HRP20020153A2 - Ciprofloxacin containing pharmaceutical composition and process for the preparation thereof - Google Patents

Description

Field of invention

The invention is from the field of pharmacology.

This invention relates to pharmaceutical mixtures containing ciprofloxacin and to the process of their preparation. In particular, this invention relates to pharmaceutical compositions containing ciprofloxacin and immediate release thereof, and to a process for the preparation of such compositions.

State of the art

Ciprofloxacin is a bacterial chemotherapeutic agent belonging to the family of fluoroquinolines (gyrase inhibitors). The chemical formula of ciprofloxacin is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid and it is used in the form of ciprofloxacin monohydrochloride monohydrate (HU 187,580).

It is known that after oral administration of ciprofloxacin it is rapidly absorbed from the digestive system. During absorption, the active ingredient is not metabolized in the liver to a significant extent, so its bioavailability is about 70%. The concentration in the serum increases in proportion to the dose and the highest concentration is reached after 1-2 hours after administration. In people with healthy kidneys, the half-life of serum concentration is about 4 hours.

In light of the above-mentioned pharmacokinetic properties of ciprofloxacin, immediate release of the active ingredient is a very important requirement so that the dosage form does not have a time lag in the absorption of the active ingredient.

Empirical experience has shown that the preparation of pharmaceutical mixtures containing ciprofloxacin, which immediately release the active ingredient, is not a simple task. After adjusting the composition of tablets containing norfloxacin [1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid, tk. an active ingredient that is closely related to ciprofloxacin; see GB 2,160,519] into ciprofloxacin, tablets were obtained that released the active ingredient very slowly (HU 196,710).

The pharmaceutical compositions described in patent GB 2,610,519 contain polyvinyl pyrrolidone or microcrystalline cellulose as a binder, lauryl sulfate as a dissolution accelerator and magnesium stearate as a lubricant. The preparation of immediate release pharmaceutical compositions containing ciprofloxacin is described in patent HU 196,710. The pharmaceutical mixtures described in this patent application contain, in addition to the active ingredient ciprofloxacin, a dry (water-insoluble) binder based on microcrystalline cellulose; decomposition agent based on starch, cellulose derivative and/or polyvinyl pyrrolidone and lubricant. Although the dissolution of ciprofloxacin tablets described in HU 196,710 is faster than that of tablets that

prepared according to GB 2,160,159, the release rate is greater than 50% after 5 minutes.

The rate of release of cirpofloxacin from pharmaceutical mixtures containing it and prepared according to patents GB 2,160,519 and HU 196,710 is shown in Table I.

Table I

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Solution of a technical problem with examples of implementation

The aim of this invention is the preparation of pharmaceutical mixtures containing ciprofloxacin, of appropriate hardness and faster release of the active ingredient, than is the case with mixtures of the prior art.

This invention achieves the above objective.

This invention relates to immediate-release pharmaceutical mixtures containing ciprofloxacin, a binder, a disintegrant and optionally other pharmaceutical excipients containing - in relation to the total mass of the mixture - 60-80% (by weight) of ciprofloxacin (in the form of ciprofloxacin hydrochloride monohydrate) . are covered with a thin coating - 2-6% substance for a thin coating.

This invention is based in part on the surprising finding that disintegrants based on carboxymethyl starch have a very favorable effect on the dissolution of the active ingredient, ciprofloxacin.

The effect of different types of disintegrants on the dissolution of ciprofloxacin tablets is shown in Table II. The table lists the composition of the tablets and also the breaking strength, and the tablet disintegration time which was measured using a compression force of 20 kN. Tablets are prepared by mixing the active ingredient, ciprofloxacin, which is suitable for direct compression into tablets with additional auxiliaries in a gravity type mixer. The powder mixture was pressed into tablets weighing 367 mg on a Fette E XI single punch machine using an 11 mm diameter concave die. Each tablet contains 275 mg of ciprofloxacin.

Table II

Effects of disintegrants on the dissolution rate of ciprofloxacin (direct compression - no binder)

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Crospovidone = cross-linked polyvinylpyrrolidone, HPE: p. 143,

Starch 1500 = partially hydrolyzed corn starch, HPE: p. 491

L-HPC = hydroxypropyl cellulose with a low degree of substitution, HPE: p. 427.

The above excipients are described in detail on the indicated pages of the "Handbook of Pharmaceutical Excipients" (HPE), 2nd edition (1994), The Pharm. Press, London (editor: A. Wade and P. Weller).

