RU2483731C1 - Solution for injections containing nalbuphine - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to pharmaceutical industry and concerns a preparation of nalbuphine hydrochloride for injections. The preparation contains (wt %): nalbuphine hydrochloride 1.0-2.0; citric acid: 1.26; sodium citrate: 0.94; sodium chloride: 0,1; sodium metabisulfite: 0.1; sodium metabisulfites: the rest.

EFFECT: invention may be used to relief pain syndromes of moderate and intense severity in myocardial infarction, in preparation for surgery, during the postoperative period, and also as an analgesic co-preparation for general anaesthesia.

2 cl, 4 ex, 4 tbl

Description

FIELD OF THE INVENTION

The invention relates to medicine and pharmacology, in particular to a solution for injection based on nalbuphine hydrochloride, which has a pronounced analgesic effect. The invention can find application in medicine to eliminate pain syndromes of moderate and severe intensity during myocardial infarction, in preparation for surgery, in the postoperative period, and also as an additional means of analgesia in general anesthesia.

State of the art

Nalbuphine has the properties of an opioid receptor antagonist agonist (kappa agonist and mu opioid receptor antagonist), which activates the endogenous antinociceptive system through kappa opiate receptors and disrupts the interneuron transmission of pain impulses at various levels of the central nervous system. Acting on the higher parts of the brain, nalbuphine changes the emotional coloring of pain, and also inhibits conditioned reflexes, and has a sedative effect. Side effects include dysphoria, miosis and agitation of the vomiting center. However, unlike morphine, nalbuphine to a lesser extent depresses the respiratory center and affects the motility of the gastrointestinal tract, does not affect hemodynamic parameters. In addition, the risk of addiction and opioid dependence with controlled use is negligible.

A pharmacological analgesic effect is manifested 2-3 minutes after intravenous administration or 10-15 minutes after intramuscular administration. The maximum plasma concentration after intramuscular administration is observed after 30-60 minutes. The duration of action is 3-6 hours, the half-life is 2.5-3 hours. The time to reach C _max with intramuscular administration is about 1 hour, with intravenous administration - 30 minutes. It is excreted mainly in the form of hepatic metabolites, mainly with bile, as well as in small quantities with urine. Penetrates through the placental barrier and is found in breast milk (less than 1% of the administered dose).

Patent RU 2362560 (published May 10, 2006) describes a pharmaceutical preparation based on methylnaltrexone or its salt, optionally containing nalbuphine, which is a solution comprising methylnaltrexone or its salt and a chelating agent, the solution having a pH from 2 to 6, and the chelating agent is ethylenediaminetetraacetic acid (EDTA) or dipotassium edetate, disodium edetate, calcium disodium edetate.

The closest analogue is the patent RU 2254852 (published on June 27, 2005), which discloses an injection solution having 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 mixture 0.5-3.5

stabilizer 0.15-0.25

complexing component 0.001-0.2

water the rest.

The disadvantage of the described solution for injection is the likelihood of side effects associated with the intravenous administration of EDTA contained in it for more than 5 days, for example, hypocalcemia, hypokalemia, exacerbation of kidney and liver diseases. In addition, the drug can cause unwanted adverse reactions in patients with diabetes, patients with low potassium levels, heart rhythm disturbances, and cardiovascular diseases. Information on the safety of the proposed drug in the description of the invention to patent RU 2254852 is not contained.

Disclosure of invention

The main objective of the invention is the expansion of the arsenal of strong analgesic agents. This problem is solved by creating a drug containing (in wt.%):

nalbuphine hydrochloride 1.0-2.0;

citric acid 1.26

sodium citrate 0.94

sodium chloride 0.1

sodium metabisulfite 0.1

water for injection rest

Also, the injection may contain 1.0 wt.% Nalbuphine.

Another objective of the invention is to overcome the main drawback of the closest analogue due to the presence of EDTA in the known preparation, namely, possible complications in cardiological diabetes patients with cardiovascular diseases. Thus, the technical result of the invention is to obtain a nalbuphine preparation for injection with reduced toxicity.

