KR910009365B1 - Pharmaceutical preparations containing ciprofloxacin - Google Patents

Abstract

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Description

Antibiotics of ciprofloxacin

The present invention relates to a medicament of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acid (hereinafter also referred to as ciprofloxacin), It relates to a process for the preparation of this formulation and to capsules and tablets containing the formulation.

1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acid and physiologically acceptable derivatives thereof are described in European patent applications No. 49,355 is described in the Federal Republic of Germany Patent Application No. 3,142,854. In addition, lactic acid solutions of ciprofloxacin that are suitable for injection and infusion are described in Federal Patent Application No. 3,333,719.

The present invention can be administered orally, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acid 30.0 -95.0 wt%, cellulose based dry binder 4.5-25.0 wt%, starch based disintegration aid 0.0-30.0 wt%, cellulose derivative and / or crosslinked polyvinylpyrrolidone based disintegration aid 0.5-10.0 wt%, flow-enhancing agent ( flow-improving agent) 0.0-2.0% by weight and a lubricant containing 0.0-3.0% by weight of the lubricant.

The pharmaceutical agents according to the present invention have high bioavailability and very good shelf life.

Formulations according to the invention are 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acid. It is suitable to contain 60.0-90.0% by weight of HCl salt monohydrate.

60-90 wt% of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acid and HCl salt monohydrate, cellulose Substrate dry binder 3.0-15.0 wt%, starch base disintegration aid 5.0-16.0 wt%, cellulose derivative and / or crosslinked polyvinylpyrrolidone base disintegration aid 1.0-7.0 wt%, flow enhancer 0.5-1.0 wt% and lubricant 0.5 A drug containing -1.0 wt%, and 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acidHCl Salt monohydrate 72.4-78.8 wt%, cellulose based dry binder 7.0-9.0 wt%, starch based disintegration aid 9.0-12.0 wt%, cellulose derivative and / or crosslinked polyvinylpyrrolidone based disintegration aid, 4.0-5.0 wt% Pharmaceuticals containing 0.6-0.8% by weight of flow enhancer and 0.6-0.8% by weight of lubricant are more suitable.

However, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acid. 72.4-78.8 wt% HCl salt monohydrate, 7.0-9.0 wt% microcrystalline cellulose, 9.0-12.0 wt% corn starch, 4.0-5.0 wt% crosslinked polyvinylpyrrolidone, 0.6-0.8 wt% colloidal silicon dioxide and stearic acid Pharmaceuticals containing 0.6-0.8% by weight magnesium acid are particularly suitable.

As a dry binder, it is suitable to use highly purified microcrystalline cellulose having a molecular weight of 30,000-50,000, a particle size of 10-50 mu and a molar content of 4-6% by weight.

Disintegration aids which can be used are on the one hand conventional starch, in particular corn starch, on the other hand cellulose derivatives and / or crosslinked polyvinylpyrrolidone.

The cellulose derivative commonly used for this purpose is, for example, sodium carboxymethylcellulose. Crosslinked PVC is commercially available, for example, under the trade names Kolloidon ^R Cl [Basf Actien Gegelsft, Ludwigschaffen (Germany)] or Plasdone ^R XL (General Aniline Ant Film Corp., New York, USA).

r Phamazie, Kosmetik und angrenzende Gebiete(Dictionary of Auxiliaries for Pharmacy, Cosmetics and associated fields), Editio Captor KG, Aulendorf I. W

tt.(독일연방공화국)참조]를 예시할 수 있다.Flow control agents that can be used are also often used as powder bases or powder bases, and are finely divided materials having properties that provide better flow and outflow capabilities to other finely divided materials with a particular cohesion. Suitable materials for this are, for example, Aerosil ^R (high purity amorphous (X-ray measured) silicon dioxide (> 99.8% SiO ₂ )), Aerosil ^R 972 (silicon dioxide with hydrophobic properties due to chemically altered methyl groups), NAL ^R and NAL ^R RS (a fine powder product made from rice starch) (also Lexikonder Hilfsstoffe f by HPFiedler)

Phamazie, Kosmetik und angrenzende Gebiete (Dictionary of Auxiliaries for Pharmacy, Cosmetics and associated fields), Editio Captor KG, Aulendorf I. W

(see Federal Republic of Germany).

Lubricants are, for example, talc, calcium stearate, magnesium stearate and solid polypropylene glycol. Of these, magnesium stearate is suitable.

