MXPA05005078A - Pharmaceutical composition having a higher ciprofloxacin bioavailability - Google Patents

Abstract

The present invention refers to the combination of ciprofloxacin and phenazopyridine in a single medicament, which is orally administered for treating urinary tract infections. The pharmacokinetic effect of the ciprofloxacin/phenazopyridine composition, combined in an oral medicament, results in an increase in the ciprofloxacin bioavailability, which is determined as the area located under the (ABC) curve of the plasmatic concentration in a time interval of from about 0 to about infinite. The increase of the ABC curve while the ciprofloxacin/phenazopyridine combination is administered allows minimum inhibitory concentrations of ciprofloxacin with an antibacterial effect to be kept in the blood for a longer period of time with respect to that attained by the administration of ciprofloxacin as a single drug.

Description

"PHARMACEUTICAL COMPOSITION OF GREATER BIODISPONIBILITY OF CIPROFLOXACINO" Background of the Invention The present invention relates to a pharmaceutical composition containing a combination of a quinolone and a urinary tract analgesic. In particular, the present invention relates to an oral pharmaceutical preparation of ciprofloxacin with phenazopyridine, which allows a greater bioavailability of ciprofloxacin than that which is obtained when the latter is administered as a single drug at the same concentration as that found in the aforementioned preparation. This preparation is directed to the treatment of bacterial infections of the urinary tract.

The treatment of bacterial infections of the urinary tract has traditionally consisted in combating infection with antimicrobials, and in the simultaneous administration of analgesics to relieve pain resulting from irritation of the lower urinary tract mucosa.

Among the therapeutic treatments to treat this type of infections is the administration of antibacterials such as trimethoprim and sulfamethoxazole (co-trimoxazole) or nalidixic acid. Despite the therapeutic success of these antimicrobials, co-trimoxazole and nalidixic acid have come to to be replaced more and more frequently by second-generation quinolones which have a fluorine atom in their molecule and are therefore known as fluoroquinolones. Ciprofloxacin, which belongs to this group, represents an important therapeutic advance in the treatment of urinary tract infections since it has a higher antibacterial potency and develops less bacterial resistance than co-trimoxazole or Acnalidixico.

With this approach, a formulation has been developed that contains a combination of ciprofloxacin and phenazopyridine in a single tablet for the treatment of acute urinary tract infections that present with pain, burning, and tenesmus, and are caused by microorganisms sensitive to ciprofloxacin.

Description of the invention The pharmaceutical compositions of the present invention contain a combination of a quinolone having an antibacterial activity and an analgesic of the urinary tract. In particular, the present invention relates to the pharmaceutical preparation of oral solid forms containing combinations of ciprofloxacin and phenazopyridine. These preparations are useful for the treatment of urinary tract infections because they provide a double benefit by fighting the infection of a wide range of microorganisms, and fighting the pain that results from the irritation of the lower urinary tract mucosa.

Ciprofloxacin has an excellent penetration in several tissues, with the advantage of eliminating the uro-pathogen germs located in the perineal, vaginal and peri-rectal regions. For its part, phenazopyridine is excreted in the urine where it exerts its topical analgesic effect on the mucosa of the urinary tract.

The ciprofloxacin employed in the present invention has the chemical name; 1-Cyclopropyl-6-fluoro-l, 4-dihydro-4-oxo-7 (l-piperazinyl) -3-quinolinecarboxylic acid represented by the formula CpHtgFNsOs, as well as its salts and hydrates. The structural formula is represented in figure 1.

The phenazopyridine employed in the present invention has the chemical name, 2,6-diamino-3-phenylazopyridine, and formula CpHp s, as well as its salts and hydrates. The structural formula is represented in figure 2.

The dosage forms (compositions) of the present invention suitable for oral administration contain a total of 300 to 700 mg of active ingredients per unit. In these pharmaceutical compositions the active ingredients may be present in a proportion of 65 to 77% w / w based on the total weight of the composition.

The active ingredients can be administered orally in solid dosage forms, such as capsules, tablets and powders. The capsules, tablets or powders may be composed of the active ingredients and excipients such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, talc, stearic acid and the like. The tablets may be coated with sugar or polymer films to mask the taste and to protect them from the environment, or they may be coated with an enteric layer to achieve selective disintegration in the gastrointestinal tract.

In the following examples, possible compositions of the present invention are presented: Example 1.

Tablets with the composition ciprofloxacin / phenazopyridine can be prepared by mixing the following ingredients, compressing into tablets and coating with a protective film.

Dry corn starch USP 24.00 Microcrystalline cellulose 50.50 Hydroxypropylmethylcellulose 10.77 Magnesium stearate 3.00 Triacetin 1.79 Example 2 Capsules with the ciprofloxacin / phenazopyridine composition can be prepared by mixing the following ingredients and filling the hard gelatin capsules with the mixture. mg capsule Ciprofloxacin monohydrate hydrochloride 125.00 Phenazopyridine hydrochloride 50.00 Anhydrous lactose USP 264.00 USP 50.00 dry corn starch Talc 15.00 Magnesium stearate 3.00 Calorimetry studies made to the ciprofloxacin / phenazopyridine formulation plus inactive ingredients show that there is no chemical interaction between them.

