DE4312016A1 - Stable ketamine solutions - Google Patents

Description

The invention relates to stable solutions, in particular Injection solutions of ketamine, especially the 5 (+) - Enantiomers, their preparation and use.

Injection solutions are sterile solutions for injection are determined in the human or animal body. They must be tested under suitable visual conditions, clear and practically free of particles. the same Requirements also apply to infusion solutions that in addition, still free of pyrogens and normally should be blood-isotonic, as they are in principle are intended to be administered in large quantities (DAB 10, 1991). The monographs of the German Pharmacopoeia Contain one in terms of particle freedom Restriction: "Virtually particle-free" does not mean absolutely particle-free, since such a requirement is not would be feasible. "Virtually particle-free" means rather, free of visible particles. The American Pharmacopoeia (USP XXII Supplement 7, 1992) contains a Specification regarding subvisual particles in small and large volume injection or Infusion solutions. For small volume injectables (<100 ml), the requirements are met if the average number of particles per container smaller than 10 000, with an effective spherical diameter the particles of <10 μm and if less than 1000 particles <25 microns per container contained in the solution. at Infusion solutions (<100 ml) are within the limits of the USP <50 particles / ml (<10 μm) and <5 particles / ml (<25 μm).  

Although highest in the production of parenterals Effort in terms of a particle-free production is operated, it is virtually impossible, an absolute produce and fill particle-free solution.

Particles are especially present in the intravenous Application is a risk to the patient. It works particles <7 μm in diameter are at particular risk because these blood capillaries in the lungs, their diameter is also about 7 microns, can not happen and for Vascular occlusion can lead to subsequent infarction (Pharmaceutical Dosage Forms: Parenteral Medications Volume I, 2nd Edition, 1992, 47).

Particles that are present in injection solutions may be from Packaging materials (glass, rubber particles, Silicone oil droplets) or may be from the environment during get into the product during production (dust particles). There are also a number of ways that can be Particles through interaction of the solution with the Container material form glass (BaSO₄, CaSO₄ · 2H₂O, silicate Hydrate) (Pharmaceutical Dosage Forms: Parenteral Medication Volume I, 2nd Edition, 1992, 217-307).

As instability of a parenteral product can be considered if the active ingredient precipitates in the solution (eg due to a pH shift in the preparation during sterilization or storage) or if as a result of a chemical instability a sparingly soluble Degradation product is formed, which precipitates crystalline.

This is for example in solutions of 2- (2-chlorophenyl) - 2- (methylamino) cyclohexanone hydrochloride (ketamine) Hydrochloride) and especially in solutions of the 5 (+) - Ketamins a known problem.

Ketamine hydrochloride, has been in clinical use since 1970 Application as fast acting anesthetic with short  Half-life allowed and is in the form of the Razemats of the Ketamine hydrochloride used. 1982 was the Configuration of the enantiomers as R (-) and 5 (+) elucidated (Ratti-Moberg et al., Acta Chemica Scandinavica 45 (1991), 108-110).

Since the late seventies, the different pharmacological effects of the two enantiomers of the Ketamins are researched and numerous publications described. S (+) - ketamine showed a clear stronger hypnotic effect than the R (-) enantiomer. Also is the analgesic effect of the S (+) enantiomer significantly stronger than that of R (-) ketamine.

While having the desired pharmacological properties S (+) - ketamine are undesirable Side effects - especially mental phenomena in the Wake up phase - attributed to the R (-) - ketamine.

As against the background of higher drug safety the demand has generally been raised in recent years, Optically pure for optically active substances It was enantiomers rather than racemates obvious, a form of injection of S (+) - ketamine too develop. However, it had to be stated that with S (+) - ketamine hydrochloride despite its good Solubility in water (the solubility of the racemate in water is 20 g / 100 ml) and optimal pH adjustment in contrast to ketamine-HCl racemate practically no particle-free, storage stable injection solutions. It forms after about 3-6 months of storage at RT fine crystalline precipitate. A mass spectroscopic Investigation of filtered particles revealed that it was the precipitate is pure S (+) - ketamine base. Ketamine has a pK value of 7.5. At a pH Adjustment to pH 3.5, the active ingredient should be 99.99% dissociated and thus in good water-soluble form available.

However, from a therapeutic point of view, there is a strong interest it was an S (+) - ketamine · HCl solution for injection Object of the invention, long-term stable solutions for To provide and the particle formation through to prevent appropriate action.

Surprisingly, it was found that the formation of a particulate precipitate in ketamine injection solutions by adjusting the surface tension of the solution to a value <40 mN / m can be prevented.

For lowering the surface tension of a solution surfactants or organic solvents are usable or also their combinations. Suitable, for example Polysorbates such. Polysorbate 80, Polyoxyethylenepolyoxypropylen polymers such as. Pluronic® F68, solubilizers such. B. Cremophor® types or quaternary ammonium compounds such. B. benzethonium chloride or benzalkonium chloride. Suitable organic Solvents are, for example, ethanol, propylene glycols or polyethylene glycols.