From the results listed in Table II, it can be seen that without a binder, tablets of appropriate hardness can only be prepared by using disintegrants recommended in patent HU 196,710, i.e. Crospovidone, which is based on polyvinyl pyrrolidone (experiment no. 1). sodium carboxymethyl cellulose, which is based on a cellulose derivative (experiment no. 2) and L-HPC, which is based on hydroxypropyl cellulose with a low degree of substitution (experiment no. 5).

The fastest decomposition is achieved if a decomposition agent based on carboxymethyl starch is used (experiment no. 9). However, the anti-breaking strength of the thus obtained tablets is weak. Tablets made using other disintegrants (corn starch starch, partially hydrolyzed starch, sodium alginate and guar gum) do not meet the requirements for either disintegration time or hardness of these tablets.

This invention is also based on the following surprising finding that disintegrants based on carboxymethyl starch show a particularly desirable effect on the dissolution of ciprofloxacin not only in the absence of binders, but also in the presence of water-soluble binders that contribute to the appropriate tablet hardness. This finding is all the more surprising since the disintegrants described in patent HU 196,710 [cellulose derivatives, such as sodium carboxymethyl cellulose, low substituted hydroxypropyl cellulose (L-HPC), polyvinyl pyrrolidone derivatives (e.g. Crospovidone ) and other disintegrants, eg sodium alginate or guar gum] are not effective enough in the presence of water-soluble (wet) binders.

In contrast, it has been found that if maltodextrin is used simultaneously as a binder and a disintegrating agent based on carboxymethyl starch, tablets containing ciprofloxacin with excellent resistance to breakage with extremely rapid release of the active ingredient are obtained.

The results are summarized in Table III.

When preparing tablets, maltodextrin is used as a binder. The components described in Table III are mixed - with the exception of magnesium stearate - the mixture is kneaded with water moistening, dried, sieved, homogenized with magnesium stearate and pressed into tablets weighing 374 mg on a Fette E XI single punch machine using a concave tool having diameter 11 mm. Each tablet contains 250 mg of ciprofloxacin.

Table III

Effect of a disintegrant on the dissolution rate of ciprofloxacin (in the presence of a wet granulation binder)

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The data in Table III clearly show that in the presence of maltodextrin as a binder, immediate release of the active ingredient can be achieved using carboxymethyl starch as a disintegrating agent. At the same time, the resistance to breaking of such tablets in which the disintegrant is carboxymethyl starch is not less than that of tablets containing disintegrants of a different type. Moreover, in some cases, the resistance to breakage of the tablets of the present invention is even higher.

Therefore, this invention is based on the knowledge that a pharmaceutical mixture containing ciprofloxacin, maltodextrin and a disintegrating agent based on carboxymethyl starch has very good mechanical strength, hardness and shows a faster release of the active ingredient than tablets prepared by prior art methods.

The pharmaceutical compositions of this invention contain ciprofloxacin preferably in the form of ciprofloxacin hydrochloride monohydrate. Taking into account the high single dose of ciprofloxacin (500 mg, i.e. 591 mg in relation to ciprofloxacin hydrochloride monohydrate), the content of the active ingredient is high, i.e. 60-80% (by weight), in relation to the total weight of the mixture.

The maltodextrin used as a binder in the pharmaceutical compositions of this invention is an oligosaccharide that can be prepared by hydrolysis of starch and forms a slightly viscous colloidal solution in cold water. Maltodextrin is described in detail in "Handbook of Pharmaceutical Excipients" (HPE), 2nd edition (1994), The Pharm. Press, London (ed: A. Wade and P. Welier), p. 289-291.

The term "mixture with immediate release of the active ingredient" refers to mixtures in which at least 80% of ciprofloxacin is released within 5 minutes, whereby the measurement was made according to the method described in USP 23, The United States Pharmacopoeia, 1995, p. 379.

The pharmaceutical compositions according to this invention contain sodium carboxymethyl starch as a disintegrating agent based on carboxymethyl starch. Such agents for decomposition, which are based on sodium carboxymethyl starch, can be prepared from different types of starch of vegetable origin by partial carboxymethylation of hydroxyl groups of the polysaccharide chain, that is, by cross-linking, to a certain degree. There are several commercially available disintegrants based on sodium carboxymethyl starch that differ from each other in terms of water solubility, pH value of the aqueous extract, and loss on drying. Sodium carboxymethyl starch is described in detail in "Handbook of Pharmaceutical Excipients" (HPE), 2nd Edition (1994), The Pharm. Press, London (ed.: A. Wade and P. Weiler), pp. 462-466.

