Ciprofloxacin-containing pharmaceutical composition and method for its obtaining

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with pharmaceutical composition of bactericidal action. The composition suggested contains ciprofloxacin in the form of hydrochloride monohydrate, maltodextrin as a binding substance, sodium carboxymethyl starch as a disintegrating agent, silica gel, a lubricant at quantities mentioned in its formula. Ciprofloxacin tablets should be obtained due to pressing technique by applying the stage of moisture granulation. If necessary, the surface of tablets should be covered with a hydroxypropylmethylcellulose-based water-soluble membrane. Simultaneous application of maltodextrin as a binding substance and sodium carboxymethyl starch as a disintegrating agent enables to obtain ciprofloxacin-containing tablets of sufficient strength and quick release of active ingredient.

EFFECT: higher efficiency of application.

6 cl, 6 ex, 9 tbl

 

The scope of the invention

This invention relates to pharmaceutical compositions containing ciprofloxacin, and how you can get it. More specifically, this invention relates to a pharmaceutical composition with quick release containing ciprofloxacin, and the way it was received.

Background of the invention

Ciprofloxacin is bactericidal chemotherapeutic agent with a wide spectrum belonging to the family of ftorhinolonov (gyrase inhibitors). Ciprofloxacin is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinil)-quinoline-3-carboxylic acid, ciprofloxacin is used in the form of monohydrochloride monohydrate (HU 187, 580).

It is known that after ingestion of ciprofloxacin is rapidly absorbed from the gastro-intestinal system. When the absorption of the active ingredient is not significantly metabolized in the liver and for this reason has a bioavailability of about 70%. Its concentration in serum is increased in proportion to dose and reaches a maximum through 1-2 hours after administration. In individuals with healthy kidneys doubling time of concentration in serum is 4 hours.

Taking into account the above pharmacokinetic properties for the immediate release of the active ingredient ciprofloxacin is very important that the dosage form is not prevented Sasi aniu active ingredient.

Experiments have shown that the preparation of pharmaceutical compositions containing ciprofloxacin, with rapid release of the active ingredient is a daunting task.

If you use the composition of tablets containing norfloxacin [1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinil)-quinoline-3-carboxylic acid that is the active ingredient that is chemically similar to ciprofloxacin; see GB 2160519], ciprofloxacin, get a tablet with a very slow release of the active ingredient (HU 196710).

The pharmaceutical composition described in GB 2160519 contain polyvinylpyrrolidone or microcrystalline cellulose as binders, surface-active substance of sodium lauryl sulfate to accelerate dissolution and magnesium stearate as lubricant. Methods of preparing pharmaceutical compositions containing ciprofloxacin, quick release, presented in HU 196710. The pharmaceutical compositions described in this patent, in addition to the active ingredient ciprofloxacin contain dry (water-insoluble) binder based on microcrystalline cellulose; disintegrity agent-based starch-derived cellulose and/or polyvinylpyrrolidone, and grease. Although dissolving tablet of ciprofloxacin described in HU 196710 that is faster than what Ableton, prepared in accordance with GB 2160519, the degree of release after 5 minutes above 50%.

The degree of release pharmaceutical composition comprising ciprofloxacin, prepared in accordance with GB 2160519 and HU 196710 shown in table 1.

Table 1
Analogs5 minutes10 minutes15 minutes30 minutes
GB 2 160 519 (example 1)3%7%9%13%
HU 196 710 (example 2)51%81%92%96%

Description of the invention

The aim of the present invention to provide a pharmaceutical composition containing ciprofloxacin, which has sufficient hardness and a more rapid release of the active ingredient than known compositions.

This goal is achieved by using the present invention.

The present invention relates to pharmaceutical compositions with quick release containing ciprofloxacin, binder, disintegrity agent and optional pharmaceutical auxiliary agents, which include, with respect to the total weight of the composition 60-80 wt.% ciprofloxacin in the form of hydrochloride mo is ohydrate, 2-10 wt.% maltodextrin, 5-15 wt.% dezintegriruetsja agent carboximetilkrahmala type, 3-6 wt.% silica gel, 1-3% wt. a lubricating agent and, in the case of coated tablets, 2-6 wt.% layer of the shell.

The present invention is based in part on the surprising discovery that dezintegriruetsja agents based on carboxymethyl amylum promote dissolution of the active ingredient ciprofloxacin.

