WO2001078732A1

WO2001078732A1 - Ciprofloxacin infusion solutions having a good storage stability

Info

Publication number: WO2001078732A1
Application number: PCT/EP2001/004163
Authority: WO
Inventors: Klaus Sommermeyer; Hans-Jörg Müller; Tilo Hniopek; Bernd Eschenbach
Original assignee: Fresenius Kabi Deutschland Gmbh
Priority date: 2000-04-15
Filing date: 2001-04-11
Publication date: 2001-10-25
Also published as: DE10018783A1; AU2001273941A1

Abstract

The invention relates to infusion solutions of the 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid (ciprofloxacin) that have a good storage stability, containing 0.015 to 0.5 g of the active substance per 100 ml of the aqueous solution and sulfuric acid in an amount sufficient to dissolve the active substance and stabilize the solution of less than 0.9 mole per 1 mole of the active substance. The invention further relates to methods for producing the infusion solutions and to their use. The inventive infusion solutions allow to reduce the acid content of the solution, have a higher storage stability than other known solutions having the same acid content, and facilitate the safe incorporation of a larger content in minor constituents in the active substance.

Description

Storage-stable infusion solution of ciprofloxacin

The present invention relates to storage-stable infusion solutions of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acid, containing 0.015 to 0.5 g of the active ingredient mentioned 100 ml of aqueous solution and a sufficient amount of a physiologically acceptable acid to dissolve the active ingredient and to stabilize the solution. The invention further relates to the method for producing and using such infusion solutions.

In particular, the invention describes ready-to-use infusion solutions as well as other dosage forms which are introduced into such infusion solutions before application, the active ingredient being 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acid is known as ciprofloxacin.

EP-A-0049 355 protects i.a. Medicines containing 7-amino-l-cyclopropyl-4-oxo-l, 4-dihydronaphtyridine-3-carboxylic acid. EP-A-0 078 362 protects 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acids. The active ingredients known from the two EPs have high antibacterial effects and are suitable as medicaments for combating bacterial infections in humans and animals.

However, the known compounds are not or only very little suitable for producing infusion and / or injection solutions because, for example, the pH and / or the solubility and / or the shelf life, in particular with regard to excretions, of the ready-to-use infusion and / or injection solutions do not meet the pharmaceutical requirements for such solutions.

DE 33 33 719 AI discloses solutions of the lactic acid salts of piperazinyl-quinolonic and / or -azaquinolonecarboxylic acids which, in addition to the lactic acid salts mentioned and optionally conventional auxiliaries, additionally contain at least one acid which does not lead to precipitation. According to DE 33 33 719 Al, acids which do not lead to precipitation include lactic acid, methanesulfonic acid, propionic acid or succinic acid, although lactic acid is by far preferred. The lactic acid content of the infusion solutions according to DE 33 33 719 AI can carry 0.1 to 90%. The lactic acid content of the solution to be applied can be 0.1 to 10%. However, it has been found in practice that solutions which, in addition to ciprofloxacin lactate, have a concentration of free lactic acid of 0.1 to 90%, are only moderately tolerated physiologically. Hardening, swelling and reddening of the injection site occur, plasma, urea and creatine values are increased and tubular kidney changes result.

