DE19730023A1 - High-purity ciprofloxacin infusion - Google Patents

Abstract

The present invention relates to high-purity ciprofloxacine aqueous solutions to be infused, wherein said solutions are contained in a glass vessel having a silicone coating on its inner surface. This invention also relates to a method for the thermal sterilisation of ciprofloxacine solutions to be infused.

Description

The invention relates to a ready-to-use, highly pure, aqueous ciprofloxacin-in fusion solution in a glass container placed on its inner surface has a silicone coating. The invention further relates to a method for Heat sterilization of ciprofloxacin infusion solutions.

From EP-A-0 138 018 it is known that ciprofloxacin (1-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acid) particularly preferred in Form of its lactic acid salts, optionally in the presence of other, physiologically tolerated and not leading to precipitation acids Preparation of infusion solutions can be used. Furthermore are Aqueous infusion solutions containing ciprofloxacin in EP-A-0 219 784 and in EP-A-0 287 926. This and other infusion solutions from the Ciprofloxacins are preferably filled into glass infusion bottles and need to avoid unwanted side effects until administration remain largely particle-free on the patient. If the salary is too high An infusion solution of particles threatens the patient with local irritant effects the application vein, occlusion of microcapillaries or deposits, for example in the lungs. For this reason, infusion solutions are available their manufacture is generally filtered through filters with a pore size of 0.2 µm, Glass infusion bottles and stoppers become particle-free with great effort rinsed and there is a visual inspection of everyone after production Infusion bottle for the absence of visually recognizable particles.

Despite these measures, all known infusion solutions contain the State of the art, especially after sterilization and during storage still a certain number of particles, especially from the solution Particles formed, such as crystalline precipitates of the active ingredient or of By-products or from reaction partners. The total number of such Particles can be removed by suitable methods, such as the light blocking method or  microscopic inspection of membrane filters after filtration of the solution be measured. The maximum permissible number of particles and their measurement methods are determined by pharmacopoeias. Because of the above Side effects, however, it is desirable to reduce the particle count from infusions lower solutions as far as possible below the limit values of the pharmacopoeia. The The number of particles that can still be detected is therefore a very important quality criterion of infusion solutions.

It was determined by investigation that the particles in the infusion solution already after filling the solution in glass bottles and their steam Sterilization and short-term storage (e.g. 1 week) occur. Even in Cipro floxacin infusion solutions, which can be found in so-called flexibags such as PVC infusion bags were, despite their manufacture under clean room Considerable number of particles found. This finding means that Solving the problem on which the invention is based certainly does not suggest.

It was therefore an object of the present invention to provide a highly pure, aqueous To provide ciprofloxacin solution for infusion in a container that is stable in storage and in particular with regard to the par contained in the solution Particle number is improved over those of the prior art.

It was also an object of the present invention to provide a method for To provide heat sterilization of ciprofloxacin solutions at which the particle formation in the solution is greatly reduced.

The object of the invention was achieved by an aqueous infusion solution of ciprofloxacin in a glass container, characterized in that the Glass container has a silicone coating on the inner surface.

The aqueous infusion solutions as such are in the prior art, for example as known from EP-A-0 138 018 or EP-A-0 219 784. The concentra  tion of ciprofloxacin or its pharmaceutically acceptable salts in infu solution is between 0.015 and 0.5 g / 100 ml. The pH of the infu solution is usually in a range between 2.5 and 7 preferably between 3.0 and 5.2, very particularly preferably between 3.5 and 4.7. It goes without saying that the infusion solution by suitable Processes, especially sterile filtration and steam sterilization after their Manufacturing is sterilized.

The glass from which the glass container is made is a Glass of glass type 1, 2 or less hydrolytic resistance according to the German Pharmacopoeia, Edition 10 (DAB 10). The glass container itself can have any removable filling volume. For the practical However, the glass containers in question have application in the Usually a removable filling volume between approx. 5 and 600 ml.