Influence dezintegriruetsja agents of various types on dissolving tablets of ciprofloxacin shown in table II. The composition of the tablets, their strength and disintegration time measured by the compression force of 20 kN, presented in the Table. Tablets are prepared by mixing the active ingredient ciprofloxacin, suitable for direct pressing, with additional auxiliary agents in the gravity type mixer. A powder mixture is compressed into tablets weighing 367 mg Fette E XI vodnoshlamovoj machine using concave stamp with a diameter of 11 mm Each tablet contains 275 mg of ciprofloxacin.

Table II
Influence dezintegriruetsja agents on dissolution of ciclopiroxolamine (directly pressed without binder).
  Disintegrity agent in accordance with HU 196,710Other dezintegriruetsja agents
No. of experiment12345678
Hydrochloride monohydrate ciprofloxacin291,0291,0291,0291,0291,0291,0291,0291,0
Magnesium stearate3,03,03,03,03,03,03,03,0
1. Crosspovidone40,0       
2. Sodium carboxymethyl cellulose 40,0      
3. Maize starch  40,0     
4. Starch 1500   40,0     
5. H-MPC    40,0   
6. Guar gum     40,0  
7. Sodium alginate      40,0 
8. Sodium carboxymethyl-starch       40,0
Strength(N)81,770,727,918,779,420,1the 33.414,6
The disintegration time (minutes)10,41,013,96,73,1a 4.945,00,4
Crosspovidone - cross-linked polyvinylpyrrolidoneNRE: str
Starch 1500 - partially hydrolyzed maize starch NRE: str
N-GOC - hydroxypropylcellulose with a low degree of substitutionNRE: str

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

From the results shown in Table II, it is clear that in the absence of binder pills required strength can be prepared using only dezintegriruetsja agents proposed in HU 196710, namely, crosspovidone, based on polyvinylpyrrolidone (experiment No. 1), sodium carboxymethyl cellulose, based on the derived cellulose (experiment No. 2), and N-GOC-based hydroxypropylcellulose with a low degree of substitution (experiment No. 5).

The most rapid disintegration is obtained using dezintegriruetsja agent-based carboxymethyllysine (experiment # 8). However, the strength of the thus obtained tablets is very low. Tablets prepared using other dezintegriruetsja agents (maize starch, partially hydrolyzed starch, sodium alginate, guar gum), do not meet the requirements both from the point of view of time of disintegration and strength tablets.

The present invented is also based on an additional amazing discovery, what dezintegriruetsja agents based on carboxymethylamino largely contribute to the dissolution of ciprofloxacin is not the absence of binders, but in the presence of water-soluble binders, which provide sufficient strength tablets. This discovery is even more amazing because dezintegriruetsja agents presented in HU 196710 [cellulose derivatives such as sodium carboxymethylcellulose, hydroxypropylcellulose with a low degree of substitution (H-MPC), derivatives of polyvinyl pyrrolidone (i.e. crosspovidone) and other dezintegriruetsja agents, that is, sodium alginate or guar gum], may not be sufficiently effective in the presence of water-soluble (wet) binders.

On the contrary, it was shown that the simultaneous use maltodextrin as a binder, and dezintegriruetsja agent-based carboxymethylamino assures ciprofloxacin.steroid tablets with excellent durability and a very fast release of the active ingredient.

The results are summarized in Table III.

When preparing tablets maltodextrin is used as a binding substance. The components are presented in Table III, are mixed dry with the exception of magnesium stearate, the mixture is formed when MacEwan and water, dried, sieved, homogenized with magnesium stearate and pressed into tablets weighing 374 mg vodnoshlamovoj car Fette E XI with concave stamp with a diameter of 11 mm Each tablet contains 250 mg of ciprofloxacin.

11. Sodium alginate
Table III
Influence dezintegriruetsja agents on dissolution of ciprofloxacin (in the presence of wet granulation binders).
No. of experiment910111214
Hydrochloride monohydrate ciprofloxacin291,0291,0291,0291,0291,0
Maltodextrin30,030,030,030,030,0
Silicon dioxideto 12.0to 12.0to 12.0to 12.0to 12.0
Magnesium stearate3,03,03,03,03,0
9. Crosspovidone38,0    
10. H-MPC 38,0  40,0
  38,0  
12. Guar gum   38,0 
13. Sodium carboxymethyl-starch    38,0
Strength (N)111,171,2103,7112,6110,6
The disintegration time (minutes)26,0the 9.738,815,77,1
Dissolution (%)     
5 minutes15,031,716,418,687,6
10 minutes22,952,023,843,496,0
15 minutes31,776,036,661,697,0
30 minutes49,796,066,0to 78.399,0

