An analgesic pharmaceutical composition, a method of preparing the same, and use thereof

Abstract

The present application relates to a kind of analgesic compositions, composition is composed of the first composition containing nalbuphine or its pharmaceutically acceptable salt and the second composition containing ketamine or its pharmaceutically acceptable salt, the molar ratio of nalbuphine or its pharmaceutically acceptable salt in composition:ketamine or its pharmaceutically acceptable salt is 1:5-1:20.The present application screens the ratio of ketamine and nalbuphine, has the advantages such as synergism, quick effect, duration extension, analgesic effect is good, significantly reduce the respiratory depression effect brought by ketamine and nalbuphine when being used alone.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to an analgesic pharmaceutical composition, its preparation method, and its application. Background Technology

[0002] Ketamine, with its sedative, hypnotic, and analgesic effects, is widely used clinically as an anesthetic. However, its short duration of analgesia and adverse reactions such as respiratory depression and circulatory excitation (or inhibition) when administered rapidly at high doses limit its clinical use. Nalbuphine, a novel opioid receptor agonist-antagonist analgesic, primarily exerts its central analgesic effect by activating κ receptors and partially antagonizing μ receptors. It is commonly used for moderate to severe pain relief, and its analgesic effect is similar to morphine. Compared to morphine, nalbuphine has advantages such as less psychological and emotional impact on patients, lower addictive potential, milder respiratory depression, and a longer duration of action (3-6 hours). However, it has drawbacks such as a slow onset of action, affecting patient analgesia. Therefore, there is a need to develop drug combinations with rapid onset, prolonged duration of anesthesia, good analgesic effect, and few side effects to meet the clinical demand for safe and effective medication. Summary of the Invention

[0003] The present invention aims to provide an analgesic pharmaceutical composition comprising a first composition and a second composition in a dual-compartment, independently packaged form. The molar ratio of nalbuphine or a pharmaceutically acceptable salt thereof to ketamine or a pharmaceutically acceptable salt thereof in the composition is 1:5 to 1:20. By mass-volume percentage, the first composition consists of 0.1-10% nalbuphine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and the second composition consists of 1-20% ketamine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The pharmaceutically acceptable salt is selected from any one or a combination of hydrochloride, nitrate, phosphate, sulfate, and acetate.

[0004] In a preferred embodiment of the present invention, the molar ratio of nalbuphine or a pharmaceutically acceptable salt thereof to ketamine or a pharmaceutically acceptable salt thereof in the composition is 1:6 to 1:15. By mass-volume percentage, the first composition contains 0.5-5% nalbuphine or a pharmaceutically acceptable salt thereof, and the second composition contains 2-15% ketamine or a pharmaceutically acceptable salt thereof.

[0005] In a preferred embodiment of the present invention, the molar ratio of nalbuphine or a pharmaceutically acceptable salt thereof to ketamine or a pharmaceutically acceptable salt thereof in the composition is 1:8-1:12. By mass-volume percentage, the first composition contains 0.8-1% nalbuphine or a pharmaceutically acceptable salt thereof, and the second composition contains 4-10% ketamine or a pharmaceutically acceptable salt thereof.

[0006] In a preferred embodiment of the present invention, the pharmaceutically acceptable carrier is selected from any one or a combination of preservatives, pH adjusters, and osmotic pressure adjusters.

[0007] In a preferred embodiment of the present invention, the preservative is selected from any one or a combination of phenoxyethanol, methylparaben, methylisothiazolinone, methylparaben, ethylparaben, propylparaben, sodium benzoate, potassium sorbate, benzoic acid or its salt, sorbic acid or its salt, benzalkonium chloride, parabens, sodium metabisulfite, chlorhexidine, sodium citrate, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol, ethylenediaminetetraacetic acid, propyl gallate, and quaternary ammonium compounds.

[0008] In a preferred embodiment of the present invention, the first composition contains 0.01-1% preservative, wherein the preservative is composed of methylparaben and propylparaben.

[0009] In a preferred embodiment of the present invention, the first composition contains 0.05-0.5% preservative, wherein the preservative is composed of methylparaben and propylparaben in a mass ratio of 9:1.