The problems occurring according to DE 33 33 719 AI (corresponds to EP-A 0 138 018) are tried to be avoided by EP-A-0 219 784 by providing infusion solutions of ciprofloxacin which contain 0.015 to 0.5 g of the active ingredient per 100 ml of aqueous solution and, depending on the active substance concentration, 0.9 to 5.0 mol, based on 1 mol of active substance, of one or more physiologically tolerated acids. The infusion solutions according to EP-A 0 219 784 contain, in addition to the active ingredient, water and other customary formulation auxiliaries, an amount of one or more acids from the group consisting of hydrochloric acid, methanesulfonic acid, propionic acid, succinic acid, glutaric acid, sufficient to dissolve the active ingredient and stabilize the solution. Citric acid, fumaric acid, maleic acid, tartaric acid, glutamic acid, gluconic acid, glucuronic acid, galacturonic acid, ascorbic acid, phosphoric acid, adipic acid, hydroxyacetic acid, sulfuric acid, nitric acid, Acetic acid, malic acid, L-aspartic acid and lactic acid. In the manner disclosed in EP A 0 219 784, it is possible to provide infusion solutions with lower toxicity, since if a ciprofloxacin concentration of less than 0.5% g / N is maintained, the amount of acids required for stabilization is below the value of 0.1%. can be reduced, which is specified in DE 33 33 719 AI as the minimum amount, but the infusion solutions according to EP A 0219784 are still in need of improvement with regard to their storage stability and also with regard to the reduction in the amount of acid auxiliaries used.

The reduction of the amount of acid to be used for stabilization is of fundamental interest, especially when the stability of infusion solutions is comparable.

EP-A-0 287 926 relates to parenterally administrable solutions of quinolonecarboxylic acids, i.a. Ciprofloxacin, where it is proposed to use particularly pure main active ingredient components to improve storage stability. In particular, EP-A-0 287 926 relates to such parenterally administrable solutions in which no more than 1 to 10 ppm, based on the main active component (ciprofloxacin) of the solution, are present on secondary components (“impurities” of the active ingredient) In the beginning, secondary components carried in by the main active ingredient in the infusion solution succeed in reducing the excretions from the infusion solutions (cloudiness during storage) in accordance with EP-A-0 287 926. However, reducing the secondary components is a relatively complex operation.

Even if very pure active ingredients are used to prepare the infusion solutions of ciprofloxacin, despite filtration of the solutions after their preparation - generally through filters with a pore size of 0.2 μm - a certain number of particles can be found after sterilization and during storage. According to EP-A-0 287 926, these particles can arise from the solution, in particular by precipitation of the active ingredient or of polycondensation products.

Furthermore, the publication DE 197 03 023 A discloses that the number of detectable particles is reduced by using glass bottles which have a silicone coating on the inner surface. This can further improve the shelf life of high-purity infusion solutions. It can therefore be assumed that the formation of precipitates is due to the number of particles that are inherently present. The more particles there are, the more particles are formed. This accelerates the formation of particles over time.

Both the process described in EP-A-0 287 926 for the production of high-purity infusion solutions and the use of special glass bottles are associated with great effort. It should be borne in mind that only a combination of both variants leads to a meaningful result.

It would therefore also be advantageous to provide infusion solutions in which less pure main active ingredients can also be used successfully. The purity of the active ingredients should still be in the medically acceptable range, but the greatest possible amount in this acceptable range of by-products should be tolerable without leading to infusion solutions that are not stable in storage. Storage stability is understood to mean the absence of excretions or precipitates in the case of practical and thus correspondingly long storage times.

The above-mentioned tasks as well as other tasks that are not explicitly mentioned are solved, however, can be derived from the introductory discussion of the prior art without further ado or result automatically from infusion solutions with all features of the independent product claim. Preferred embodiments of the infusion solutions according to the invention are the subject of the claims which refer back to claim 1.

Infusion solutions of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acid (ciprofloxacin), containing 0.015 to 0.5 g of the active ingredient in 100 ml of aqueous Solution and sulfuric acid in an amount sufficient to dissolve the active ingredient and to stabilize the solution of less than 0.9 mole based on 1 mole of active ingredient are surprisingly stable in storage, allow the acidity in the infusion solutions of ciprofloxacin to be reduced to substoichiometric values and allow use of ciprofloxacin active ingredients with significantly higher minor component proportions of more than 10 ppm, without there being any excretions from or clouding of the infusion solutions of ciprofloxacin.