The data presented in Table III clearly show that when used as a binder maledict is in the rapid release of the active ingredient can be obtained only when using as dezintegriruetsja substances sodium carboxymethyl amylum. The strength of these tablets prepared using dezintegriruetsja agent-based carboxymethylamino, not lower than that of tablets containing dezintegriruetsja agents of another type. Moreover, in some cases, the strength of the tablets of the present invention is even higher.

Thus the present invention is based on the recognition that a pharmaceutical composition comprising ciprofloxacin, maltodextrin and disintegrity agent-based carboxymethylamino, has very good mechanical strength and shows a more rapid release of the active ingredient than tablets prepared in accordance with previous methods.

The pharmaceutical composition of the present invention contains ciprofloxacin mainly in the form of the hydrochloride monohydrate. Taking into account the highest individual dose of ciprofloxacin (500 mg, that is, 591 mg in the form of the hydrochloride monohydrate), the percentage of active ingredient in the pharmaceutical composition is high and is 60-80 weight. % relative to the total weight of the composition.

Maltodextrin used as a binder in the pharmaceutical compositions of this invention is an oligosaccharide which can be prepared by hydrolysis of starch and which forms in cold water number is oigny solution of low viscosity. Maltodextrin is described in detail in "Handbook of Pharmaceutical Excipients" (HPE) 2nd edition (1994), The Pharm. Press, London (editor: A.Wade and .Weller), pages 289-291.

The term “composition with rapid release of the active ingredient” refers to compositions in which at least 80% of ciprofloxacin released within 5 minutes when measured according to the method presented in USP 23 (The United States Pharmacopeia, 1995, page 379).

The pharmaceutical composition of the present invention contains sodium carboximetilkrahmal as dezintegriruetsja agent-based carboxymethyllysine. Such dezintegriruetsja agents based on sodium carboxymethylamino, can be prepared from different types of starch vegetable origin by partial karboksimetilirovaniya hydroxyl groups of the polysaccharide chains or education between different numbers of cross-linking. There are several commercially available dezintegriruetsja agents based on sodium carboxymethylamino, which differ from each other in solubility in water, pH of water extracts and losses during drying. Sodium carboximetilkrahmal described in detail in "Handbook of Pharmaceutical Excipients" (HPE) 2nd edition (1994), The Pharm. Press, London (editor: A.Wade and .Weller), pages 462-466.

The pharmaceutical composition of the present invention contains 3-6 weight. % silica gel. is the hydrophilic, finely granular substance, insoluble in water. Silica gel can be used in the compositions of the present invention in the form of precipitated product and also in the so-called colloidal form, obtained as a result of thermal decomposition. It was found that a composition having a higher strength and more rapid dissolution of the active ingredient, can be obtained by using 3-6% of silica relative to the total weight of the composition. It can be assumed that this is due to the fact that silica gel prevents the formation of a solid compact granules during granulation. Colloidal silica is described in detail in "Handbook of Pharmaceutical Excipients" (HPE) 2nd edition (1994), The Pharm. Press, London (editor: A. Wade and P. Weller), pages 424-427.

In order to reduce friction during tablet pressing, such compositions can contain a lubricant. For this purpose, can be used in some suitable lubricants, namely magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, paraffin, etc. Can preferably be used magnesium stearate.

The pharmaceutical composition of the present invention may be in the form of tablets or in the form of coated tablets. The last dosage form contains a layer of membrane that covers the tablet. Such component is icii may be dominated by shell, based on soluble in water hypromellose.

In accordance with a further aspect of the present invention, we present a method of preparation of pharmaceutical compositions quick release, which mix the following components in the following quantities: 60-80 wt.% ciprofloxacin in the form of the hydrochloride monohydrate, 2-10 wt.% maltodextrin, 5-15 wt.% dezintegriruetsja agent carboximetilkrahmala type and 3-6 wt.% silica gel, relative to the total weight of the composition, the mixture is then granularit adding water, dried, homogenized with 1-3 wt.% lubricant and pressed into tablets and, if desired, coated tablets with a layer of shell in the amount of 2-6 wt.%.

