Injection solution with expressed analgesic effect and method for its preparing

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

 

The group of inventions relates to medicine, in particular, the pharmacology for solutions for injection on the basis of alfabia hydrochloride, with a pronounced analgesic effect, and methods for their preparation. The group of inventions can be used to eliminate pain moderate and severe intensity of myocardial infarction, in preparation for surgery (prevention) and in the postoperative period, as well as additional funds anesthesia under General anesthesia.

Alfabia hydrochloride (chemical name: (5-alpha, 6-alpha)-17-(Cyclobutylmethyl)-4,5-epoxypropane-3,6,14-triol) refers to the pharmacological group of opioids and is a derivative of morphine, however, the characteristic feature of its molecules is the presence of methylcyclobutene radical.

Drugs, analgesic (narcotic). Has properties of agonist-antagonist opioid receptors. Depresses CNS has analgesic, sedative, antitussive action. Stimulates mu-receptors and blocks the Kappa-receptors.

The closest solution for injection, with a pronounced analgesic effect, discovered in the “Instructions for medical use of the drug NUBAIN (Nubain)” (approved by the state Pharmacological Committee of Ministry of health of Russia on 12 November 1998, p is otocol No. 9-1). The solution for injection contains 10 mg alfabia hydrochloride in 1 ml of solution and excipients: a buffering agent (citric acid and sodium citrate in water), stabilizers (sodium chloride) and water for injection.

Alfabia hydrochloride is a white or almost white crystalline powder, soluble in water. A known solution alfabia stable in slightly acidic environment, however, with the increase of pH above 6 two molecules alfabia react with each other with the formation of binalbagan. The intensity of this process increases with increasing temperature, when exposed to light and in the presence of heavy metal ions, which leads to the loss of stability of the dosage form during the shelf life of the drug.

The task of the invention to provide domestic drug with strong analgesic effect, meets the requirements of the global Fund XI, stable storage for more than 2.5 years.

The problem is solved solution for injection, with a pronounced analgesic effect, containing nalbufina hydrochloride buffer mixture, the stabilizer and water for injection, the solution further comprises a complexing component in the following ratio, wt.%:

Nalbufina hydrochloride 0,8-2,2

A buffer mixture of 0.5-3.5

The stabilizer 0,15-0,25

Complexing components the t of 0.001 to 0.2

Water the Rest

In private embodiments of the invention the problem is solved by the fact that:

as the complexing component solution may contain disodium salt of ethylenediaminetetraacetic acid (Trilon B), or other known complexing agents, for example, tetatsin calcium;

as a buffer mixture, it may contain a mixture of citric acid and at least one substance selected from the group comprising sodium citrate, sodium digitaltruth, sodium hydrogen phosphate, sodium dihydrophosphate or crystalline mentioned substances;

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

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

The task is also solved by a method of obtaining a solution for injection, in accordance with which exercise the bubbling water for injection of inert gas at 25-30°C for 30-60 minutes, then, without interrupting the bubbling in the water consistently make the buffer mixture, stabilizer, complexing agents and nalbufina hydrochloride, then the resulting solution is cooled to 2° With, spend sterilizing filtration, ampoule filling, sealing and sterilisation.

Preferably sterilizing filtration, ampoule filling and sealing to be executed in the atmosphere of inert gas, and sterilization of ampoules carried out at 120±5°C for 5-12 minutes.

The invention consists in the following.

Use as excipients buffer mixture, stabilizers and additional introduction of complexing component in the claimed amounts can improve the stability of the solution alfabia.

Great influence on the oxidation process of the medicinal product has the presence of heavy metal ions Fe+3, Mn2+and so on, which are catalysts of oxidation. Heavy metal ions often pass in solutions of glass, apparatus, or may be present as a manufacturing impurity.

To stabilize legkookisljajushchihsja substances used complexing agent EDTA is ethylenediaminetetraacetic acid. The complexing agents gives the ability to form water-soluble chelate compounds with a large number of cations. Best in this case properties as complexing agents has Trilon B, representing the disodium salt of ethylenediaminetetraacetic acid. In this case, the mouth is echeveste complex compounds is so great, it is impossible to detect the corresponding cation.

The buffer mixture in the claimed amount is introduced into the solution to create the optimum ranges of pH values. We have found that as an alternative to the sodium citrate used as components of a buffer mixture in a known solution, can also be used such sodium substances as sodium digitaltruth, sodium hydrogen phosphate, sodium dihydrophosphate or crystalline mentioned substances. When the total number of buffer mixture in a solution of 0.5-3.5 wt.%, will be desirable that the content of citric acid in it was 0.1-3.4 wt.%. For faster stabilization of the pH of the drug add sodium chloride.

To obtain stable over a long period of time the drug is also important is how this product is obtained.

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

The invention is carried out as follows.

System solution preparation and bottling is purged with inert gas (argon or nitrogen). All manufacturing operations are carried out under the protection of inert gas.