Moreover, this invention relates to the manufacturing method of the effective compound preparation by this invention.

For this purpose, 30.0-95.0% by weight of active compound ciprofloxacin, 4.5-25.0% by weight of cellulose-based dry binder, up to 30.0% by weight of starch-based disintegration aids, cellulose derivative and / or ) 0.5-10.0% by weight of crosslinked polyvinylpyrrolidone-based disintegration aid, 2.0% by weight of flow neutralizing agent and, if necessary, 3.0% by weight of lubricant, and then the mixture is pressed in a dry state. It was ground, sieved, and pressed as necessary to form tablets or filled into capsules.

One variation of the above production method involves granulating by spraying the active compound mixture with water or binder aqueous solution continuously in a fluidized bed granulator, simultaneously passing it in warmth, sieving the resulting granules and The mixture is compressed to form a tablet.

In another variant, the effective mixture ciprofloxacin is optionally granulated with cellulose based dry binders and other cellulose derivatives and / or crosslinked polyvinylpyrrolidone based disintegration aids in the presence of starch based disintegration aids, followed by sieving the granules. If necessary, it is mixed with the residual additives, and then the mixture is compressed to form tablets or filled into capsules.

It is advantageous to provide 0.8-2 mm diameter granules by the sieving process in a further process of tablets or capsules.

Also suitably, in the following process, the active compound is mixed with cornstarch, Avicel ^R and Aerosil ^R, and the mixture is mixed with crosslinked polyvinylpyrrolidone and magnesium stearate after granulation, and then the resulting material is compressed. To prepare tablets.

The preparations according to the invention exhibit a broad antibacterial spectrum against Gram-positive and Gram-negative bacteria, in particular Enterobacteriaceae, in particular penicillin, cephalosporins, aminoglycosides, sulfonamides and tetracyclines, for example. It is active against bacteria that are resistant to various antibiotics and is characterized by low toxicity.

Such useful properties make it possible to use the formulations according to the invention as chemotherapeutic effective compounds in pharmaceuticals.

The formulations according to the invention are effective against a very broad spectrum of microorganisms. This formulation can be used to kill gram-negative and gram-positive bacteria, and bacteria-like microorganisms, and to prevent, alleviate, and / or treat diseases caused by these pathogens.

The formulations according to the invention are particularly effective against bacteria and bacteria-like microorganisms. This preparation is therefore particularly suitable for the prevention of local and systemic infections caused by the pathogen and for human and veterinary medicine for chemotherapy.

For example, local and / or systemic diseases caused by the following pathogens, or mixtures thereof, may be treated and / or prevented. Micrococcaceae, such as Staphylococci (eg Staph.aureus and Staph.epidermidis), Streptococci [eg, Streptococcus pyogenes ), α- and β-hemolytic streptococci and non-γ-haemolysing Streptococci, enterococci and pneumococcal pneumoniae (Lactobacteriaceae) such as (pheumococci); Escherichia bacteria (e.g., Escherichia coli), Enterobacter bacteria (e.g., E.aerogenes and Enterobacter in the Eschedrion group) E.cloacae], Klebsiella bacteria (e.g., K.pneumoniae), Serratia (e.g., Serratia marcescens), Proteus group Enterobacteriaceae, such as Protaea bacteria; Proteus bacteria (eg, P. vulgaris, Morgan modified bacteria (Pr. Morganii), Lettger modified bacteria (Pr. Retgeri) and parasite modified bacteria (Pr.mirabilis)); Pseudomonadaceae, such as Pseudomonas bacteria (eg, Ps.aeruginosa); Bacteroidaceae, such as Bacteroides bacteria (eg, Bacteroides fragilis); Mycoplasma (eg, Mycoplasma pneumonia); And Mycobacteria (eg Mycobacterium tuberculosis, Mycobacterium leprae) and atypical] Microbacteria.

The above pathogens are merely exemplary and never have a limiting meaning. Diseases that can be prevented, alleviated and / or treated by the preparations according to the invention include otitis, pharyngitis, pneumonia, peritonitis, pyelonephritis, cystitis, endocarditis, systemic infection, bronchitis, arthritis, local infection and pulmonary disease Can be mentioned.

The invention also relates to a medicament in the form of a dosage unit. Examples of medicaments include tablets, dragees, capsules and pills, and the amount of active compound corresponds to a fraction or multiple of a single dose. Dosage units may, for example, contain 1,2,3 or 4 times a single dose, or contain 1/2, 1/3 or 1/4 times a single dose. It is suitable to contain in a single dose the amount of the active compound presented in a single dose, which amount is usually equivalent to the full amount, 1/2, 1/3 or 1/4 of the daily dose.