It was particularly surprising that this result could be obtained using sulfuric acid as an acid auxiliary. Since EP-A-0 219 784 lists, inter alia, lactic acid, phosphoric acid, adipic acid, hydroxyacetic acid and sulfuric acid as possible auxiliaries in an amount of 0.9 to 5 mol per 1 mol of active ingredient, these alternatives are completely missing in EP 0 219 784 B1 , wherein the amount of acid (s) according to EP 0 219 784 B should be between 1.04 and 2.2 moles per 1 mole. Hydroxyacetic acid and phosphoric acid in substoichiometric amounts do not give usable results. In this respect, the successful use of sulfuric acid was not obvious, at least not in the amount according to the invention of less than 0.9 mol per 1 mol of active ingredient.

According to the present invention, those infusion solutions are of particular interest which are distinguished by the fact that the total sulfuric acid content is less than 0.8 mol based on 1 mol of ciprofloxacin (active ingredient). Also very particularly preferred are infusion solutions in which the total sulfuric acid content is less than 0.6 mol per 1 mol of active ingredient. Quite unexpectedly, it has also been found that the use of sulfuric acid together with certain additional acids enables infusion solutions of ciprofloxacin in which the stabilization is superadditive, quasi synergistic. Special infusion solutions are characterized in that they have an additional acid, in addition to sulfuric acid, a mono- or diester of orthophosphoric acid with glycerol or a higher-value physiologically compatible sugar such as glucose, sucrose, fructose or sugar alcohol such as sorbitol, mannitol or xylitol, the total content of sulfuric acid and additional acid is less than 1.04 mol per 1 mol of active ingredient. This makes it possible to provide infusion solutions that are even more stable in storage and at the same time are less prone to excretion or clouding, even if the content of secondary components from the active ingredient is greater than 50 ppm.

The acid to be used for additional stabilization of the infusion solutions of ciprofloxacin is particularly preferably glycerol esters of orthophosphoric acid. Monoglycerin orthophosphoric acid esters are particularly preferred. Of very great interest are infusion solutions in which, in addition to sulfuric acid, the acid (s) glycerol-1-phosphate, glycerol-2-phosphate or a mixture of the glycerol-phosphoric acid monoesters is or are. Diphosphates are also particularly suitable acids. These include in particular glucose diphosphate and fructose 1,6-diphosphate. The acids mentioned are about as strong as phosphoric acid. However, additions of glycerol 1-phosphate, glycerol 2-phosphate, glucose diphosphate and / or fructose 1,6-diphosphate significantly exceed phosphoric acid in terms of improving the storage stability.

The minimum amount of acid required per mole of active ingredient to dissolve naturally also depends on the active ingredient concentration and the acid (s) used and is therefore not constant. It should also be noted that the information in the amounts of acid relates only to the amounts which, according to generally known basic chemical rules, are not converted into the corresponding salt (s) by adding bases. Dissociation of the acids was not taken into account in the quantities, so that they relate to the dissociated and undissociated quantity of acids.

The infusion solutions according to the invention can also contain further formulation agents such as complexing agents, antioxidants, isotonizing agents and / or agents for adjusting the pH. The osmolality of the infusion solutions is 0.20 to 0.70 Osm / kg, preferably 0.26 to 0.39 Osm / kg and is adjusted by isotonic agents such as NaCl, mannitol, glucose, sucrose and glycerol or mixtures of such substances. If necessary, substances can also be used that are contained in common, commercially available infusion carrier solutions.

The usual infusion carrier solutions include infusion solutions with an electrolyte supply without carbohydrates such as saline, Ringer's lactate solution, etc. and those with carbohydrates and solutions for the supply of amino acids, each with and without carbohydrate content. Examples of such infusion carrier solutions are in Rote Liste 1998, list of finished medicinal products of the members of the Federal Association of the Pharmaceutical Industry, Editio Cantor, Aulendorf / Württ. listed.

