DE10112325A1 - Storage stable ready-to-use infusion solutions of paracetamol - Google Patents

Abstract

Disclosed are storage-stable, particle and discoloration-free, parenterally administrable, in particular infusible, aqueous solutions of paracetamol, comprising in mixture a) 1 to 17 grams per liter of paracetamol and b) 0.01 to 0.17 grams per liter of one or more physiologically compatible Antioxidants selected from the group consisting of ascorbic acid, N-acetyl-L-cysteine and SH group-containing stabilizer compounds which are different from N-acetyl-L-cysteine; the aqueous solution being free from organic solvents and having a pH in the range from 5.5 to 6.5 and an oxygen content of less than 0.50 milligrams per liter. A method for producing such solutions and containers made of glass or plastic which contain such solutions are also disclosed.

Description

The present invention relates to paracetamol medicinally usable Solutions. In particular, the invention relates to a storage-stable, particle and discoloration-free, parenterally administrable, in particular infusible, aqueous Paracetamol solution, process for the preparation of such a solution and on containers containing such solutions.

Paracetamol is a standard analgesic that has been established for decades due to its favorable pharmacological properties (analgesic and antipyretic effect with very little antiphlogistic effect) Example routinely for postoperative pain therapy in childhood is used. The application is mainly prophylactic at Anesthetic induction or usually rectally during surgery performed.

As an intravenous drug form, acetaminophen has only been in the form of a sterile powder of an ester prodrug commercially (pro-dafalgam, active ingredient propacetamol, chemically the diethylaminoglycine ester of paracetamol). This dosage form must first reconstituted and then with an infusion carrier solution such as B. Glucose 5% or isotonic saline, on a suitable ready-made Infusion solution to be diluted further. This process is with Handling disadvantages connected. In addition, the manufacture of the prodrug and freeze-drying the ester to sterile lyophilisate with high manufacturing costs connected.

EP 0 916 347 A1 describes attempts to produce a finished paracetamol Injection form described in which with the help of organic solvents a sufficient solubility of the paracetamol is achieved so that for intramuscular forms of injection in which the dosage volume is natural  is limited, sufficient amounts of the paracetamol dissolved in small volumes can be. The above publication discloses for the solution in organic solvents still a pH optimum of 5.5-5.6 and the use of stabilizers such as sodium EDTA and sodium bisulfite.

The latter antioxidant is known to have serious disadvantages in the form of imm wanted side effects that make the use obsolete.

For paracetamol infusion solutions where higher volumes are intravenous are given, is a solubility of the active ingredient to the extent described in EP 0 916 347 A1 is specified, not essential. For example, pro-dafalgam after reconstitution in 20 ml citrate buffer with 100 ml isotonic saline or 5% glucose solution to the ready-to-use infusion solution diluted. For such a preparation the water solubility would in itself be Paracetamols sufficient. Nevertheless, due to stability problems there are none Commercial infusions of paracetamol.

Rather, aqueous solutions of paracetamol tend to be low Storage times for the formation of discoloration. It also comes to Occurrence of turbidity as well as the formation of particles or precipitation. Correspondingly aged paracetamol infusion solutions are of course no longer usable.

It was therefore the task of a stable, physiologically acceptable and Develop inexpensive paracetamol pre-infusion solution.

These are solved as well as other not literally mentioned, but are derived from the introductory discussion readily resulting tasks by a watery Solution of paracetamol, which has all the features of claim 1. Surprisingly, it has been possible in the context of the invention to use an aqueous  Develop paracetamol formulation that is storage stable, d. that is shows no discolouration after storage and no particles or Precipitation developed during storage.

A storage-stable, particle- and discoloration-free, parenteral according to the invention administrable, in particular infusible, aqueous solution of paracetamol has in mixture a) 1 to 17 grams per liter of paracetamol and b) 0.01 to 0.17 Gram per liter of one or more physiologically acceptable antioxidants which are selected from the group consisting of ascorbic acid, N-acetyl-L- Cysteine and SH group-containing stabilizer compounds derived from N-acetyl L-cysteine are different, the aqueous solution being free of organic solvents, has a pH in the range of 5.5 to 6.5 and has an oxygen content of less than 0.50 milligrams per liter.

