; and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. a starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; /sweeteners; wetting agents, -such as lecithin, polysorbates, laurysulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations.

The liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions. Liquid carriers include water, syrup, peanut oil, olive oil and the like.

The syrup may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/ or sorbitol.

The invention further provides the use of 3-(N-piperidinomethyl-azino)methylrifamycin S in the preparation of a medicament suitable for oral administration in the treatment of bacterial infection. Antibacterial activity may be exhibited against Gram-positive and Gram-negative bacteria and against Mycobacterium Tuberculosis.

The following Example illustrates the invention.

Example 1

The different solubility and instrinsic dissolution rate of FCE 22250 and FCE 22807 are reported in the following Tables 1 and 2.

TABLE 1

Solubility at 370C (after 3 hours) - mcg/ml (by HPLC method) FCE 22807 FCE22250 H 2 0 6.3 1 pH 1.2 (Chloride buffer) 168.4 1 pH 3.1 (glycine buffer) 16.6 1 pH 5.5 (acetate buffer) 6.55 1 pH 6.8 (phosphate buffer) 20.0 6.9 pH 7.4 (phosphate buffer) 58.8 34.0 Ionic strength - 0 TABLE 2

Intrinsic dissolution rate =g/CM2 -/sec FCE 22807 6.592 x 10-' FCE 2225 3.12 x 10- 5 by the Paddle method - U.S.P. XXI 300 r.p.m; T - 370C; pH 7.4 phosphate buffer; ionic strength - 0.1 Lipophilic properties of FCE 22807 and of FCE 22250 as compared with rifampicin have been also determined by chromatography in reverse phase according to the method disclosed in the literature for the Ansamycin compounds (see: IL FARRACO, Ed. Sc., 28, 298 (1973). The results (lipophilic index, stated as value of chromatographic mobility) which have been obtained are:

Rifampicin FCE 22250 FCE 22807 m -0.305 m -0.280 m -0.325 and show that the lipophilic properties of FCE 22807 are better than those of FCE 22250 and even also of rifampicin.

Claims (4)

1. An orally administrable pharmaceutical composition comprising a pharmaceutically acceptable carrier and/or diluent and, as active substance, 3-(N-piperidinomethylazino)methylrifamycin S.

2. A composition according to Claim 1 in unit dosage form comprising from 10 to 200mg of the active substance.

3. A composition according to Claim 1 or 2 wherein the carrier and/or diluent comprises lactose, dextrose, saccharose, cellulose, corn starch or potato starch, silica, talc, stearic acid, magnesium or calcium stearate, a polyethylene glycol, starch, an arabic gum, gelatin, methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, starch, alginic acid, an alginate, sodium starch glycolate, an effervescing mixture, a dyestuff, sweetener, wetting agent, lecithin, a polysorbate, or laurylsulphate.

4. Use of 3-(N-piperidinomethyl-azino)methylrifamycin S in the preparation of a medicament suitable for oral administration in the treatment of a bacterial infection.

Published 1990 atThe Patent office. State House, 66f71 High Holborn, LondOnWC1R4TP. Further copies maybe obtainedfrom The PatentOffice. Sales Branch, St Mary Gray, Orpington, Kent BR5 3RD. Printed by Multiplex techniques ltd, St Mary Gray, Kent, Con. 1187