[0010] In a preferred embodiment of the present invention, the pH of the first composition is 5-7, wherein the pH adjuster is selected from any one or a combination of citrate buffer, acetate buffer, carbonate buffer, phosphate buffer, citric acid, potassium citrate, sodium citrate, citric acid, sodium citrate, potassium citrate, malic acid, sodium malate, potassium malate, potassium hydroxide, sodium bicarbonate, sodium hydroxide, potassium carbonate, sodium carbonate, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, monoethanolamine, diethanolamine, triethanolamine, lactic acid, sodium lactate, potassium lactate, acetic acid, sodium acetate, potassium acetate, propionic acid, sodium propionate, potassium propionate, tartaric acid, sodium tartrate, sodium fumarate, potassium fumarate, potassium fumarate, fumaric acid, or their hydrates.

[0011] In a preferred embodiment of the present invention, the osmotic pressure of the first composition is 280-330 mOsm / L, and the osmotic pressure regulator is selected from any one or a combination of glucose, sodium chloride, potassium chloride, calcium chloride, sodium carbonate, and potassium carbonate.

[0012] In a preferred embodiment of the present invention, the first composition contains, by mass-volume percentage, 0.1-10% nalbuphine hydrochloride, 0.1-1% citric acid, 0.1-2% sodium citrate, 0.1-1% preservative, and 0.01-1% sodium chloride, with the balance being water. The preservative is composed of methylparaben and propylparaben in a mass ratio of 9:1.

[0013] In a preferred embodiment of the present invention, the first composition contains, by weight and volume percentage, 0.5-5% nalbuphine hydrochloride, 0.5-5% citric acid, 0.5-5% sodium citrate, 0.05-0.8% preservative and 0.05-0.8% sodium chloride, with the balance being water. The preservative is composed of methylparaben and propylparaben in a weight ratio of 9:1.

[0014] In a preferred embodiment of the present invention, the first composition contains, by mass-volume percentage, 0.8-1% nalbuphine hydrochloride, 0.8-1% citric acid, 1-2% sodium citrate, 0.1-0.5% preservative, and 0.1-0.5% sodium chloride, with the balance being water. The preservative is composed of methylparaben and propylparaben in a weight ratio of 9:1.

[0015] In a preferred embodiment of the present invention, the second composition contains 0.001-0.1% preservative by weight-volume percentage, preferably 0.004-0.05%, and more preferably 0.005-0.01%.

[0016] In a preferred embodiment of the present invention, the second composition contains 5-10% ketamine hydrochloride and 0.001-0.1% benzalkonium chloride by mass-volume percentage, with the remainder being water.

[0017] In a preferred embodiment of the present invention, the second composition contains 4-8% ketamine hydrochloride and 0.004-0.05% benzalkonium chloride by mass-volume percentage, with the remainder being water.

[0018] In a preferred embodiment of the present invention, the first composition and the second composition are solutions, preferably injection solutions.

[0019] In a preferred embodiment of the present invention, the first composition contains, by weight and volume percentage, 1% nalbuphine hydrochloride, 0.94% citric acid, 1.26% sodium citrate, 0.2% preservative, and 0.2% sodium chloride, with the balance being water. The preservative is composed of methylparaben and propylparaben in a weight ratio of 9:1.

[0020] In a preferred embodiment of the present invention, the second composition contains 4% ketamine hydrochloride and 0.008% benzalkonium chloride by mass-volume percentage, with the remainder being water.

[0021] In a preferred embodiment of the present invention, the mass ratio of nalbuphine or a pharmaceutically acceptable salt thereof to ketamine or a pharmaceutically acceptable salt thereof in the composition is 1:9.

[0022] In a preferred embodiment of the present invention, the mass ratio of nalbuphine or a pharmaceutically acceptable salt thereof to ketamine or a pharmaceutically acceptable salt thereof in the composition is 1:6.

[0023] In a preferred embodiment of the present invention, the mass ratio of nalbuphine or a pharmaceutically acceptable salt thereof to ketamine or a pharmaceutically acceptable salt thereof in the composition is 1:4.5.