The method of the present invention can be implemented as follows: the pellets prepared from the active ingredient ciprofloxacin, maltodextrin, dezintegriruetsja agent carboximetilkrahmala type and silica gel method, known as "wet blending". The granulation can be carried out by the procedure of the so-called "mixing" with the help of various mixers or spraying in a fluidized bed. When the granulation water added to the powder mixture consisting of the above components in a suitable mixer, or in the case of spraying in a fluidized bed water spray until formed Gras is uly required size, then the granules are dried in a known manner, the dried granules are screened and, if desired, the surface of the tablets covered with a layer of shell. The layer may be primarily a shell of water-soluble hydroxyethylcellulose.

The method of the present invention can be advantageously performed using known methods. For example, you can refer to the information sources: Tablets, 2ndedition, Marsel Dekker (1990); Remington's Phamaceutical Sciences, 18thedition, Mack Publ.Co.(1990).

Additional details of the present invention refer to the following Examples without limiting the scope of protection of this invention.

Example 1

The granulation in the fluidized bed.

873 g of the hydrochloride monohydrate ciprofloxacin and 60 g of colloidal silica gel is sifted through a sieve (18 mesh) and the mixture is placed in a container installation for granulation fluidized bed type Glatt GPCG 1. To the mixture of 60 g of maltodextrin and 123 g of sodium carboxymethyl amylum. The mixture is homogenized using a fluidized stream of air, granularit by spraying 700 g of water to the mixture and dried. The granules were sieved again, and then add 9 g of magnesium stearate and the mixture is pressed into tablets having an average weight of 375 mg, on a rotating teletrauma machine type Manesty B3B using concave stamp with a diameter of 11 mm

Strength tablets SOS is to place 120,7 N.

The solubility of the tablets is shown in the following table IV.

Table IV
5 minutes10 minutes15 minutes30 minutes
83,0%90,8%95,7%the 98.9%

Example 2

The method of granulation by “mixing”

873 g of the hydrochloride monohydrate ciprofloxacin, 60 g of colloidal silica gel, 60 g of maltodextrin and 122 g of sodium carboxymethyl amylum is placed in the apparatus for pelleting type Lodiqe M5R. The mixture is homogenized for 3 minutes, then add 400 g of water, the mixture is homogenized by mixing for 10 minutes and dried on a tray in an oven at 50°C. the Granules are sieved through a sieve (18 mesh), and then add 9 g of magnesium stearate and the mixture is pressed into tablets having an average weight of 375 mg, on a rotating teletrauma machine type Manesty B3B using concave stamp with a diameter of 11 mm

The strength of the tablets is 97.1 N.

In apparatus of the type Glatt GC 250, intended for coating tablets, pills is applied to a 10 weight. % liquid suspension covering agent with the commercial name Opadry. Thus, on the surface of the tablets formed shell weighing 10 mg

The dissolution of the tablets is shown in the following table V.

Table V
5 minutes10 minutes15 minutes30 minutes
81,3%94,6%97,7%98,8%

Example 3

Tablets containing 500 mg ciprofloxacin

Granules are prepared in accordance with Example 1, but the granules are compressed into tablets weighing 750 mg contains 500 mg of ciprofloxacin, teletrauma machine type Kilian RTS 2 ID using a 17 mm oblong stamp. The strength of the tablets is 150 N.

The solubility of the tablets is shown in the following table VI.

Table VI
5 minutes10 minutes15 minutes30 minutes
82,1%93,8%95.6%of96,1%

Example 4

The film-coated tablets containing 100 mg ciprofloxacin.

Granules are prepared in accordance with Example 2, but the granules are pressed into tablets weighing 150 mg with concave stamp with a diameter of 9 mm, and then, on the surface of the tablets put on 4 mg Opadry white (manufacturer use) covering layer from a liquid suspension.

The solubility of the tablets is shown in the following table VII.

Table VII
5 minutes10 minutes15 minutes30 minutes
86,0%97,0%97,6%98,1%

Example 5

Effect of the number of auxiliary agents used in accordance with the present invention the solubility of ciprofloxacin.