An essential component of the solution according to the invention is paracetamol. The amount of paracetamol contained in the solution according to the invention can vary over a certain range. Depending on the application, one is aimed for the highest possible concentration of paracetamol in the solution. The solubility of the Paracetamols in water at room temperature is about 17 grams per liter. However, the solubility may be dependent on the solution contained in the solution other ingredients can also be higher than 17 grams per liter. For a number of applications, it is expedient that the solution 5 to 15, preferably 7.5 to 12.5, grams per liter of paracetamol. A particularly user-friendly and excellent for most standard cases suitable solution has a paracetamol active ingredient content of 10 grams per liter.

The solution for infusion according to the invention contains as another essential Part of a physiologically compatible antioxidant. This is about are compounds selected from the group consisting of Ascorbic acid, N-acetyl-L-cysteine and SH group-containing stabilizer  Compounds other than N-acetyl-L-cysteine exist. To the latter group belongs e.g. B. Cysteine. Amazingly, it turned out that by using these substances a particularly effective Stabilization is also possible over longer storage times without the Tolerability of the paracetamol infusion solutions suffers. This was all the more surprising as the known stabilizing compounds such as Sodium EDTA or sodium bisulfite show undesirable side effects. Particularly preferred among those in question for the invention antioxidant compounds is N-acetyl-L-cysteine. Of course you can use a single connection as a stabilizer. But it can also Mixtures of two or more of the stabilizing compounds Application.

The concentration of the stabilizing compounds in the infusion solution is in the range between 0.01 and 0.17 grams per liter. In a preferred variation the solution of the invention has 0.05 to 0.15, preferably 0.075 to 0.125 Gram per liter of stabilizing compound, particularly preferably N-acetyl-L-cysteine.

The ratio of paracetamol a) to stabilizing compound b) is conveniently in the range of 10: 1 to 1000: 1, based on the weight of the Links. A weight ratio of a) to b) is particularly preferred Range from about 50: 1 to 500: 1, expediently 80: 1 to 200: 1. Very good Stability data are obtained when the weight ratio a): b) is approximately Is 100: 1.

The solution according to the invention is free from organic solvents. this includes all essentially low molecular weight known to those skilled in the art organic compounds used exclusively for the purpose of increasing the Solubility of the paracetamol can be used in water. These include:  all alcohols such as ethanol, benzyl alcohol and other low molecular weight organic compounds containing hydroxyl groups.

The solutions of the invention have a defined pH, which in one Range is between 5.5 and 6.5. This helps to stabilize the Solution as well as to ensure the physiological tolerance of the Solution at. Solutions that have a pH in the Range between 5.75 and 6.25, preferably between 5.9 and 6.1. Surprisingly, the optimal pH for the best stability is Solution at about 6.0 to 6.1, while EP-A 0 916 347 is an optimum of about 5.5 disclosed.

The stability of the solution according to the invention is reduced by a reduction in Free oxygen content in the solution increased. The oxygen content of the The solution is less than 0.50 milligrams per liter. The is preferred Oxygen content of the solution as low as possible. Of special interest are solutions that are characterized by the fact that they have an oxygen content of less than 0.35 milligrams per liter, expediently 0.25 milligrams per liter, even more convenient 0.15 milligrams per liter, and most preferably less than 0.10 milligrams per liter.

Especially through the combination of special antioxidants and Low oxygen content of the solution results in storage stability Solutions.

The setting of the preferred pH value for the solution according to the invention Area can be made easier, for example, with a buffer system. That's the way it is preferred that the solution be one for adjusting the pH to desired value sufficient amount of a physiologically acceptable Has buffer system. For this come those familiar to the expert Substances in question. This is a particularly preferred embodiment  characterized as being a pH buffer glycerol 1 (2) dihydrogen phosphate having.

The solution of the invention can have further additives. So it can make sense be isotonicize the solution. Therefore special solutions of the invention characterized in that it contains one or more isotonizing agents, preferably have NaCl or glycerol. Particularly useful under The physiological point of view is the use of NaCl during the use of glycerin can improve the solubility of paracetamol.