A setting of the surface tension on such a low value is with surfactants that are parenteral Application are allowed, but only with guarantor Ammonium compounds possible, this is preferred as Preservative common benzethonium chloride particularly suitable.

The use of surfactants, d. H. the influence of the Surface tension, for the stabilization of parenterals is currently only used in special cases.

In peptide preparations, it may lead to denaturation of the sensitive peptide molecules come to interfaces, be it at the interface gaseous / liquid, d. H. at the Liquid surface or at the interface solid / liquid, d. H. on the container wall. Next to it will be  often a drug loss due to adsorption of the most low-dose peptide drugs on the glass wall of the Ampoules or vials observed. Both effects can be through Addition of polysorbate 80 or Pluronic F 68 in suitable Concentration can be prevented (Pharmaceutical Dosage Forms: Parenteral Medication Volume I, 2nd Edition, 1992, 304-305).

Surfactants are also described in the literature, to stabilize parenteral depot dosage forms (Pharmaceutical Technology, Thieme Verlag, 1991, 562). These are usually suspensions, d. H. around Disperse systems of the solid / liquid type. Surfactants like Pluronics and polysorbate can here the agglomeration of usually prevent very finely ground solid particles, resulting in a physical stabilization of the preparation leads, because the sedimentation tendency finely distributed Particle is significantly smaller than the agglomerated, coarser particles.

Another application of surfactants is the Solubilization or solubilization poorly soluble Drugs by inclusion in micelles.

In the present case of S (+) - Ketamine HCl solution for injection however, it is neither a peptide drug still a parenteral suspension. The active ingredient is in Opposite very good water-soluble. The stabilization of Preparations of highly water-soluble active ingredients Reduction of the surface tension by means of surfactants is therefore a completely surprising and novel process.

Ketamine racemate, 5 (+) - and R (-) - enantiomer differ Practical in their surface-active properties not (see Table 1).  

Table 1

Surface tension of aqueous ketamine-HCl solutions

It is all the more surprising that, on the one hand, the tendency to go out precipitate aqueous precipitates in aqueous solutions, in the series Ketamine Razemat <S (+) - Ketamine <R (-) - Ketamine and on the other hand with S (+) - ketamine the precipitation Training by adjusting the surface tension of the Solution can be prevented. Whether this also applies to R (-) - Ketamine is possible was not investigated, because no therapeutic interest exists.

For the formation of a crystalline precipitate in 5 (+) - To prevent ketamine HCl solutions is falling short a critical surface tension required.

In Table 2, the concentration-dependent Surface tension of aqueous benzethonium chloride solutions and the corresponding S (+) - ketamine-benzethonium chloride- Solutions with the same benzethonium chloride concentrations and the particle formation faced.

The particle formation was in sterilized solutions (121 ° C, 20 min.) According to the DAC method (Sample 5) (German Arzneimittel-Codex, 1986). The patterns became one Stress test at elevated temperature (30 ° C or 60 ° C) for 4 Subjected for weeks. All approaches with one  Surface tension, which is significantly smaller than the pure aqueous solution of active substance, had SE₂₀- at 60 ° C storage Values that were <4.5 and thus the acceptance limits comply with the DAC method. A comparison solution without Adjustment of the surface tension showed at 60 ° C Storage a much higher, unacceptable Value.

Table 2

Benzethonium chloride concentration, surface tension and particle formation of S (+) - ketamine solutions

In column A, the benzethonium chloride concentration is Solutions listed in weight percent, column B shows the Surface tension of these solutions and column C the Surface tensions of the corresponding S (+) - ketamine-HCl- Solutions.

The limit of the DAC sample 5 is SE₂₀ <4.5

Even at 30 ° C stored samples show after 4 weeks already a significant difference in the particle content between Solutions of high and low surface tension.  

Other surfactants such. B. Benzalkonium chloride, polysorbate 80 and Pluronic F 68 (see Table 3) also show a stabilization tendency, However, in the case of Pluronic F 68 not so clear is pronounced. Of benzalkonium chloride are bronchoconstrictive side effects in the literature (Miszkiel et al., Br. J. Clin. Pharmac., 25, 157 (1988)). When using polysorbates in parenteral is reported from deaths in premature babies (Butler et al., Am. J. Hosp. Pharm. 41, 1514-1516 (1984)). That's why benzethonium chloride appears as a stabilizer especially suitable, especially since it is also effective as a preservative is what the bottling of S (+) - Ketamine · HCl Injection solution in multi-dose containers possible.

Table 3

Surface tension and particle formation as a function of the surfactants used

In column A of Table 3, the concentrations of used surfactants in weight percent, their solutions listed in column B. Have surface tensions and in column C the  Surface tensions of the corresponding S (+) - ketamine-HCl- Solutions.

The surfactant concentrations of those described in Table 3 Approaches vary in height. The reason is the different critical micelle formation concentrations (CMC) of the surfactants used and each at Measured concentrations above the CMC Surface tensions. The concentrations became like that chosen that the CMC was exceeded and thereby the lowest adjustable with the respective surfactant Surface tension in the solution was present.