Also, the inventors unexpectedly found that the exclusion of complexing compounds from the composition of the drug can increase the shelf life of up to 3 years. The problem is solved by the method of obtaining a solution for injection, in which:

a) nalbuphine hydrochloride is dissolved in water for injection, followed by bubbling nitrogen,

b) sodium citrate, citric acid, sodium chloride and sodium metabisulfite are added to the solution obtained in stage a) in the indicated order, with an optional adjustment of the pH to a value in the range from 3.4 to 3.7 and subsequent bubbling of nitrogen,

C) the solution obtained in stage b) is subjected to sterilizing filtration, and

d) the solution obtained in stage c) is filled in ampoules, which are then sealed and sterilized.

The achievement of technical results in the implementation of the invention is confirmed by the following examples.

Example 1. Preparation of a solution of nalbuphine hydrochloride for injection.

In a glass apparatus with a capacity of 1.5 l and equipped with a stirrer, a thermometer and a bubbler, prepared in accordance with the current sanitary standards, 920-930 ml of water for injection with a temperature of 15-25 ° C is loaded and 10.0 g of nalbuphine hydrochloride is dissolved with stirring. Nitrogen is supplied to the apparatus through a bubbler.

After that, with stirring, 9.4 g of sodium citrate of 5.5-hydrate, 12.6 g of citric acid, 1.0 g of sodium chloride and 1.0 g of sodium metabisulfite are added to the solution, controlling the completeness of dissolution of the component before adding the following. The pH value is adjusted to a value in the range from 3.4 to 3.7 by the addition of a 1M hydrochloric acid solution, after which the volume of the solution is adjusted to 1.0 L and sparged with nitrogen.

The resulting solution is pressed with nitrogen pressure through a system of two successive filters with a cutting capacity of 1.0 μm and 0.2 μm into the prepared collection. A sterile solution in a stream of nitrogen is placed in ampoules of syringe filling 1 ml per ampoule. Sealed ampoules are sterilized at 120 ± 1 ° C for 15 minutes.

Conduct selective quality control according to the indicators given in table 1.

Table 1 Indicator Description or value Transparency Clear liquid Color The colorless or colored liquid is not more intense than standard No. 7b pH 3.0-4.2 Foreign matter (by HPLC analysis) Single admixture: not more than 1.5%; Impurity content - not more than 3.0% The content of nalbuphine hydrochloride 0.0090-0.0110 g / mg (determined spectrophotometrically)

All ampoules from the sample (N = 10) meet the quality criteria.

Example 2. Assessment of the toxicity of a solution of nalbuphine hydrochloride for injection

Acute toxicity was studied on sexually mature white mice of both sexes with intragastric (IM) and intramuscular (IM) administration in doses of 500-1500 mg / kg and 150-600 mg / kg, respectively. An insignificant percentage of death of animals in a state of sleep was noted 14-20 minutes after administration of the drug. The surviving animals showed no deviations of the integral and functional indicators, as well as mass coefficients and macroscopic characteristics of the internal organs after opening. A randomized study of acute toxicity gave an LD50 of 772 mg / kg for iv and 600 mg / kg for iv. Thus, the studied drug belongs to low-hazard substances (hazard class 4).

Subchronic toxicity was studied in Wistar rats of both sexes with a body weight of 210-240 g with 14-day intramuscular (IM) doses of 3 and 30 mg / (kg · day) and intragastric (IM) doses of 10 and 100 mg / (kg · day), which exceeds the maximum therapeutic daily dose for humans by 1.25 and 12.5 times, respectively. The ratio of the maximum total dose (1400 mg / kg i / w and 420 mg / kg i / m) to the average lethal dose was 1.81 (i / w) and 0.7 (i / m). The death of animals is not marked. The physiological, hematological and biochemical parameters of animals during the study did not go beyond the limits of the natural norm. The determination of the morphological characteristics of the internal organs after opening did not show pathological changes. Irritating effect on the gastrointestinal tract and at the injection site was not noted. With a satisfactory condition of all animals after a 14-day study, taking into account the ratio of the maximum total dose to the average lethal dose, it can be argued that the studied drug does not have pronounced cumulativeness.