[0024] Another object of the present invention is to provide a method for preparing an analgesic pharmaceutical composition, wherein the composition comprises a first composition and a second composition packaged in two separate chambers, wherein the molar ratio of nalbuphine or a pharmaceutically acceptable salt thereof to ketamine or a pharmaceutically acceptable salt thereof in the composition is 1:5-1:20. By mass-volume percentage, the first composition comprises 0.1-10% nalbuphine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and the second composition comprises 1-20% ketamine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The pharmaceutically acceptable salt is selected from any one or a combination of hydrochloride, nitrate, phosphate, sulfate, and acetate. The method comprises the following steps:

[0025] (1) Weigh the required amount of nalbuphine or its pharmaceutically acceptable salt, pH adjuster, osmotic pressure adjuster and preservative, add water for injection, stir at 30°C and 700 rpm until completely dissolved, add water for injection to make up the volume, filter with a 0.22 μm filter membrane, and fill the first composition into the front chamber of a dual-chamber syringe.

[0026] (2) Weigh the required amount of ketamine or its pharmaceutically acceptable salt and preservative, add water for injection, stir at 20-40℃ and 700rpm until completely dissolved, add water for injection to make up the volume, filter through a 0.22um filter membrane, and fill the second composition into the rear chamber of a double-chamber syringe to obtain the product. The volume ratio of the front chamber to the rear chamber is 0.8-10:1. Mix the two chambers of the drug before use.

[0027] In a preferred embodiment of the present invention, the volume ratio of the anterior chamber to the rear chamber is 0.8-4:1, preferably 0.9-2:1, and more preferably (1.2-1.4):1.

[0028] Another object of the present invention is to provide the use of the pharmaceutical compositions of the present invention in the preparation of analgesic drugs.

[0029] Unless otherwise stated, when this invention relates to percentages between liquids, the percentage is volume / volume percentage; when this invention relates to percentages between liquids and solids, the percentage is volume / weight percentage; when this invention relates to percentages between solids and liquids, the percentage is weight / volume percentage; the remainder is weight / weight percentage.

[0030] Compared with the prior art, the present invention has the following beneficial technical effects:

[0031] 1. This invention scientifically combines ketamine and nalbuphine and packages them in two separate chambers to avoid infection caused by immediate preparation and use. The resulting drug composition has the advantages of rapid onset of action, doubled duration of action, good analgesic effect, accurate dosage, reduced dosage (≥50%) and cost (≥30%), and significantly reduced side effects such as respiratory depression. It is convenient for clinical use, easy to operate, and more economical to use. In addition, it can exert a strong analgesic effect and treat post-traumatic stress disorder in patients with moderate to severe pain accompanied by massive bleeding, fractures and other injuries, unstable circulation, and emotional agitation.

[0032] 2. The preparation method of the present invention has the advantages of simple operation, significantly shortened production cycle, significantly reduced production cost, and suitability for large-scale industrial production. Attached Figure Description

[0033] Figure 1 A comparative study of the incubation period of foot contracture in experimental groups 1-3, control groups 1-4, and blank group.

[0034] Figure 2 A comparative study of respiratory rates among experimental groups 1-3, control groups 1-4, and the blank group.

[0035] Figure 3 Comparative study of minute ventilation in experimental groups 1-3, control groups 1-4, and blank group. Detailed Implementation

[0036] The present invention will be described below with reference to the embodiments. However, the present invention is not limited to the embodiments.

[0037] Example 1: Preparation of nalbuphine hydrochloride injection

[0038] The composition of nalbuphine hydrochloride injection is as follows:

[0039]

[0040] The preparation of nalbuphine hydrochloride injection includes the following steps:

[0041] Weigh out the required amounts of nalbuphine hydrochloride, citric acid, sodium citrate, sodium chloride, methylparaben, and propylparaben. Dissolve them by stirring at 30°C and 700 rpm. Add water for injection to bring the volume to 20 ml. Filter the prepared solution twice through a 0.22 μm filter membrane to obtain the final product.