Pharmacokinetics The increase in the bioavailability of ciprofloxacin when the drug is administered as a combination drug ciprofloxacin / phenazopyridine by mouth, with respect to what is obtained when administered has only been demonstrated in a double-blind, cross-over, randomized, 2-period study. 2 sequences, carried out in 24 healthy Mexican volunteers, at the General Hospital of Mexico to which they were administered, in a single dose, the combined medication (ciprofloxacin 500 mg plus phenazopyridine 200 mg) or the drug alone (500 mg ciprofloxacin) Figure 3 shows the increased bioavailability of ciprofloxacin in the combination drug. In the following table the results are shown; the area under the curve (ABC) of ciprofloxacin when given in combination with phenazopyridine is greater than when ciprofloxacin is administered as a single drug: * The numerical values represent the average and the standard error.

According to the statistical method used (Schuirmann test), in the treatments with ciprofloxacin 500 mg and with the combination (ciprofloxacin 500 mg and phenazopyridine 200 mg) the Cmax values do not differ statistically. The ABC from 0 to t, and from 0 to inf. it is statistically higher in the group that received the combination medication.

Based on the phapnacokinetic profiles, the difference in ABCs is attributed to the excretion phase of ciprofloxacin.

The increase in the AUC of ciprofloxacin in the combination drug, without an increase in Cmax, allows maintaining high plasma concentrations for a longer time, which favors the antimicrobial effect compared to the administration of ciprofloxacin as a single drug.

Therefore, the combination of the antibacterial ciprofloxacin with the urinary analgesic phenazopyridine in a single drug to which the present invention refers, represents a form of treatment of bacterial infections of the urinary tract superior to that which has been using ciprofloxacin alone .

Bibliographic references Mascellino, M.T., Farinelli, S., Iegri, F., lona, E. & De Simone, C. (1998). Antimicrobial activity of fluoroquinolones and other antibiotics on 1,116 clinical gram-positive and gram-negative isolates. Drugs imder Experimental and Clinical Research2, 139-51.

Goldstein, E.J.C., Citron, D.M., Hunt Gerardo, S., Hudspeth, M. & Merriam, C. V. (1997). Comparative in vitro activities of DU-6859a, levofloxacin, ofloxacin, sparfloxacin and ciprofloxacin against 387 aerobic and anaerobic bite wound isolates. Antimicrobial Agents and Chemotherapy 41, 1193-5.

Gaspari R, Bosker G. Urinary Tract Infection: Risk Stratification, Clinical Evaluation, and Evidence-Based Antibiotic Therapy- Year 2003 Update. Primary Care Consensus Reports, American Health Consultant, January 15, 2003.

Petri W. Antimicrobial Agents: Sulfonamides, Trimethoprim-Sulfamethoxazole, Quinolones, and Agents for Urinary Tract Infections. In: Goodman and Gilman's The Pharmacological Basis of Therapeutic, Hardman J., Limbird L. and Gilman G. eds. 10th Ed. McGraw-Hill, Intl. Ed. 2001, Chap.44, pp 1171-1188.

National Committee for Clinical Laboratory Standars 2002. Performance Standards for Antimicrobial Susceptibility Testing. Sixth Informational Supplement. NCCLS document M0OO S14, Vol.24 No. 1. National Committee for Clinical Laboratory Standards Wayne, Pa. USA.

Claims (5)

CLAIMS Based on the description made of the present invention, I consider as a novelty and therefore claim of my exclusive property, what is contained in the following clauses:

1. - A solid pharmaceutical composition containing from 10% to 50% (w / w) of ciprofloxacin of chemical name: l-cyclopropyl-6-fluoro-l, 4-dihydro-4-oxo-7 (l-piperazinyl) - 3- quinolinecarboxylic represented by the formula C? Hi8FN3O3, as well as its salts and hydrates and from 5% to 20% (w / w) of phenazopyridine having the chemical name, 2,6-diamino-3-phenylazopyridine, and formula CnHnNs, as well as their salts and hydrates.

2. - The pharmaceutical composition of claim 1 wherein the ciprofloxacin and the phenazopyridine are mixed with inactive components formulated in tablets for oral use.

3. - The pharmaceutical composition of claim 1 wherein the ciprofloxacin and phenazopyridine are mixed with inactive components formulated in capsules for oral use.

4. - The pharmaceutical composition of claim 1 wherein the ciprofloxacin and the phenazopyridine are mixed with inactive components formulated in powders for oral use.

5. - The use of the solid pharmaceutical composition claimed in the preceding claims for preparing a medicament for the treatment of urinary tract infections.