Preferred are infusion solutions which, in addition to water, active ingredient and other formulation auxiliaries, contain such an amount of sodium chloride or other auxiliaries customary for isotonization that a solution which is isotonic or slightly hypotonic or hypertonic with the tissue fluid of the human or animal body is present. The infusion solutions according to the invention have a pH of 3.0 to 5.2. pH values of 3.6 to 4.7 and 3.9 to 4.5 are preferred. PH values in the range from 4.1 to 4.3 are very particularly preferred.

The infusion solutions according to the invention can be present in dosage units suitable for infusion with removable contents of 40 to 600 ml, preferably 50 to 120 ml.

The present invention also relates to a process for the preparation of infusion solutions according to the independent claim relating to the infusion solutions, which is characterized in that a suitable amount of the active ingredient, optionally in the form of a salt such as alkali or alkaline earth metal salt or addition salt, a hydrate or a hydrate of the salt or in the form of mixtures of these salts or hydrates, with a quantity of sulfuric acid and optionally a physiologically compatible monoester or diester of orthophosphoric acid or a mixture of several physiologically compatible monoester or diester derivatives of orthophosphoric acid, the total amount of acid being less than 0.9 Mole per 1 mole of active ingredient, optionally adding formulation auxiliaries and filling up with water or a conventional infusion carrier solution in such a way that a concentration range of 0.015 to 0.5 g is established for the active ingredient, be when using an alkali or alkaline earth metal salt of the active ingredient, the amounts required for dissolution are also contained in the amounts necessary for neutralizing the active ingredient anion and, when using an addition salt, part of the required amount of acid is already contained in the active ingredient to be used.

During production, it should also be noted that the solutions correspond to the properties already listed with regard to pH, amounts of acid and osmolality. In the event of using the active ingredient in salt form It is expedient to use an acid whose anion corresponds to the anion of the active ingredient salt or of the salt hydrate.

The pH of the infusion solutions according to the invention can be adjusted to the above-mentioned values with (physiologically) compatible acids and / or bases, i.e. Set 3.0 to 5.2, especially 3.6 to 4.7. To accelerate the manufacturing process, in particular the dissolving of solid components, the solutions or only a part thereof can be slightly warmed, preferably to temperatures between 20 ° C and 80 ° C

The solutions according to the invention can be produced particularly economically using concentrated solutions. For this purpose, the amounts of active ingredient required for a batch with the main amount of acid required for the batch (e.g. 95% based on molar basis) are dissolved in a little water - if necessary with heating. This concentrate is then diluted. After dilution, any other auxiliary substances - such as Table salt for isotonization - added, as well as the possibly missing amount of acid.

After the solution has been prepared, it is generally filtered in order to remove most of the particles. Suitable filtering methods are known per se, so that reference can be made to the prior art. The number of particles is limited to what is medically necessary and economically sensible. These data and suitable methods are known from specialist books.

After filtering the solution, it can be filled into suitable containers. Without being restricted thereby, glass bottles or bags made of plastic films are generally used for this purpose, which are suitable for medical use. PVC-free bags are particularly preferred based on polyolefins. To improve the shelf life, these bags can optionally be provided with a further outer packaging.

The solutions according to the invention show a high storage stability, which is not limited by the number of particles. The effort as described in documents EP 0 287 926 and DE-A-197 30 23 to make the solutions durable can be dispensed with.

Examples

The following examples and comparative examples serve to explain the invention in more detail, without any intention that this should impose a restriction. Water for infusion solutions was used to prepare the solutions.

example 1

3 mmol (1 g) of ciprofloxacin were suspended in 250 ml of water. To this suspension was added 196.5 ml of a sulfuric acid solution, which was obtained by diluting 15.5 ml of sulfuric acid (c = 0.1 mol / 1; Merck AG) with 181 ml of water. The total amount of sulfuric acid added was 1.5 mmol. The addition took place over a period of 2 hours, the pH not falling below 3.0. A clear solution was obtained which had a pH of 4.5. This solution was then mixed with 50 ml of a NaCl solution containing 4.41 g of NaCl and then diluted with water to 500 ml with water.