The pharmaceutical mixture according to this invention contains 3-6% (by weight) of silicon dioxide. It is a hydrophilic substance in the form of fine granules that are insoluble in water. The silicon dioxide used in the mixture of this invention can be used as a settled product and also in the so-called colloidal form prepared by pyrogenic process. It was found that the mixture has a greater resistance against breaking and that a faster dissolution of the active ingredient is achieved if 3-6% of silica is used, in relation to the total mass of the mixture. It can be assumed that this is a consequence of the fact that silicon dioxide prevents the formation of hard compact granules during granulation. Colloidal silica is described in detail in "Handbook of Pharmaceutical Excipients" (HPE), 2nd edition (1994), The Pharm. Press, London (ed.: A. Wade and P. Weller), p. 424-427.

To reduce friction during tablet compression, the compositions of this invention may contain lubricants. Any suitable lubricant can be used for this purpose, eg magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, paraffin, etc. Preferably, magnesium stearate can be used.

The pharmaceutical compositions of this invention may be in the form of tablets or thin-coated tablets. The latter contain a thin layer that covers the tablet. Such mixtures may preferably contain a thin coating based on hydroxypropyl methylcellulose.

According to a further aspect of the present invention, a process is defined for the preparation of an immediate release pharmaceutical composition comprising mixing (with respect to the total weight of the mixture) 50-80% (by weight) of ciprofloxacin in the form of ciprofloxacin hydrochloride monohydrate, 2-10% (by weight) of maltodextrin, 5-15% (by weight) decomposing agents of the type carboxymethyl starch and 3-6% (by weight) silicon dioxide, granulating the mixture with the addition of water, drying, homogenizing with 1-3% (by weight) lubricant, and compressing the mixture into tablets and, if desired, application to the tablet surface of a thin layer in the amount of 2-6% (by weight).

The process of this invention can be carried out in the following way: the granules are prepared from the active ingredient ciprofloxacin, maltodextrin, a disintegrant of the carboxymethyl starch type and silica in a manner known per se using the "wet mixing" process. Granulation can be carried out by the so-called by "kneading" using different mixers or by the "fluid-bed" atomization process. During granulation, water is added to the powder mixture of the above-mentioned components in a suitable mixer, or during the atomization process, water is added by spraying until granules of the desired size are formed, after which the granules are dried in a known manner. The dry granules are sieved and, if desired, a thin coating is added to the surface of the tablets. The thin coating layer may preferably be a layer of water-soluble hydroxypropylmethyl cellulose.

The procedures set forth in this invention can be performed in a manner known per se. For example, the following can serve as a reference: Pharmaceutical Dosage Forms: Tablets, 2nd edition, Marcel Dekker (1990); Remington's Pharmaceutical Sciences, 18th ed., Mack Publ. Co. (1990).

The following examples will illustrate the details of the present invention, and the scope of protection is not limited to these examples.

Example 1

The process of fluidizing granulation

873 mg of ciprofloxacin hydrochloride monohydrate and 60 g of colloidal silicon dioxide were sieved through a sieve (18 mesh) and the mixture was placed in the tank of a device for fluidizing-granulation by spraying, type Glatt GPCG 1. 60 g of maltodextrin and 123 g of sodium carboxymethyl starch were added to the mixture. The mixture was homogenized with a flow of fluidizing air, granulated by spraying 700 g of water on the mixture and dried. The granulate was sieved again, 9 g of magnesium stearate was added and the mixture was compressed into tablets with an average weight of 375 mg on a Manesty B3B type rotary tableting machine using an 11 mm diameter countersink.

The force required to break the tablet is 120.7 N.

The tablet dissolution results are shown in Table IV.

Table IV

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Example 2

Granulation process by kneading

873 mg of ciprofloxacin hydrochloride monohydrate, 60 g of colloidal silica, 60 g of maltodextrin and 122 g of sodium carboxymethyl starch were placed in the hopper of a Lodige M5R granulating machine. The mixture was homogenized for 3 minutes, after which 400 g of water was added, the mixture was homogenized by kneading for 10 minutes and dried in a plate dryer at 50°C. The granules were sieved through a sieve (18 mesh), 9 g of magnesium stearate was added and the mixture was compressed into tablets with an average weight of 375 mg on a Manesty B3B type rotary tableting machine using an 11 mm diameter countersink.

The force required to break the tablet is 97.1 N.

In a Glatt GC 250 coating machine, a 10% (by weight) aqueous suspension of a coating agent under the trade name Opadry was applied to the tablets. In this way, a coating layer of 10 mg was made on the surface of the tablets.

The dissolution results of the thin-coated tablets are shown in Table V.