With regard to the siliconization of the inner surface of the glass container can to common procedures known from the prior art and Findings are referred. Siliconized glass surfaces and their Manufacture are, for example, in Glass Technical Reports 51 (1978) No. 3, page 55 to 61 and in the Journal of Parenteral Science and Technology, 1988, Supplement, Vol. 42, No. 45, Technical Report No. 12, pages S3 to S13 described.

According to the common siliconization processes, the siliconization of the Inner surface products based on silicone oil in the form of their aqueous silicone oil emulsion used. As a silicone oil within the scope of the present inven polydimethylsiloxane (Dimethicone). As a silicone oil can but also polymethylhydrogensiloxane or any other pharmacological harmless silicone oil can be used. The concentration of the silicone oil in the aqueous emulsion is between 0.1 and 2.0% by weight, preferably between 0.2 and 1.0% by weight. The glass bottles were made with this emulsion  rinsed or sprayed on the inner surface and then at one Temperature between 250 and 350 ° C, especially between 300 and 320 ° C thermally treated.

In connection with the present invention, it was also found that the trace concentration of polyvalent cations, such as Al ³⁺ , Ba ²⁺ or Zn ²⁺ , is greatly reduced in the infusion solution. In principle, such contaminations in infusion solutions are physiologically undesirable; on the other hand, multivalent cations with ciprofloxacin can form complex compounds.

According to the invention, it has now been found that the contamination of the Ci profloxacin solution with the cations Al ³⁺ , Ba ²⁺ or Zn ²⁺ , when the solution is stored in glass containers siliconized on the inside, compared to solutions in glass containers stored that are not siliconized on the inside, are significantly reduced.

It was also found that the particle numbers in ciprofloxacin Infusion solutions that have been sterilized and stored in glass containers that have a silicone layer on the inner surface, also compared to the Particle counts from infusion solutions in plastic bags (flexibags), e.g. B. made of PVC are further reduced significantly.

The invention further relates to a method for heat sterilization, in particular for Steam sterilization of ciprofloxacin containing infusion solutions, whereby the ciprofloxacin solution for infusion is in a glass container placed on the inner surface has a silicone coating. Heat sterilization, steam sterilization, in particular, can be carried out under normal conditions be performed. Generally turn out in connection with the present invention temperatures between 80 and 150 ° C, preferably between 100 and 130 ° C, over a period of 5 to 60 minutes as advantageous.  

The process according to the invention has the advantage that after heat sterilization the number of particles in the infusion solution is very low, if not even is negligible. Under conventional conditions, that is Heat sterilization of the ciprofloxacin infusion solution in untreated glass or Plastic containers, this effect cannot be achieved.

The use of glass containers siliconized on the inner surface in heat sterilization, especially steam sterilization, of ciprofloxacin Solutions for the production of drugs suitable for infusion is therefore another important aspect of the invention.

The ciprofloxacin heat-sterilized by the process according to the invention Infusion solutions have a very low average particle number of for example ≦ 1 particle ≧ 10 µm / ml, in many cases even ≦ 0.1 particle ≧ 10 µm / ml, measured with the membrane filtration method.

The invention is illustrated by the following examples, without ever to be limited to that.

Examples

The particulate purity was determined according to the US Pharmacopoeia (USP 23) in the light blocking process or by Membrane filter count determined.

In order to determine a higher method sensitivity when determining To achieve particle numbers, the sample preparation for the evaluation of the Membrane filter method changed. Usually (e.g. in USP 23) the Filter entire solution from a bottle and the particles on the filter counted. After preliminary tests had shown that in Ciprofloxacin infusion the vast majority of the particles in the first  Volume shares, only the first 25 ml of a 5 bottles were Bottle used for testing. This enriches the particles on the filter on and the influences are thus more recognizable.

Evaluation of ion contamination by the method of Emission spectral analytical elemental analysis is in the German standard DIN 38 406/22.

example 1

2.00 kg of ciprofloxacin was added in 4 kg of water for injections and 3.218 kg Lactic acid 20% dissolved with stirring. 9.00 kg sodium chloride was in 940 kg Dissolved water for injection with stirring. The two solutions were mixed. The pH of the solution was adjusted to 4.2 with 1 M hydrochloric acid. It was made up with water for injections to a total weight of 990.782 kg filled and filtered through a filter with an effective pore size of 0.2 µm.