The solution thus obtained was filtered into a glass bottle for medical

Filled purposes and then sterilized at 121 ° C. The sterile so obtained

Solution was stored at room temperature for 6 months and checked visually regularly. No changes were visually observed after this period. The subvisual particles, determined by the usual method of light blocking, were low and also remained unchanged. They corresponded to the specifications in the Ph.Eur. are fixed for such solutions.

Example 2

Example 1 was essentially repeated. However, the solution obtained was not filled into a glass bottle but into a polyolefin-based bag, which is also suitable for medical purposes.

No changes were visually observed after storage for 6 months.

The subvisual particles, determined by the usual method of light blocking, were low and also remained unchanged. They corresponded to the specifications in the Ph.Eur. are fixed for such solutions.

Comparative Example 1

3 mmol (1 g) of ciprofloxacin were suspended in 250 ml of water. A solution of 2.9 mmol (0.22 g) of hydroxyacetic acid in 200 ml of water was slowly added to this suspension. The suspension did not completely dissolve. A review of the shelf life was therefore obsolete.

Comparative Example 2

3 mmol (1 g) of ciprofloxacin were suspended in 250 ml of water. A solution of 2.9 mmol (0.26 g) lactic acid in was slowly added to this suspension 200 ml of water added. The suspension did not completely dissolve. A review of the shelf life was therefore obsolete.

Comparative Example 3

3 mmol (1 g) of ciprofloxacin were suspended in 250 ml of water. A solution of 3 mmol phosphoric acid in 200 ml water was slowly added to this suspension. The addition took place over a period of 2 hours, the pH not falling below 3.0. A clear solution was obtained. This solution was then mixed with 50 ml of a NaCl solution containing 4.41 g of NaCl and then diluted to 500 ml with water.

The solution thus obtained was filtered like Example 1, filled into a glass bottle for medical purposes and then sterilized at 121 ° C. The sterile solution thus obtained was stored at room temperature for 2 months and regularly checked visually. After two months there was a visually detectable crystal formation. The attempt was then stopped.

The experiments and comparative experiments clearly show that solutions with a substoichiometric acid / ciprofloxacin ratio can only be obtained using sulfuric acid. The solutions according to the invention can be stored over a long period of time without problems with stability. In contrast, prior art infusion solutions form precipitates. This is shown particularly clearly by comparative experiment 3. So far, highly pure ciprofloxacin solutions have been used to solve this problem, as described in documents EP 0 287 926 and DE-A-197 30 23. Such precautions can be dispensed with when using sulfuric acid.

From a medical point of view, solutions that have the lowest possible particle content should be preferred. Because of economical reasons However, the purification must be kept within limits. It should be taken into account here that possibly particles can also get into the solution when the infusion solution is applied via tubes etc. There is therefore no reason to reduce the particle content below a certain number, which is also supported by economic considerations, as long as they correspond to the limit values for the visual and subvisual particles, as they are fixed in the corresponding pharmacopoeia.

It should therefore be noted that the particles that may may be responsible for the limited shelf life of the ciprofloxacin solutions obtained using lactic acid or phosphoric acid, and may not lead to the formation of precipitate or subvisual particles when using sulfuric acid.

It should be noted that the solutions according to the invention remain stable. Deposits such as those described for the lactic acid solutions in EP-A-0287 926 as polycondensation products are obviously not formed. Efforts as described in EP 0 287 926 or DE-A-197 3023 to obtain stable solutions are accordingly not necessary. This unexpected result enables an inexpensive method of manufacturing long-term durable ciprofloxacin solutions.

Claims

claims

1. Storage-stable infusion solutions of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -quinoline-3-carboxylic acid (ciprofloxacin), containing 0.015 to 0.5 g of the active ingredient 100 ml of aqueous solution and sulfuric acid in an amount sufficient to dissolve the active ingredient and to stabilize the solution of less than 0.9 mole per 1 mole of active ingredient.

