Composition for treatment of inflammation of the middle ear with a perforation, and a method of obtaining a composition

 

(57) Abstract:

The proposed composition comprising ciprofloxacin, and how you can get it. The composition includes from 0.12 to 0.6 g/ml hydrochloride monohydrate ciprofloxacin (equivalent to 0.1-0.5% of free base), 0.5 to 3.0 g/ml of a buffer system capable of providing a pH of from 4 to 5, 0.05 to 0.3 g/ml naanovo surfactant, from 0.5 to 2.0 g/ml thickener and water up to 100 ml Method is the dispersion of a thickening agent when heated, the addition of surfactants, acetic acid and sodium acetate solution, ciprofloxacin and establish a pH of 4.5 and 4.9. The composition is free from preservatives, stable. 2 S. and 9 C.p. f-crystals, 1 table.

This invention relates to aqueous compositions containing ciprofloxacin, useful for the preparation of pharmaceutical drugs dose for topical application in the treatment of otitis of the middle ear with a perforation. The invention relates also to the use of these compositions and to the method of obtaining them.

According to The Merck Index 11th Edition, p. 360 (1989), ciprofloxacin is an international trivial name (International Non-propritary Name-INN) 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinil)-3 - quinoline-carboxylic acid, the General formula

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In the head of the European Pharmacopoeia related to preparations for the treatment of diseases of the ear, States that in cases when there is a perforation, middle ear, pharmaceutical products must be sterile, free from preservatives and shipped in packagings containing the drug in doses at once.

In the European patent 0219784 describes aqueous solutions of ciprofloxacin with pH in the range from 3.0 to 5.2 and a concentration in the range between 0.015 to 0.5 g of active ingredient per 100 ml of solution. The solutions described in this document are intended for use in the infusion or perfusion, i.e. for the system, and not a local application, the number of drugs for the treatment of diseases of various types, among which mention of otitis media.

In the PCT application WO93/05816 describes aqueous solutions on the basis of quinolone, among which indicates ciprofloxacin for the treatment of diseases of the eye and ear. The main objective of the invention of this application is to achieve stability of solutions of physiological pH or pH close to physiological, using a mixture of quinolones with sulfonated polymers polystyrene type. Described compositions contain preservatives, such as chloride benthically drugs ciprofloxacin single dose, free of preservatives that can be used topically to treat inflammation of the middle ear with a perforation, so due to the high efficiency and broad-spectrum antibacterial action of this active ingredient, there is a need to develop new compositions containing this active ingredient and suitable for this application.

The purpose of this invention is to obtain water compositions ciprofloxacin suitable for topical application in the treatment of otitis of the middle ear with a perforation.

This goal is achieved using the compositions indicated in the beginning of the description of the type, which differ in that they contain the following components in the amounts set forth in % (weight/volume):1) 0.12 to 0.6% of ciprofloxacin hydrochloride monohydrate (equivalent to 0.1-0.5% of free base); 2) 0,5 - 3,0% buffer system to maintain pH in the range from 4 to 5; 3) 0,05 - 0,3% naanovo surfactants; 4) 0.5 to 2.0% of a thickener; and 5) water to 100 ml.

In accordance with this invention, these compositions are preferably free from preservatives.

In addition to the above main components of the composition of this invention can NeoMaster the components do not show significant ototoxicity.

Ciprofloxacin hydrochloride monohydrate can be easily obtained at the place of sale or can be prepared by any of the methods described in the patents Spain ES-2006099 and ES-2006098.

The buffer system may be any pharmaceutically acceptable system to maintain the pH of the medium in the range of from 4 to 5. Especially preferred is the system acetic acid - sodium acetate, where the components are taken in such molar ratios in which the pH is from 4.5 to 4.9, more preferably in the range from 4.6 to 4.8.

Naonym surface-active substance can be Polysorbate, i.e., ester of fatty acid and ethoxylated sorbitan, such as Polysorbate 20 or Polysorbate 80 and lecithin-derived soybean oil.

The thickener is used to regulate the viscosity of the solution, and among the most preferred can be selected derivatives of cellulose, such as methylcellulose, and polyvinyl alcohol.

Among the optional components can be referred to (not limited list) the following: emollient and moisturizing substances, such as polyols of the type of glycerol, mannitol and polyethylene glycol, with the exception of propylene glycol due to IGNOU acid (EDTA) and/or type of antioxidant, such as sodium bisulfite and potassium metabisulfite.

Compositions of the present invention Packed in a package at one time, suitable for release of the drug in the form of drops. These packages can be of different types from those that may be in the place of manufacture and sale, although the packaging is made of suitable molded of polyethylene or propylene, are very suitable.

After filling compositions of this invention the package is sterilized by known methods, such as moist heat (autoclave), - radiation or the solution is sterilized by sterile filtration before filling.