The solution for infusion, as is the subject of the invention, can additionally Paracetamol contain other active pharmaceutical ingredients. Especially Solutions that mix one or more with paracetamol are interesting further active pharmaceutical ingredients from the group of local anesthetics, Have analgesics and antispasmodics.

For example, the common one is preferred for some applications Administration of paracetamol and lidocaine. Such can preferably Formulation additionally have a content of codeine phosphate. Furthermore, an infusion solution according to the invention with contents on is preferred Paracetamol, lidocaine and hyoscin-N-butyl bromide.

The invention also relates to a method for producing a solution as described and defined herein, in which

• A) Water for injections with less oxygen presented as 0.50 mg / l;
• B) acetaminophen, antioxidants, buffers, isotonizing agents and optionally other pharmaceutical active ingredients in the desired Quantities with the greatest possible exclusion of oxygen in the Template A) triggers; and  
• C) optionally the pH of the solution by adding a physiologically acceptable acid adjusted to the desired value.

Expediently, one then proceeds in such a way that one

• A) the solution adjusted to the desired pH by Filtered membrane filter 0.2 µm and then in container for Bottles infusion solutions and heat sterilized at 121 ° C for 15 min.

Another preferred variant of the method for producing the Solution according to the invention provides that one expels the oxygen passes an inert gas through the water in step A) and that at Mix in step B) and, if necessary, in all further steps Inert gas atmosphere works. As inert gases or protective gases come to Example nitrogen or argon in question.

The invention particularly also includes containers having one therein defined solution. The containers can be bottles or bags as they are for Ready-to-use solutions are common.

Glass or plastic containers are preferred. Unless it is Plastic containers are, they preferably consist of one Polyolefins based material and if necessary. With a second bag, which contains an oxygen barrier layer, possibly with a Oxygen absorber between the bags.

A very particularly stable solution for infusion is within the scope of Invention before when a special buffer system to a pH from 5.5-6.5 (glycerophosphate buffer) with the use of acetyl cysteine as Stabilizer in connection with the manufacture of the product under nitrogen Protective fumigation, d. H. Exclusion of oxygen.  

The invention is illustrated below by examples and comparative examples explained in more detail:

General manufacturing instructions

• 1. There is a defined amount of water (984 ml) for at room temperature Submitted for injection purposes. Nitrogen can be passed through the template, so as to reduce the oxygen content of the water.
• 2. There are the predetermined amounts of a) paracetamol (10 g), b) antioxidant (0.1 g N-acetyl-L-cysteine), c) buffer substance (1.5305 g glycerol-1 (2) - dihydrogen phosphate, mixture of disodium salts × 5 H2O) and d) Sodium chloride (6.60 g) under an inert gas atmosphere with stirring for presentation given and dissolved.
• 3. If necessary, a necessary correction of the pH to the Range from 5.7 to 6.3 by adding a small amount of 0 to 0.44 ml per liter of 25% hydrochloric acid.
• 4. The solution obtained in 3. is filtered several times, lastly in a storage tank through a membrane filter 0.2 µm.
• 5. The solution is placed under an inert gas atmosphere in a glass or plastic container filled and sealed airtight.
• 6. The closed containers are sterilized at 121 ° C for 15 min.
• 7. The sterilized and cooled containers are kept for 2 or 3 months at 4- 8 ° C in the refrigerator, at 25 ° C or at 40 ° C in the warming cabinet.
• 8. After the storage time, the containers are visually assessed and it is measured the pH.

Comparative Example 1 (corresponding to Experiment No. 1.2a)

An infusion solution with 10 g / L paracetamol was prepared with the pH Value 6 isotonicized with saline. The solution was placed in a glass container. No antioxidant was added  Buffer solution. A protective gas atmosphere was not used. The Preparation showed a storage after 3 months at room temperature or 40 ° C Discoloration as well as particles and precipitation, at the same time the pH value dropped significantly, probably due to hydrolysis.

Comparative Example 2 (corresponding to Experiment No. 1.2e)

In addition to the measures taken in Comparative Example 1, the pH Set the value to 4.8 with HCl.

In this case too, the batch showed discoloration, sediment after storage as well as a strong pH shift due to the hydrolysis.

Comparative Example 3 (corresponding to Experiment No. 1.2c)

A batch was prepared as in Comparative Example 1 with a pH Adjustment to pH 6.2.