Example 3. The study of the stability of the solution of nalbuphine hydrochloride for injection during storage ("accelerated aging")

The stability of the nalbuphine hydrochloride solution for injection during storage was evaluated by the quality indicators given in table 1. “Accelerated aging” was carried out at a temperature of 45 ° C or 55 ° C. The results are shown in tables 2 and 3, respectively.

table 2 Shelf life 45 ° C, day Equ. storage period, year Transparency Color pH Foreign impurities,% Content, g / ml one 2 3 four 5 6 7 Source Transparent Colorless 3.42 Units 0.36 0,0100 Amount 0.86 46 0.5 Transparent Colorless 3.45 Units 0.56 0.0099 Amount 1.23 92 one Transparent Colorless 3.46 Units 0.36 0.0101 Amount 1,11 138 1,5 Transparent Not int. 3.45 Units 0.54 0.0102 floor No. 7b Amount 1.33 230 2,5 Transparent Not int. 3.36 Units 0.33 0.0104 floor No. 7b Amount 0.90 276 3 Transparent Not int. 3.44 Units 0.35 0,0100 floor No. 7b Amount 0.81

Table 3 Shelf life 55 ° C, day Equ. storage period, year Transparency Color pH Foreign impurities,% Content, g / ml Source Transparent Colorless 3.42 Units 0.36 0,0100 Amount 0.86 23 0.5 Transparent Colorless 3.45 Units 0.47 0.0101 Amount 1,11 46 one Transparent Colorless 3.44 Units 0.35 0.0098 Amount 0.86 92 2 Transparent Not int. 3.43 Units 0.36 0.0103 floor No. 7b Amount 0.98 138 3 Transparent Not int. 3.43 Units 0.34 0.0101 floor No. 7b Amount 0.92

From the above data it follows that the shelf life of a preparation prepared in accordance with the invention is estimated to be 3 years, which was confirmed by testing a batch stored at room temperature.

Example 4. A comparative study of the stability of a solution of nalbuphine hydrochloride for injection, prepared in accordance with patent RU 2254852, during storage ("accelerated aging")

The stability of the solution of nalbuphine hydrochloride for injection, prepared in accordance with the patent RU 2254852, during storage was evaluated by the quality indicators listed in table 1. "Accelerated aging" was carried out at a temperature of 55 ° C. The results are shown in table 4.

Table 4 Shelf life 55 ° C, day Equ. storage period, year Transparency Color pH Foreign impurities,% Content, g / ml Source Transparent Colorless 3.38 Units 0.34 0,0106 Amount 0.51 23 0.5 Transparent Not int. 3.42 Units 0.35 0.0098 floor No. 7b Amount 0.81 46 one Transparent Not int. 3.44 Units 0.44 0.0104 floor No. 7b Amount 0.88 92 2 Transparent Not int. 3.44 Units 0.67 0.0102 floor No. 6b Amount 1.42 138 3 Transparent Not int. 3.40 Units 0.73 0.0101 floor No. 6b Amount 1,53

From the above data it follows that with an equivalent shelf life of more than 2 years, in a solution of nalbuphine hydrochloride for injection, prepared in accordance with patent RU 2254852, there is an increase in color intensity, as well as a noticeable increase in the content of impurities.

Thus, the naflubine hydrochloride injection solution proposed according to the present invention, the hydrochloride belongs to low toxicity substances, does not have cumulativeness and exhibits low subchronic toxicity in in vivo models. In addition, the shelf life of such a solution exceeds the shelf life of the closest analogue.

Claims (2)

1. An injection solution based on nalbuphine hydrochloride having a pronounced analgesic effect, characterized in that it contains, wt.%:
nalbuphine hydrochloride 1.0-2.0 lemon acid 1.26 sodium citrate 0.94 sodium chloride 0.1 sodium metabisulfite 0.1 water for injections rest 2. The injection solution according to claim 1, characterized in that it contains 1.0 wt.% Nalbuphine.