Table V

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Example 3

Tablets containing 500 mg of ciprofloxacin

The granules were prepared in accordance with example 1 and were pressed into tablets weighing 750 mg containing 500 mg of ciprofloxacin, using a tableting device Kilian RTS 21D with a 17 mm rectangular tool.

The force required to break the tablet is 150 N.

The tablet dissolution results are shown in Table VI.

Table VI

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Example 4

Film-coated tablets containing 100 mg of ciprofloxacin

Granules were prepared in accordance with example 2, where they were compressed into tablets weighing 150 mg using a tool with a recess having a diameter of 9 mm, so the surface of the tablet was coated with a thin layer from an aqueous suspension containing 4 mg of the white agent Opadry (manufacturer Colorcon).

The dissolution results of thin-coated tablets are shown in Table VII.

Table VII

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Example 5

The effect of the amount of excipient according to the present invention on the dissolution of ciprofloxacin

In an Erweka type laboratory mixer, a mixture of 291 g of ciprofloxacin hydrochloride, colloidal silica, sodium carboxymethyl starch and maltodextrin in the amount shown in Table VIII was mixed after the addition of 160 g of water for 15 minutes. The mixture was then dried in a drying oven at 50°C, sieved through a sieve (18 mesh) and homogenized with the indicated amount of magnesium stearate. Tablets containing 250 mg of ciprofloxacin were compressed from the homogenized mixture that was made in this way on a Fette EXI type single-hole machine using a recessed tool with a diameter of 11 mm.

Table VIII

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Example 6

Procedure for trial factory production

14.55 kg of ciprofloxacin hydrochloride monohydrate, 1.0 kg of maltodextrin, 2.05 kg of sodium carboxymethyl starch and 1.0 kg of colloidal silicon dioxide were weighed into a 100-liter container into a mixture that was homogenized for 15 minutes. The homogenized mixture was granulated in a Glatt WSG 15 type fluidizing granulation machine by spraying 10.0 kg of ion-exchanged water onto the mixture. The granules are dried. The dry granules were sieved through a sieve (18 mesh) and homogenized in a 100-liter tank of an Engelsmann drum mixer with 0.15 kg of magnesium stearate.

A third portion of each homogenized mixture was compressed in a Kilian RTS 21D type tableting machine using a tool to size tablets weighing 750 mg, 375 mg, and 150 mg, and containing 500 mg, 250 mg, and 100 mg of ciprofloxacin. In a Glatt GC400 type tablet coating machine, an aqueous suspension of 5 kg of white Opadry Y-1-7000 type coating agent (manufactured by Colorcon Ltd.) was applied. In this way, the tablets were coated with 16 mg, 8 mg and 4 mg. The composition of the tablets is shown in Table IX.

Table IX

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Claims (8)

1. A pharmaceutical mixture with immediate release containing ciprofloxacin, a binder, a disintegrating agent and an optional additional auxiliary agent, indicated by the fact that it contains, in relation to the total weight of the mixture - 60-80% (by weight) of ciprofloxacin (in the form of ciprofloxacin hydrochloride monohydrate), 2-10% (wt) maltodextrin, 5-15% (wt) carboxymethyl starch type disintegrant, 3-6% (wt) silica, 1-3% (wt) lubricant and, in the case of thin-coated tablets, 2-6% substance for thin coating. 2. Pharmaceutical mixture according to claim 1, characterized in that it contains sodium carboxymethyl starch as a carboxymethyl starch type breaking agent. 3. Pharmaceutical mixture according to claim 1 or 2, characterized in that it contains magnesium stearate as a lubricant. 4. Tablet with a thin coating according to any claim 1-3, characterized in that it contains hydroxypropylmethyl cellulose on the surface in a thin layer that is soluble in water. 5. The method for preparing a pharmaceutical mixture with immediate release according to claim 1, characterized in that it includes mixing (in relation to the total mass of the mixture) 60-80% (by weight) of ciprofloxacin, in the form of ciprofloxacin hydrochloride monohydrate, 2-10% (by weight) of maltodextrin . lubricant, and compression into tablets and, if desired, applying a thin coating to the tablets in the amount of 2-6% (by weight). 6. The method according to claim 5, characterized in that it contains sodium carboxymethyl starch as a decomposing agent of the carboxymethyl starch type. 7. The method according to claim 5 or 6, characterized in that it contains magnesium stearate as a lubricant. 8. The method according to any claim 5-7, characterized in that it includes the application to the tablet surface of 2-6% (by weight) in a thin layer of a water-soluble agent based on hydroxypropylmethyl cellulose.