[0042] Example 2: Preparation of ketamine hydrochloride injection

[0043] The composition of ketamine hydrochloride injection is as follows:

[0044] 1000mg of ketamine hydrochloride

[0045] Benzalkonium chloride 2mg

[0046] The preparation of ketamine hydrochloride injection includes the following steps:

[0047] Weigh out the required amounts of ketamine hydrochloride and benzalkonium chloride, and dissolve them by stirring at 40°C and 700 rpm. Add water for injection to bring the volume to 25 ml. Filter the prepared solution twice through a 0.22 μm filter membrane to obtain the final product.

[0048] Example 3: Preparation of the analgesic drug composition of the present invention

[0049] The preparation of the analgesic pharmaceutical composition of the present invention includes the following steps:

[0050] 1) 2.1 ml of the ketamine hydrochloride injection solution prepared in Example 2 was filled into the front chamber of a dual-chamber syringe at 18-25°C and a filling speed of 30-40 syringes / min;

[0051] 2) Fill 1.2 ml of the nalbuphine hydrochloride injection prepared in Example 1 into the rear chamber of a dual-chamber syringe at 18-25°C and a filling speed of 30-40 syringes / min.

[0052] Example 4: Preparation of the analgesic drug composition of the present invention

[0053] The preparation of the analgesic pharmaceutical composition of the present invention includes the following steps:

[0054] 1) 2.1 ml of the ketamine hydrochloride injection solution prepared in Example 2 was filled into the front chamber of a dual-chamber syringe at 18-25°C and a filling speed of 30-40 syringes / min;

[0055] 2) Fill 1.75 ml of the nalbuphine hydrochloride injection prepared in Example 1 into the rear chamber of a dual-chamber syringe at 18-25°C and a filling speed of 30-40 syringes / min to obtain the final product.

[0056] Example 5: Preparation of the analgesic drug composition of the present invention

[0057] The preparation of the analgesic pharmaceutical composition of the present invention includes the following steps:

[0058] 1) 2.1 ml of the ketamine hydrochloride injection solution prepared in Example 2 was filled into the front chamber of a dual-chamber syringe at 18-25°C and a filling speed of 30-40 syringes / min;

[0059] 2) Fill 2.3 ml of the nalbuphine hydrochloride injection prepared in Example 1 into the rear chamber of a dual-chamber syringe at 18-25°C and a filling speed of 30-40 syringes / min.

[0060] Experimental Example 1: Study on the analgesic effect of the pharmaceutical composition of the present invention

[0061] Eighty SPF-grade male SD rats weighing 180-220g were selected. During the experiment, the animals had free access to food and water, and were housed in cages of 5. The animals were randomly divided into 8 groups of 10 each. The test drug was administered to the animals via intramuscular injection at a dose of 0.4ml.

[0062] Experimental group 1: The drug composition of Example 3, with an injection dose of 1.0 mg / kg of nalbuphine hydrochloride;

[0063] Experimental Group 2: The drug composition of Example 4, with an injection dose of 1.5 mg / kg of nalbuphine hydrochloride;

[0064] Experimental group 3: The drug composition of Example 5, with an injection dose of 2.0 mg / kg of nalbuphine hydrochloride;

[0065] Control group 1: Nalbuphine injection solution of Example 1, with an injection dose of 1.0 mg / kg of nalbuphine hydrochloride;

[0066] Control group 2: Nalbuphine injection solution of Example 1, with an injection dose of 1.5 mg / kg of nalbuphine hydrochloride;

[0067] Control group 3: Nalbuphine injection solution of Example 1, with an injection dose of 2.0 mg / kg of nalbuphine hydrochloride;

[0068] Control group 4: Ketamine injection solution from Example 2, with an injection dose of 9 mg / kg of ketamine;

[0069] Blank group: 0.9% sodium chloride injection.