A mixture of 291 g of the hydrochloride ciprofloxacin, colloidal silica, sodium carboxymethyl amylum and maltodextrin used in amounts shown in Table VIII, mix after adding 160 g of water for 15 minutes in a laboratory mixer type Erweka. The mixture is then dried in tray drier at 50°C, sieved (18 mesh) and homogenized with the specified amount of magnesium stearate. From the thus obtained homogeneous mixture is pressed to tablets containing 250 mg ciprofloxacin, vodnoshlamovoj car Fette EXI using concave stamp with a diameter of 11 mm

Table VIII
 AndBInGd
Hydrochloride monohydrate ciprofloxacin291,0291,0291,091,0 291,0
Maltodextrin20,010,010,015,020,0
Silicon dioxide20,020,014,020,014,0
Sodium carboximetilkrahmal40,050,033,045,020,0
Magnesium stearate3,03,03,03,03,0
Weight pills374,0374,0344,0364,0338,0
Strength(N)byr111.498,486,784,8114,6
The disintegration time (minutes)2,60,80,81,53,0
Dissolution (%)     
5 minutes93,590.789,882, for 91.3
10 minutes96,698,897,094,497,2
15 minutes97,597,297,494,997,3
30 minutesof 98.299,6100,098,7of 99.1

Example 6

Experimental setup for performing the method

In a 100-gallon container of mixed drum type Engelsmann download 14,55 kg hydrochloride monohydrate ciprofloxacin, 1 kg of maltodextrin, 2,05 kg of sodium carboxymethyl amylum and 1.0 kg of colloidal silica gel, the mixture is homogenized for 15 minutes. Gomogenizirovannogo mixture granularit in installation for granulation fluidized bed type Glatt WSG 15 by spraying 10,0 kg of water treated by the method of ion exchange on the mixture. The granules are dried. Dried granules are sieved through a sieve (18 mesh) and homogenized in 100-liter container of the mixer drum Engelsmann with 0.15 kg of magnesium stearate. One third of each of the thus obtained mixture is pressed on teletrauma machine type Kilian RTS 2 ID using the stamps of the appropriate size into tablets weighing 750 mg, 375 mg and 150 mg and containing, respectively, 500 mg, 250 mg and 100 mg cipro is loxacin. In an appliance designed for coating tablets, type Glatt GC400 on the pill cause 5 kg of liquid suspension covering agent type Opadry white Y-1-7000 (use manufacturer Ltd.). Thus, the tablets covered with a layer 16 mg, 8 mg and 4 mg, respectively. The composition of the tablets is shown in Table IX.

Table IX
 500 mg250 mg100 mg
Hydrochloride monohydrate ciprofloxacin582,0291,0116,4
Sodium carboximetilkrahmal82,041,016,4
Maltodextrin40,020,08,0
Silicon dioxide40,020,08,0
Magnesium stearate6,03,01,2
The weight of tablets (mg)750,0375,0350,0
OpadyY-1-700016.08.04.0
The weight of the tablet shell (mg)766,0of 383.0354,0
Strength(N)123,0127,0124,0
The disintegration time (minutes)that 0 4,010,0
Dissolution (%)   
5 minutes94,386,887,7
15 minutes95,492,4br93.1
30 minutes98,599,399,8

1. The pharmaceutical composition of bactericidal action quick release containing the following ingredients in amounts relative to the total weight of the composition: 60-80 wt.% ciprofloxacin (in the form of the hydrochloride monohydrate ciprofloxacin),

2-10 wt.% maltodextrin as a binder, 5-15 wt.% sodium carboxymethyl amylum as dezintegriruetsja agent, 3-6 wt.% silica gel, 1-3% wt. lubricants and in the case of coated tablets, 2-6% layer shell, provided that the total amount of ingredients of the composition is 100%.

2. The pharmaceutical composition according to claim 1, comprising magnesium stearate as the lubricant.

3. The pharmaceutical composition according to claim 1 or 2 in the form of tablets, coated tablets, including the surface tablets 2-6 wt.% water-soluble layer of the wrapper-based hydroxypropylmethylcellulose.

4. A method of obtaining a pharmaceutical composition bactericidostatic with quick release, characterized in claim 1, in which mix ciprofloxacin in the form of the hydrochloride monohydrate, maltodextrin, sodium carboximetilkrahmal and silica gel, the mixture granularit adding water, dried, homogenized with a lubricating substance, pressing the mixture into tablets and, if necessary, cover the surface of the tablets.

5. The method according to claim 4, whereby as a lubricating substance use magnesium stearate.

6. The method according to claim 4 or 5, in accordance with which the tablet surface cover water-soluble membrane-based hydroxypropylmethylcellulose.



 

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