Water for injection pre-filled with an inert gas at a temperature of 25-30°C for 30-60 minutes. In the water make sledovatelno while maintaining the specified temperature and without ozonation, the estimated amount of the buffer mixture (citric acid and at least one substance selected from the group comprising sodium citrate, sodium digitaltruth, sodium hydrogen phosphate, sodium dihydrophosphate or crystalline mentioned substances). Then make a measured amount of sodium chloride and trylon B. Then add a measured amount alfabia hydrochloride and, if necessary, antioxidants, bring the solution volume to the required water for injection. The solution is cooled to a temperature of 20°and conduct sterilizing filter on the filtration system installation Pall with the size of the pores of 0.45 and 0.22 μm. Filtering are peretaplivanii inert gas. Ampoule filling and sealing are in the current of inert gas. Sterilization of ampoules carried out at 120±2°C for 8 minutes.

Example 1.

Prepared experimental formulations containing from 9.0 to 21.0 g/l (0.9 to 2.1 wt.%) aflubin, sodium chloride (0.15 to 0.25 wt.%), the hydrochloric acid solution with a concentration of 0.1-1 mol/l solution of sodium hydroxide with a concentration of 0.1-1 mol/l to pH 3.0 to 5.5, trylon B 0.02 wt.%, water for injection - rest.

The compositions were obtained in normal conditions. During observations it is established that these compounds are insufficiently stable: after sterilization, the pH of the preparations was increased to 5.5 and more that led to changes in enego the form of a solution (the appearance of opalescence and yellowish color).

Example 2. Same as in example 1. All operations were carried out under inert gas is nitrogen or argon. It helped to reduce the opalescence of the solution and increase the intensity of the paint not only upon receipt of drugs in sweetamanda equipment, but without protection from light. The value of pH was 4.02 reached 5,95 after 6 months of storage of the drug.

Example 3.

Same as in example 2, but additionally in the solutions were introduced citric acid in an amount of from 0.1 to 0.15 wt.%. In this case citric acid acted acid agent, stabilizing the pH value in a given range of 3.0 to 5.5. However, despite the stabilization of the pH of the consistency of the final product depends heavily on the quality of raw materials and auxiliary substances.

Example 4 (in accordance with the invention)

Same as in example 3, but additionally injected 0.5 to 1.2 wt.%, at least one substance selected from the group comprising sodium citrate, sodium digitaltruth, sodium hydrogen phosphate, sodium dihydrophosphate or crystalline mentioned substances. These components, taken in the appropriate proportions with citric acid, to form a buffer system with a preset optimal stable pH value of 3.0-5.5 solution of the drug. The absence of sodium hydrosulfite, sodium metabisulfite and/or sodium thiosulfate allow you to plug the em to use these compounds 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 drugs had the appearance slabohopalestirutaya and slightly coloured liquid. For all compositions, the pH values within 10 months of observations remained unchanged and stood at 3,61-3,65 for compositions with a content of alfabia about 1.0 wt.% and 4,53-4,57 content alfabia about 2.0 wt.%.

Example 5.

Same as in example 4, but additionally injected antioxidants.

The drugs had the appearance slabohopalestirutaya and almost colorless liquid. For all compositions, the pH values within 10 months of observations remained unchanged and stood at 4,72 was 4.76 for compositions with a content of alfabia about 1.0 wt.% and 4,85-4,94 content alfabia about 2.0 wt.%.

1. Solution for injection, with a pronounced analgesic effect, containing nalbufina hydrochloride buffer mixture, the stabilizer and water for injection, characterized in that it further comprises a complexing component in the following ratio, wt.%:

Nalbufina hydrochloride 0,8-2,2

A buffer mixture of 0.5-3.5

The stabilizer 0,15-0,25

Complexing component of 0.001 to 0.2

Water the Rest

2. RAS is a thief according to claim 1, characterized in that as the complexing component it contains disodium salt of ethylenediaminetetraacetic acid.

3. The solution according to claim 1, characterized in that as a buffer mixture contains a mixture of citric acid and at least one substance selected from the group comprising sodium citrate, sodium digitaltruth, sodium hydrogen phosphate, sodium dihydrophosphate or crystalline mentioned substances.

4. The solution according to claim 3, characterized in that the mixture contains 0.1 to 3.4 wt.% acid lemon.

5. The solution according to claim 1, characterized in that the stabilizer comprises sodium chloride.

6. The solution according to claim 5, characterized in that it contains 0.18 to 0.22 wt.% sodium chloride.

7. The solution according to claim 1, characterized in that it further contains antioxidants in the amount of 0.2-2.0 wt.%.

8. The solution according to claim 7, characterized in that as antioxidants contains sodium hydrosulfite, and/or sodium metabisulfite, and/or sodium thiosulfate.

9. A method of obtaining a solution for injection in accordance with any of claims 1 to 8 formulas, characterized in that exercise bubbling water for injection of inert gas at 25-30°C for 30-60 min, and then, without interrupting the bubbling in the water consistently make the buffer mixture, stabilizer, complexing agents and nalbufina hydrochloride, then the resulting solution is cooled to 20° With, spend sterilizing filtration, ampoule filling, sealing and sterilisation.

10. The method according to claim 9, characterized in that the sterilizing filter, ampoule filling and sealing is carried out in an atmosphere of inert gas.

11. The method according to claim 9, characterized in that the sterilization of ampoules carried out at (120±5)°C for 5-12 minutes



 

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