RU2254852C1 - Injection solution with expressed analgesic effect and method for its preparing - Google Patents

Abstract

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to the injection solution based on nalbuphine hydrochloride eliciting the expressed analgesic effect, and to a method for its preparing. The injection solution comprises the following components, wt.-%: nalbuphine hydrochloride, 0.8-2.2; buffer mixture, 0.5-3.5; stabilizing agent, 0.15-0.25; Trilon B (chelating component), 0.001-0.2, and water, the balance. Invention provides preparing the domestic preparation with analgesic effect and stability for above 2.5 years.

EFFECT: improved and valuable medicinal properties of solution.

11 cl, 1 tbl, 5 ex

Description

The group of inventions relates to medicine, in particular to pharmacology - to injection solutions based on nalfubine hydrochloride, which have a pronounced analgesic effect, and methods for their preparation. The group of inventions can be used to eliminate pain syndromes of moderate and severe intensity during myocardial infarction, in preparation for surgery (prophylaxis) and in the postoperative period, and also as an additional means of analgesia for general anesthesia.

Nalfubine hydrochloride (chemical name: (5 alpha, 6 alpha) -17- (Cyclobutylmethyl) -4,5-epoxymorphinan-3,6,14-triol) belongs to the pharmacological group of opioids and is a derivative of morphine, however, a characteristic feature of its molecule is the presence of methylcyclobutyl radical.

Pharmacological action - analgesic (narcotic). It has the properties of an opiate receptor antagonist agonist. It depresses the central nervous system, has an analgesic, hypnotic, antitussive effect. Excites mu receptors and blocks kappa receptors.

The closest injection solution with a pronounced analgesic effect is disclosed in the “Instructions for the medical use of the drug NUBain” (approved by the Pharmacological State Committee of the Ministry of Health of Russia on November 12, 1998, protocol No. 9-1). The injection contains 10 mg of nalfubine hydrochloride in 1 ml of solution and excipients: buffers (citric acid and aqueous sodium citrate), stabilizers (sodium chloride) and water for injection.

Nalfubine hydrochloride is a white or almost white crystalline powder, soluble in water. The known nalfubine solution is stable in a slightly acidic environment, however, when the pH rises above 6, two nalfubin molecules react with each other to form bismalbuphine. The intensity of this process increases with increasing temperature, under the influence of light and in the presence of heavy metal ions, which leads to a loss of stability of the dosage form over the shelf life of the drug.

The objective of the invention is to obtain a domestic drug with a strong analgesic effect, corresponding to the requirements of GF XI, stable during storage for more than 2.5 years.

The problem is solved by injection, with a pronounced analgesic effect, containing nalbuphine hydrochloride, a buffer mixture, a stabilizer and water for injection, while the solution additionally contains a complexing component in the following ratio, wt.%:

Nalbuphine Hydrochloride 0.8-2.2

Buffer mix 0.5-3.5

Stabilizer 0.15-0.25

Complexing component 0.001-0.2

Water Else

In private embodiments of the invention, the problem is solved in that:

as a complexing component, the solution may contain ethylenediaminetetraacetic acid disodium salt (trilon B) or another known complexing agent, for example, calcium tetacin;

as a buffer mixture, it may contain a mixture of citric acid and at least one substance selected from the group consisting of sodium citrate, sodium dihydrogen citrate, sodium hydrogen phosphate, sodium dihydrogen phosphate or crystalline hydrates of the aforementioned substances;

said mixture may contain 0.1-3.4 wt.% citric acid; as a stabilizer, the solution may contain sodium chloride, in particular 0.18-0.22 wt.% sodium chloride;

additionally, the solution may contain antioxidants in an amount of 0.2-2.0 wt.%, which can be used sodium hydrosulfite and / or sodium metabisulfite, and / or sodium thiosulfate.