Tablets, dragees, capsules, pills, and granules may be formulated with conventional coatings and shells, optionally with milky agents, which may be formulated with a composition that releases only the active compound (s), or optionally polymerizable. It is possible to formulate a composition which is released only at a certain part of the intestinal tract in a continuous manner using a sealing composition which can use materials and waxes.

The effective compound (s) may be formulated in microcapsule form with one or more of the excipients as necessary.

The formulation form according to the invention may also contain colorants, preservatives and additives (eg peppermint oil and eucalyptus oil) and sweeteners (eg saccharin) which increase odor and flavor.

The following examples relate to HCl salt monohydrate, other salts, derivatives or pure bases that can be used similarly.

EXAMPLE

Claims (13)

1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acid 30.0-95.0 wt%, cellulose based dry binder 4.5- 25.0 wt%, starch based disintegration aid 0.0-30.0 wt%, cellulose derivative and crosslinked polyvinylpyrrolidone based disintegration aid 0.5-10.0 wt%, flow enhancer 0.0-2.0 wt% and lubricant 0.0-3.0 wt% Antibiotics of flofloxacin. The 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acid-HCl salt monohydrate 60.0 according to claim 1 Antibiotic containing -90.0% by weight. The 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acid HCl salt according to claim 1 or 2. An antibiotic containing 60-88% by weight monohydrate, 5.0-15.0-% by weight dry binder based on cellulose, 5.0-16.0% by weight starch based disintegration aid, cellulose derivative and 0.5-1.0% by weight. The 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acid according to claim 1 or 2 72.4-78.8% by weight of HCl salt monohydrate, 7.0-9.0% by weight of cellulose based dry binder, 9.0-12.0% by weight of starch based disintegration aid, 4.0-5.0% by weight of cellulose derivative and crosslinked polyvinylpyrrolidone based disintegration aid, Antibiotics containing 0.6-0.8% by weight flow enhancer and 0.6-0.8% by weight lubricant. The compound of claim 4, wherein 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acid HCl salt monohydrate 72.4 -78.8 wt%, microcrystalline cellulose 7.0-9.0 wt%, corn starch 9.0-12.0 wt%, cross-linked polyvinylpyrrolidone 4.0-5.0 wt%, colloidal silicon chloride 0.6-0.8 wt% and magnesium stearate 0.6-0.8 Antibiotics containing percent by weight. 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acid 30.0-95.0 wt%, cellulose based dry binder 4.5 -25.0 wt%, 0.0-30.0 wt% starch based disintegration aid, 0.5-10.0 wt% cellulose derivative and crosslinked polyvinylpyrrolidone based disintegration aid, 0.0-2.0 wt% flow enhancer and 0.0-3.0 wt% lubricant Capsule of ciprofloxacin antibiotic. 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acid 30.0-95.0 wt%, cellulose based dry binder 4.5 -25.0 wt%, 0.0-30.0 wt% starch based disintegration aid, 0.5-10.0 wt% cellulose derivative and crosslinked polyvinylpyrrolidone based disintegration aid, 0.0-2.0 wt% flow enhancer and 0.0-3.0 wt% lubricant Purification of Ciproproxacin Antibiotics. 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acid HCl salt monohydrate 72.4-78.8% by weight, fine Ciprofloxacin containing 7.0-9.0% by weight of crystalline cellulose, 9.0-12.0% by weight of corn starch, 4.0-5.0% by weight of crosslinked polyvinylpyrrolidone, 0.6-0.8% by weight of colloidal silicon chloride and 0.6-0.8% by weight of magnesium stearate Purification of antibiotics. The antibiotic according to claim 1, wherein the substrate of the disintegration aid is crosslinked polyvinylpyrrolidine. The antibiotic according to claim 3, wherein the substrate of the disintegration aid is crosslinked polyvinylpyrrolidine. The antibiotic according to claim 4, wherein the substrate of the disintegration aid is crosslinked polyvinylpyrrolidine. The antibiotic according to claim 6, wherein the substrate of the disintegration aid is crosslinked polyvinylpyrrolidine. 8. The antibiotic according to claim 7, wherein the substrate of the disintegration aid is crosslinked polyvinylpyrrolidine.