In contrast to Comparative Example 1, however, the approach with nitrogen fumigated, so oxygen excluded. Surprisingly, this one Trial found that no discoloration occurred and no pH There was a shift. However, a sediment was again found 3 months of storage noted.

Example 4 (according to Experiment No. 1.2f)

The pH was raised in this example with a glycerophosphate buffer Adjusted pH 5.6 and added 100 mg / L acetyl cysteine as a stabilizer. In addition, work was carried out under an inert gas atmosphere. After 3 months Storage was found that no discoloration occurred, the Approach without precipitation and the pH value as expected by the Buffer remained constant.  

The hydrolysis rate with this approach remained very low.

Example 5 (according to experiment no. 1.2i)

In this example, in contrast to example 5, ascorbic acid was used as Stabilizer used. After 2 months of storage, it was found that the Solution was free of particles and discoloration and a low hydrolysis rate had.

The acetate content of the solution can be used as a measure of the hydrolysis of the active ingredient Paracetamol can be viewed during and after storage. He will determined enzymatically. At the start of storage, the acetate content is approximately 0.2 mg / l. The lower the content determined after storage, the less of Paracetamols is hydrolyzed.

Claims (17)

1. Storage-stable, particle- and discoloration-free, parenterally administrable, in particular infusible, aqueous solution of paracetamol, comprising a mixture

• a) 1 to 17 grams per liter of paracetamol and
• b) 0.01 to 0.17 grams per liter of one or more physiologically compatible antioxidants selected from the group consisting of ascorbic acid, N-acetyl-L-cysteine and SH group-containing stabilizer compounds which are derived from N-acetyl-L Cysteine are different;

the aqueous solution being free from organic solvents and having a pH in the range from 5.5 to 6.5 and an oxygen content of less than 0.50 milligrams per liter. 2. Solution according to claim 1, characterized in that it 5 to 15 preferably 7.5 to 12.5 grams per liter of paracetamol. 3. Solution according to claim 1 or 2, characterized in that it 0.05 to 0.15, preferably 0.075 to 0.125 grams per liter of N-acetyl-L- Has cysteine. 4. Solution according to one of the preceding claims, characterized in that she a pH in the range between 5.75 and 6.25, preferably between 5.9 and 6.1. 5. Solution according to one of the preceding claims, characterized in that she an oxygen content of less than 0.35 milligrams per liter, preferably less than 0.25 milligrams per liter.   6. Solution according to one of the preceding claims, characterized in that she sufficient to adjust the pH to a desired value Has an amount of a physiologically compatible buffer system. 7. Solution according to claim 6, characterized in that it has glycerol-1 (2) -dihydrogenphosphate as pH buffer. 8. Solution according to one of the preceding claims, characterized in that she one or more isotonizing agents, preferably NaCl or glycerol, having. 9. Solution according to one of the preceding claims, characterized in that she mixed with paracetamol one or more other pharmaceutical Active substances from the group of local anesthetics, analgesics and Antispasmodics and has. 10. Solution according to claim 9, characterized in that it Lidocaine has. 11. Solution according to claim 10, characterized in that it has codeine phosphate in addition to lidocaine. 12. Solution according to claim 10, characterized in that it hyoscin-N-butyl bromide in addition to lidocaine. 13. A method for producing a solution according to claims 1 to 12, characterized in that

• A) presents water for injections with an oxygen content of less than 0.50 mg / l;
• B) acetaminophen, antioxidants, buffers, isotonizing agents and optionally other pharmaceutical active ingredients in the desired amounts with the greatest possible exclusion of oxygen in template A); and
• C) if necessary, the pH of the solution is adjusted to the desired value by adding a physiologically acceptable acid.

14. The method according to claim 13, characterized in that one

• A) the solution adjusted to the desired pH is filtered through a 0.2 µm membrane filter and then filled into containers for infusion solutions.

15. The method according to claim 13 or 14, characterized in that to expel the oxygen an inert gas through the water in step A) conducts and that when mixing in step B) and optionally all further steps works under an inert gas atmosphere. 16. Container having a solution according to claims 1 to 12. 17. A container according to claim 16 made of glass or plastic, preferably from a material based on polyolefins.