The problem is also solved by the method of obtaining a solution for injection, in accordance with which bubbling water for injection with an inert gas at 25-30 ° C for 30-60 minutes, then, without interrupting the bubbling, a buffer mixture, stabilizer, complexing agent are introduced into the water and nalbuphine hydrochloride, then the resulting solution is cooled to 20 ° C, sterilizing filtration is carried out, ampoules are filled, sealed and sterilized.

It is advisable to sterilize the filtration, fill the ampoules and seal them in an inert gas atmosphere, and sterilize the ampoules at 120 ± 5 ° C for 5-12 minutes.

The invention consists in the following.

The use of buffer mixture, stabilizers as auxiliary substances, and the additional introduction of a complexing component in the claimed amounts can improve the stability of the nalfubine solution.

The presence of heavy metals Fe ⁺³ , Mn ²⁺ , etc., which are oxidation catalysts, has a great influence on the oxidation process of a drug. Heavy metal ions often pass into solutions from glass, equipment, or may be present as industrial impurities.

To stabilize readily oxidizing substances, complexing substances EDTA - ethylenediaminetetraacetic acid are used. The complexing agent gives the ability to form intra-complex water-soluble compounds with a large number of cations. Trilon B, which is a disodium salt of ethylenediaminetetraacetic acid, has the best properties in this case as a complexing agent. In this case, the stability of the complex compounds is so great that it is impossible to detect the corresponding cation.

The buffer mixture in the declared amount is introduced into the solution to create optimal pH boundaries. We have found that, as an alternative to sodium citrate, which is used as a component of a buffer mixture in a known solution, sodium-containing substances such as sodium dihydrogen citrate, sodium hydrogen phosphate, sodium dihydrogen phosphate or crystalline hydrates of the aforementioned substances can also be used. When the total amount of the buffer mixture in the solution is 0.5-3.5 wt.%, It will be desirable for the content of citric acid in it to be 0.1-3.4 wt.%. For faster stabilization of the pH of the drug, sodium chloride is added.

To obtain a stable drug for a long time, it is also important how this drug is obtained.

In our method, pre-saturation of water for injection with an inert gas is carried out, and all subsequent operations are also carried out in a neutral gas environment.

The invention is as follows.

The solution and bottling system is purged with an inert gas (argon or nitrogen). All production operations are carried out under the protection of inert gas.

Water for injection is pre-saturated with an inert gas at a temperature of 25-30 ° C for 30-60 minutes. The calculated amount of the buffer mixture (citric acid and at least one substance selected from the group consisting of sodium citrate, sodium dihydrogen citrate, sodium hydrogen phosphate, sodium dihydrogen phosphate or crystalline hydrates of the aforementioned substances is added sequentially to water at a specified temperature and without stopping bubbling) ) Then make a measured amount of sodium chloride and Trilon B. Then add a measured amount of nalfubine hydrochloride and, if necessary, antioxidants, adjust the volume of the solution to the required water for injection. The solution is cooled to a temperature of 20 ° C and sterilizing filtration is performed on a Pall system filtration unit with pore sizes of 0.45 and 0.22 μm. Filtration is carried out by crushing inert gas. Ampoules are filled and sealed in an inert gas stream. Ampoules are sterilized at 120 ± 2 ° C for 8 minutes.

Example 1

Prepared experimental compositions containing from 9.0 to 21.0 g / l (0.9-2.1 wt.%) Naflubina, sodium chloride (0.15-0.25 wt.%), Hydrochloric acid solution with a concentration 0.1-1 mol / L or a solution of sodium hydroxide with a concentration of 0.1-1 mol / L to a pH of 3.0-5.5, Trilon B 0.02 wt.%, Water for injection - the rest.

The compositions were obtained under ordinary conditions. In the course of observations, it was found that these compositions are not stable enough: after sterilization, the pH of the preparations increased to 5.5 or more, which led to a change in the appearance of the solution (the appearance of opalescence and yellowish color).

Example 2. The same as in example 1. All operations were carried out under an inert gas - nitrogen or argon. This made it possible to reduce the opalescence of the solutions and the increase in the intensity of the paint, not only upon receipt of the preparations in lightproof equipment, but also without protection from light. The pH value from 4.02 reached 5.95 after 6 months of storage of the drug.