In this procedure 9 lots of ciprofloxacin solution for infusion were prepared and in colorless glass type 2 infusion bottles of 204 each, not according to the invention ml filled.

Furthermore, 7 further batches of ciprofloxacin infusion solution were prepared in this process and filled into colorless glass 2 infusion bottles according to the invention, which had previously been siliconized internally as follows:
The bottles were cleaned and dried and rinsed with a 1% emulsion of silicone oil (= polydimethylsiloxane, dimethicone) in water. The bottles were then thermally treated at about 320 ° C. for about 20 minutes.

The filled bottles were filled with an infusion stopper was laminated with a fluoropolymer film, sealed and crimped. The Bottles were steam sterilized at 121 ° C for 20 minutes.

Examination of the particle numbers with the light blocking method showed that in Table 1 values.  

Table 1

Particle numbers Example 1

Method: light blocking method

On average of all lots, the internal siliconization according to the invention gave the for Ciprofloxacin solution for infusion, bottles used a significant reduction (p <0.01) the particle number.  

Example 2

25.00 g of ciprofloxacin, 45.00 g of sodium chloride and 100.00 g of 1 M hydrochloric acid were added dissolved with stirring in 4700 g of water for injections. The pH of the Lö solution was adjusted to pH 4.0 with 13.19 g of 2 m sodium hydroxide solution and the batch was made up to 5 liters with 399.5 g of water for injections. The Solution was sterile filtered through 0.2 µm membrane filter made of regenerated cellulose.

A portion of the solution was filled to 102 ml in colorless 100 ml Glass infusion bottles of glass type 2, coated with fluoropolymer Infusion stopper closed, crimped and over 20 minutes at 121 ° C steam sterilized.

Another part of the solution was filled to 102 ml in 100 ml glass infusion bottles colorless of glass type 2, previously insensili as described in Example 1 had been conified. The filled bottles were made with fluoropolymer coated infusion stopper closed, crimped and over 20 minutes Steam sterilized at 121 ° C.

After the production of both sublots, the particle numbers were determined by Aus count determined by membrane filters. The values in Table 2 were obtained.

Table 2

Particle numbers example 2

Method: membrane filtration

The particulate purity of those filled in siliconized bottles Ciprofloxacin solution was significantly better after steam sterilization than after Filling into standard glass 2 infusion bottles.

Example 3

There were 10 lots of ciprofloxacin solution according to that described in Example 1 Process manufactured.

5 lots of it were in non-siliconized colorless 250 ml infusion Bottles of glass type 2 filled with 204 ml each. 5 more lots were made in colorless 250 ml glass type 2 infusion bottles filled with 204 ml each, the same as in Bei game 1, had been siliconized on the inside.

In addition, 12 batches of the ciprofloxacin infusion solution from Example 1 were obtained PVC infusion bags (flexibags) filled and ver closed.

The filled glass bottles and PVC bags were filled with an infusion stopper, which was covered with a fluoropolymer film on the product side, closed and crimped. The bottles and bags were steam sterilized.

An examination of the particle numbers with the membrane filtration method showed the values listed in Table 3.  

Table 3

Particle numbers of ciprofloxacin infusion solutions from Example 3

Method: membrane filtration

Example 4

A portion of the solution from Comparative Example 3b was branched off and in 150 ml Infusion bottles filled, which previously described in Example 1 Processes had been siliconized internally. The bottles were infused stopper which were lined with fluoropolymer film on the product side, flanged and steam sterilized at 121 ° C for 20 minutes. After that, the Particle numbers determined with the membrane filter method. The results are in the Table 4 reproduced below.

Table 4

Particle numbers example 4

Method: membrane filtration

A direct comparison with the particle numbers of Example 3b shows the favorable one Influence of the internal siliconization according to the invention on the particle number of Ci profloxacin solution for infusion: the number of particles is reduced by a factor of 72.