Depending on the preferred components of the most preferred compositions of the invention, different content components, the number of which is given hereinafter in % (wt./volume) (g/100 ml): 1) 0.12 to 0.6% of ciprofloxacin hydrochloride monohydrate (equivalent to 0.1 - 0.5% of free base); 2) 0,5 - 3,0% buffer system acetic acid - sodium acetate to maintain the pH of the medium in the range from 4.5 to 4.9; 3) 0,05 - 0,3% naanovo surfactant selected from the group comprising Polysorbate 20 and Polysorbate 80; 4) 0.5 to 2.0% methylcellulose; 5LASS="ptx2">

The appropriate method for obtaining the compositions of the present invention, includes the following stages:

a) dispersing a thickening agent in water at a temperature in the range from 20 to 90oC, until complete hydration of the thickener;

b) dissolving naanovo surfactants in water, adding the resulting solution to a solution of thickener obtained in the previous phase, and then adding acetic acid, the corresponding buffer acetic acid - sodium acetate, and other optional components;

c) dissolving sodium acetate, corresponding to a buffer of acetic acid-sodium acetate, in water and adding the resulting solution to the solution obtained at the previous stage;

d) adding ciprofloxacin hydrochloride monohydrate and stirring until complete dissolution; and

e) adding water while maintaining the pH in the range from 4.5 to 4.9.

In accordance with a preferred embodiment of the solution is filled into the packaging at once and sterilized in the autoclave or radiation.

Thus obtained compositions have excellent properties in terms of physical and microbial stability without the need for preservatives and persons is of this description the following are examples which do not limit the scope of the present invention.

Example 1

are 162.5 g of methylcellulose was dispersed in approximately 3800 g of water, heated to 80 - 90oC, then to the warm solution was added with stirring 13800 g of water with a temperature in the range from 10 to 20oC. the thus Obtained solution is kept at 10-12 h for complete hydration of methylcellulose.

25 g of Polysorbate 20 was dissolved in approximately 500 g of water and this solution is added with stirring to a solution of methylcellulose, and then add 237,5 g glycerol and 63,75 g glacial acetic acid with stirring.

170 g of sodium acetate of three-hydrate dissolved with stirring at approximately 1500 g of water and the resulting solution is added to the solution obtained at the previous stage. After that add a 58.3 g of ciprofloxacin hydrochloride monohydrate and stirred until complete dissolution.

Water is added to obtain a total volume of approximately 24500 ml and the pH adjusted to a value in the range from 4.7 to 4.8 by adding 1N hydrochloric acid or 1N solution of sodium hydroxide. The total volume is brought up to 25,000 ml by adding required amount of water and for the enlightenment of the solution f is further components in quantities expressed in % (wt./volume):

0,23% ciprofloxacin hydrochloride monohydrate (equivalent to 0.2% of free base);

of 0.25% acetic acid;

0,68% of three-hydrate sodium acetate;

0,10% Polysorbate 20;

0,65% methylcellulose;

0,95% glycerol and

water to 100 ml.

The solution is Packed in polypropylene packaging single dose of 0.5 ml (10 drops), followed by sterilization in an autoclave.

Examples 2-6

Get listed in table. 1 composition in which the content of components specified in % (wt./volume).

1. Composition for treatment of inflammation of the middle ear with a perforation, including ciprofloxacin, characterized in that it further comprises a buffer system to maintain a pH of 4.0 to 5.0, naenae surfactant, thickener and water in a ratio of components, wt.%/about (g/100 ml):

Ciprofloxacin hydrochloride monohydrate (equivalent to 0.1-0.5% of free base) - 0,12 - 0,6

The buffer system capable of maintaining a pH in the range from 4 to 5 0,5 - 3,0

Naenae surfactant - 0,05 - 0,3

Thickener - 0,5 - 2,0

Water Up to 100 ml

2. The composition according to p. 1, characterized in that it is free from preservatives.

3. Composed to contain a single dose medicines for topical application in the form of drops.

4. Composition according to one of paragraphs.1-3, characterized in that as naanovo surfactant contains Polysorbate 20 or Polysorbate 80.

5. Composition according to one of paragraphs.1-4, characterized in that as a thickener contains methylcellulose.

6. Composition according to one of paragraphs.1-5, characterized in that it contains a buffer system of acetic acid and sodium acetate.

7. Composition according to one of paragraphs.1-6, characterized in that its pH is in the range from 4.5 to 4.9.

8. Composition according to one of paragraphs.1-7, characterized in that it also contains glycerin.

9. Composition according to one of paragraphs.1-8, characterized in that it contains components in the ratio, wt.%/about (g/100 ml):

Ciprofloxacin hydrochloride monohydrate (equivalent to 0.1-0.5% of free base) - 0,12 - 0,6

The buffer system acetic acid-sodium acetate to maintain pH in the range from 4,5-4,9 - 0,5 - 3,0

Naenae surfactant selected from the group comprising Polysorbate 20 and Polysorbate 80 - 0,05 - 0,3

Methylcellulose - 0,5 - 2,0

A softener selected from the group comprising glycerol, mannitol and polyethylene glycol - 0,5 - 3,0

Water Up to 100 ml

10. A method of obtaining a composition for l C until full hydration, add an aqueous solution naanovo surfactants, acetic acid and an aqueous solution of sodium acetate, respectively buffer the system from acetic acid and sodium acetate, other optional components, then ciprofloxacin hydrochloride monohydrate is stirred until dissolved and add water until a pH of 4.5 and 4.9.

11. The method according to p. 10, characterized in that the solution is filled into the packaging at once and sterilized in an autoclave or by radiation.

 

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14 cl, 36 ex

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