As can be seen from Table 4 is also by addition organic solvents or co-solvents Surface tension of aqueous solutions significantly reduced.

Table 4

Surface tension of aqueous cosolvent solutions

That even with the help of these solvents the Can suppress particle formation, the results show in Table 5:

Table 5

Surface tension and particle formation in cosolvent systems

In column B of Table 5 are the surface tensions listed solvent systems and listed in Column C the surface tensions of the corresponding 5 (+) - Ketamine HCl solutions.

The following examples illustrate the stabilized solutions of the invention and the methods for their production.

example 1 5 (+) - Ketamine HCl Injection Solution (without setting the Surface tension)

To prepare a solution of the composition

S (+) - Ketamine HCl | 57.668 g sodium chloride 6,000 g Hydrochloric acid 0.01 N 75,000 g Water for injections 1876.132 g Pure nitrogen q.s. Σ 2014.8 g (equivalent to 2 l)

in a 2 l glass container in about 1850 g of water f. I. 57688 g of S (+) - ketamine HCl and 6.000 g of sodium chloride Stirring solved. After complete dissolution will be at least stirred for 15 minutes. Then the pH of the solution adjusted to pH 3.5 by adding 0.01 N HCl solution. The solution is f. I. replenished to 2014.8 g, and stirring is continued for 10 minutes. The solution will be then sterile-filtered over 0.2 μm membrane filter and under nitrogen in 2 ml Aufbrennampullen bottled. The sealed ampoules will be 20 minutes sterilized at 121 ° C. After cooling, the Ampoules by color test for tightness and by means of 100% visual inspection for particle freedom.

Example 2 5 (+) - ketamine HCl solution for injection with benzethonium chloride (0.01%)

To prepare a solution of the composition

S (+) - Ketamine HCl | 57.668 g sodium chloride 6,000 g benzethonium 0.200 g Hydrochloric acid 0.01 N 75,000 g Water for injections 1875.932 g Pure nitrogen q.s. Σ 2014.8 g (equivalent to 2 l)

in a 2 l glass container in about 1850 g of water f. I. 57.668 g of S (+) - ketamine HCl and 6.000 g of sodium chloride and 0.200 g of benzethonium chloride are dissolved with stirring. To Full dissolution will take at least 15 minutes  touched. Then the pH of the solution is increased by adding 0.01 N HCl solution adjusted to pH 3.5. The solution will be with water f. I. replenished to 2014,8 g, and it will be 10 Stirred for another minute. The solution is then over 0.2 μm membrane filter sterile filtered and under Nitrogen fumigation filled in 2 ml Aufbrennampullen. The sealed vials are left at 121 ° C for 20 minutes sterilized. After cooling, the ampoules are Color test for tightness and 100% visual Inspection checked for particle freedom.

Example 3 5 (+) - Ketamine HCl Injection Solution with Polyethylene Glycol 400 (30% m / v)

To prepare a solution of the composition

S (+) - Ketamine HCl | 57.668 g sodium chloride 6,000 g Polyethylene glycol 400 600,000 g Hydrochloric acid 0.01 N 440,000 g Water for injections ad 2,000 l Pure nitrogen q.s.

in a 2 l glass container in about 850 g of water f. I. and 600.0 g of polyethylene glycol 400 mixed and in the Mixture 57.668 g S (+) - Ketamine HCl and 6,000 g Dissolve sodium chloride while stirring. After complete Dissolution is stirred for at least 15 minutes. Than it will be the pH of the solution by adding 0.01 N HCl solution adjusted to pH 3.5. The solution is placed in a volumetric flask with water f. I. replenished to 2014,8 g, and it will be 10 Stirred for another minute. The solution is then over 0.2 μm membrane filter sterile filtered and under Nitrogen fumigation filled in 2 ml Aufbrennampullen. The sealed vials are left at 121 ° C for 20 minutes sterilized. After cooling, the ampoules are  Color test for tightness and 100% visual Inspection checked for particle freedom.

Claims (8)

1. Aqueous solutions of S (+) - Ketamin · HCl in one Concentration range of 0.1-5.0% with a Surface tension of <60 mN / m. 2. Solutions according to claim 1 with a surface tension of <40 mN / m. 3. S (+) - ketamine-HCl solutions according to claim 1 or 2, characterized in that they are pharmacologically compatible surfactants and / or organic solvents to adjust the surface tension. 4. Solutions according to claim 3, characterized in that they are polysorbates, polyoxyethylene-polyoxypropylene Polymers, Cremophor® solubilizers or quaternary Contain ammonium compounds. 5. Solutions according to claim 3, characterized in that they contain benzethonium chloride. 6. Solutions according to claim 3, characterized in that they are ethanol, propylene glycol or polyethylene glycol contain. 7. Solutions according to claim 4 or 5, characterized characterized in that they additionally contain ethanol, Propylene glycol or polyethylene glycol included. 8. Use of surfactants and / or organic Solvents for the Preparation of Stable S (+) - Ketamine HCl solutions for injections.