Example 5

100 g ciprofloxacin, 321.8 g lactic acid solution 10%, and 900 g sodium chloride were dissolved in 44.78 kg of water for injections. The pH was adjusted to 1 m Hydrochloric acid set to 4.2 and it was made up with water for injections filled a total weight of 50.25 kg. The solution was filtered through a 0.2 µm effective pore size filtered.

6 batches were produced in this way. 2 games were compared filled in 100 ml glass infusion bottles of glass type 1, one party also for comparison purposes in 100 ml glass infusion bottles of glass type 2 and 3 lots according to the invention in siliconized glass infusion bottles Glass type 2. The bottles were sealed with infusion stoppers and flaps closed and steam sterilized at 121 ° C for 20 minutes.

The concentrations of the ions Al ³⁺ , Ba ²⁺ and Zn ^{2+ were} then determined by means of elemental analysis and the results shown in Table 5 were obtained.

Table 5

Ion concentrations in the solutions of Example 5

Influence of internal siliconization on the delivery of ions to ciprofloxacin infusion solutions:
The concentration of Al ³⁺ in the ciprofloxacin infusion solutions according to the invention is reduced by a factor of 15-52 compared to filling in bottles of glass type 1 and by a factor of 2-6 compared to filling in bottles of glass type 2.

The concentration of Ba ²⁺ is reduced by a factor of 23-82 compared to filling in glass type 1.

The concentration of Zn ²⁺ is reduced by a factor of 4-428 compared to filling in glass type 1 and by a factor of 29-280 compared to filling in glass type 2.

In contrast, the delivery of Ca ²⁺ to ciprofloxacin infusion solution is hardly influenced ^according to the invention. The corresponding reduction factors are 1.2-1.5 for glass type 1 and 1.1 for glass type 2 and are irrelevant within the scope of the accuracy of the measurement method.

Ion siliconization thus brings about a significant reduction in the release of Al ³⁺ , Ba ²⁺ and Zn ²⁺ ions from the glass to the ciprofloxacin solution.

Example 6

4000 liters of ciprofloxacin infusion solution were prepared according to the procedure described in Example 1. The solution was filled into colorless 50 ml glass 2 infusion bottles of 51 ml each, which had been pretreated as follows:
The bottles were sprayed with a 0.25% emulsion of silicone oil (= polydimethylsiloxane, dimethicone) in water from the inside. The bottles were then thermally treated at about 300 ° C for about 8 minutes.

The filled bottles were filled with an infusion stopper was laminated with a fluoropolymer film, sealed and crimped. The fla were steam sterilized at 121 ° C for 20 minutes.

Claims (12)

1. Aqueous solution for infusion of ciprofloxacin in a glass container, characterized in that the glass container has a silicone coating on the inner surface. 2. Infusion solution according to claim 1, characterized in that it is a Ciprofloxacin concentration of 0.015 to 0.5 g / 100 ml. 3. Infusion solution according to claim 1 or 2, characterized in that it has a pH in a range from 2.5 to 7.0. 4. Infusion solution according to any one of claims 1 to 3, characterized records that the glass container from a glass of glass type 1 or 2 (according to DIN 52339) exists. 5. Glass container containing an aqueous solution of ciprofloxacin, thereby characterized in that the glass container on the inner surface a Has silicone coating. 6. Glass container according to claim 5, characterized in that the aqueous solution is a solution for infusion. 7. Glass container according to claim 5 or 6, characterized in that the aqueous solution a ciprofloxacin concentration of 0.015 to 0.5 g / 100 ml having. 8. Glass container according to any one of claims 5 to 7, characterized records that it consists of a glass of glass type 1 or 2 (according to DIN 52339).   9. Glass container according to any one of claims 5 to 8, characterized records that it has a removable filling volume of 40 to 600 ml. 10. Use of glass containers siliconized on the inside for Storage and storage of ciprofloxacin-containing aqueous Infusion solutions. 11. Process for heat sterilization of aqueous containing ciprofloxacin Infusion solutions, characterized in that the to be sterilized Infusion solution is in a glass container, which is on the inside has a silicone coating. 12. The method according to claim 11, characterized in that the Heat sterilization is steam sterilization.