Example 3

The same as in example 2, but additionally citric acid was added to the solutions in an amount of from 0.1 to 0.15 wt.%. In this case, citric acid served as an acid agent that stabilizes the pH in a given range of 3.0-5.5. However, despite the stabilization of pH, the constancy of the final product is highly dependent on the quality of the feedstock and excipients.

Example 4 (in accordance with the invention)

The same as in example 3, but additionally introduced 0.5-1.2 wt.%, At least one substance selected from the group including sodium citrate, sodium dihydrogen citrate, sodium hydrogen phosphate, sodium dihydrogen phosphate or crystalline hydrates of the substances . These components, taken in appropriate proportions with citric acid, form buffer systems with a predetermined optimal stable pH value of 3.0-5.5 of the drug solution. The absence of sodium hydrosulfite, sodium metabisulfite and / or sodium thiosulfate in the compositions allows the use of these compositions in asthmatic patients sensitive to sulfur-containing components.

Table 1 shows the compositions obtained in accordance with this example (compounds 4-1, 4-2, 4-3 and 4-4).

As a result, the preparations were in the form of slightly opalescent and slightly colored liquid. For all compositions, the pH values during the 10 months of observation remained virtually unchanged and were at a level of 3.61-3.65 for compositions with a nalfubine content of about 1.0 wt.% And 4.53-4.57 with a nalfubine content of about 2, 0 wt.%.

Example 5

The same as in example 4, but additionally introduced antioxidants.

The preparations had the appearance of a slightly opalescent and almost colorless liquid. For all formulations, the pH values during the 10 months of observation remained virtually unchanged and were at a level of 4.72-4.76 for formulations with a nalfubine content of about 1.0 wt.% And 4.85-4.94 with a nalfubine content of about 2, 0 wt.%.

Claims (11)

1. An injection solution having a pronounced analgesic effect, containing nalbuphine hydrochloride, a buffer mixture, a stabilizer and water for injection, characterized in that it additionally contains a complexing component in the following ratio, wt.%: Nalbuphine Hydrochloride 0.8-2.2 Buffer mix 0.5-3.5 Stabilizer 0.15-0.25 Complexing component 0.001-0.2 Water Else 2. The solution according to claim 1, characterized in that, as a complexing component, it contains a disodium salt of ethylenediaminetetraacetic acid. 3. The solution according to claim 1, characterized in that it contains a mixture of citric acid and at least one substance selected from the group consisting of sodium citrate, sodium dihydrogen citrate, sodium hydrogen phosphate, sodium dihydrogen phosphate or crystalline hydrates of the substances mentioned as a buffer mixture . 4. The solution according to claim 3, characterized in that the mixture contains 0.1-3.4 wt.% Citric acid. 5. The solution according to claim 1, characterized in that the stabilizer contains sodium chloride. 6. The solution according to claim 5, characterized in that it contains 0.18-0.22 wt.% Sodium chloride. 7. The solution according to claim 1, characterized in that it further comprises antioxidants in an amount of 0.2-2.0 wt.%. 8. The solution according to claim 7, characterized in that it contains sodium hydrosulfite and / or sodium metabisulfite and / or sodium thiosulfate as antioxidants. 9. A method of producing an injection solution in accordance with any one of claims 1 to 8 of the formula, characterized in that the water for injection is bubbled with an inert gas at 25-30 ° C. for 30-60 minutes, then, without interrupting the bubbling, the buffer mixture, stabilizer, complexing agent and nalbuphine hydrochloride are successively introduced into the water, then the resulting solution is cooled to 20 ° C, sterilizing filtration, filling of ampoules, their sealing and sterilization are carried out. 10. The method according to claim 9, characterized in that the sterilizing filtration, filling of the ampoules and their sealing are carried out in an inert gas atmosphere. 11. The method according to claim 9, characterized in that the sterilization of the ampoules is carried out at (120 ± 5) ° C for 5-12 minutes