2. Infusion solutions according to claim 1, characterized in that the total sulfuric acid content is less than 0.8 mol based on 1 mol of active ingredient.

3. Infusion solutions according to claim 1, characterized in that. the total sulfuric acid content is less than 0.6 mol per 1 mol of active ingredient.

4. Infusion solutions according to one of the preceding claims, characterized in that they contain, as additional acid, a mono- or diester of orthophosphoric acid with glycerin or a higher-value physiologically compatible sugar such as glucose, sucrose, fructose or sugar alcohol such as sorbitol, mannitol or xylitol, the Total sulfuric acid and additional acid content is less than 1.04 mol per 1 mol of active ingredient.

5. Infusion solutions according to claim 4, characterized in that. the additional acid is glycerol-1-phosphate, glycerol-2-phosphate, glucose diphosphate and / or fructose-1,6-diphosphate.

6. Infusion solutions according to one or more of the preceding claims, characterized in that they contain complexing agents, antioxidants, isotonizing agents and / or agents for adjusting the pH as formulation aids.

7. Infusion solutions according to one or more of the preceding claims, characterized in that they have an osmolality of 0.20 to 0.70 osm / kg and isotomizing agents such as NaCl, sorbitol, mannitol, glucose, sucrose, xylitol, fructose, glycerol or mixtures contain such substances and / or if appropriate substances which are contained as constituents in conventional infusion carrier solutions.

8. Infusion solutions according to claims 1 to 7, characterized in that they have a pH in the range from 3.0 to 5.2, preferably in the range from 3.6 to 4.7, preferably in the range from 3.9 to 4.5, particularly preferably in the range from 4.1 to 4.3.

9. Infusion solutions according to one of the preceding claims, characterized in that they contain, in addition to the active ingredient, water and other formulation auxiliaries, such an amount of sodium chloride or other auxiliaries customary for isotonization that an isotonic or slightly hypotonic or hypertonic with the tissue fluid of the human or animal body Solution is available.

10. Infusion solutions according to one or more of the preceding claims, characterized in that they contain 0.96 mol of a mixture of glycerol-1-phosphate and glycerol-2-phosphate (based on 1 mol of active substance) and based on active ingredient, water and other formulation auxiliaries contain 0.6 to 2.2 mol NaCl per 100 ml solution.

1 1. Infusion solutions according to claims 1 to 10, in dosage units suitable for infusion, which can be made both from glass or from suitable plastics, with removable contents from 40 to 600 ml, preferably from 50 to 120 ml.

12. A process for the preparation of infusion solutions according to claims 1 to 11, characterized in that a suitable amount of the active ingredient, optionally in the form of a salt such as alkali or alkaline earth metal salt or addition salt, a hydrate or a hydrate of the salt or in the form of mixtures thereof Salts or hydrates, with an amount of sulfuric acid and optionally a physiologically compatible monoester or diester of orthophosphoric acid or a mixture of several physiologically compatible monoester or diester derivatives of orthophosphoric acid, the total amount of acid being less than 0.9 mol per 1 mol of active ingredient, optionally formulation auxiliaries added and filled with water or a conventional infusion carrier solution in such a way that a concentration range of 0.015 to 0.5 g for the active ingredient is obtained, wherein when using an alkali or alkaline earth metal salt of the active ingredient in the dissolution he required amounts of acid are also contained in the amounts necessary to neutralize the active ingredient anion and, when using addition salts, part of the required amount of acid is already contained in the active ingredient salt to be used.

13. The method according to claim 12, characterized in that the pH of the fusion solution is adjusted to 3.0 to 5.2 using (physiologically) compatible buffer systems.

14. The method according to claim 12 or 13, characterized in that the preparation of the infusion solutions is carried out by heating.

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15. Use of infusion solutions and / or other

Dosage forms, which are converted into the infusion solutions according to claims 1 to 11 before application, for the production of dosage units suitable for infusion with removable contents of 40 to 600 ml.