[0070] 2. Drug analgesic efficacy experiment

[0071] A hind paw incision pain model was used. Rats were placed in an anesthesia box and administered sevoflurane until the righting reflex disappeared. The left hind paw was disinfected with iodine. A 1cm incision was made from 0.5cm proximal to the toe. After the skin was cut, the paw muscle was lifted with ophthalmic forceps and longitudinally cut, keeping the origin, insertion, and attachment of the muscle intact. After applying pressure to stop bleeding, the skin was sutured with fine sutures. Five minutes after the rats regained consciousness, each group of drugs was injected intramuscularly. During administration, the rat was held by the tail and lifted with one hand, placed on a relatively rough surface or cage. An assistant held the rat's tail with one hand and pulled it backward, while using the thumb and forefinger of the left hand to grasp the skin of the head and neck, and holding the skin of the upper back of the rat with the other hand to lift the rat. The operator held one hind limb of the rat with one hand, disinfected the injection site with an alcohol swab, and then took the syringe (with a No. 5 needle) with the other hand, inserted it into the muscle at a 60° angle, and injected the drug solution after aspiration showed no reflux. After injection, apply pressure to the injection site with a dry cotton ball for a moment to prevent bleeding (Note: the dosage should be controlled at 0.2 ml / 100 g). The thermal pain threshold of rats was measured 30 min before model preparation, and 15 min, 2 h, 4 h, and 6 h after drug injection. The thermal pain threshold was measured using the hot plate test, and the magnitude of the thermal pain threshold was measured by the rat's paw withdrawal latency, and the results were recorded. Changes in the thermal pain threshold before and after drug administration were compared within each group, and the thermal pain thresholds of rats in each group were compared between groups.

[0072] Effects of drugs on respiratory depression in rats: The respiratory module parameters of the whole-body volume plethysmography system were adjusted, and a continuous airflow (2 L / min) was introduced into the chamber to maintain constant temperature and humidity. Rats were placed in circular plexiglass chambers for 60 min to allow them to acclimatize to the testing environment until their breathing stabilized. One rat was placed in each chamber. A pressure sensor was used to detect changes in air pressure caused by rat respiration within the chamber, and the collected signals were converted using a signal acquisition system. The respiratory parameters were recorded and processed using the Ponemah data acquisition and analysis system. After intramuscular injection of the drug into each group of rats, their respiratory status was observed for 1 hour.

[0073] Time values ​​and pain scores for each group are expressed as mean ± standard deviation, and p < 0.05 indicates a significant difference. One-way ANOVA was used to compare data between groups, followed by paired t-tests for pairwise comparisons. Repeated measures ANOVA was used for within-group comparisons. Respiratory parameters of rats are expressed as mean ± standard deviation, and two-way ANOVA was used to compare differences between groups, followed by Bonferron i-test. P < 0.05 indicates a significant difference.

[0074] See results Figures 1-3As shown in the figure. Compared with the control group 3 and the blank group, the latency period of foot withdrawal in the experimental group 3 was significantly longer 1 hour after administration, and there was still a significant analgesic effect, with a significant difference (p<0.05). Compared with the blank group, the combined use did not increase the risk of respiratory depression side effects.

[0075] The above description of specific embodiments of the present invention does not limit the present invention. Those skilled in the art can make various changes or modifications based on the present invention, and as long as they do not depart from the spirit of the present invention, they should all fall within the scope of protection of the claims of the present invention.

Claims

1. An intramuscularly injectable analgesic composition, said composition comprising a first composition and a second composition packaged in two separate chambers, wherein the molar ratio of nalbuphine hydrochloride to ketamine in the composition is 1:5-1:8, and the first composition, by mass-volume percentage, contains 0.1-10% nalbuphine hydrochloride, 0.1-1% citric acid, 0.1-2% sodium citrate, 0.1-1% preservative, and 0.01-1% sodium chloride, with the balance being water, wherein... The preservative is composed of methylparaben and propylparaben in a mass ratio of 9:

1. The second composition contains 5-10% ketamine hydrochloride and 0.001-0.1% benzalkonium chloride by mass-volume percentage, with the balance being water. The first and second compositions are injection solutions.

2. The composition of claim 1, wherein the pH of the first composition is 5-7, wherein, The pH adjuster is selected from a combination of citric acid and sodium citrate.

3. The composition according to claim 1, wherein the osmotic pressure of the first composition is 280-330 mOsm / L, and the osmotic pressure regulator is selected from sodium chloride.

4. The composition of claim 1, wherein, by weight-volume percentage, the first composition contains 0.8-1% nalbuphine hydrochloride, 0.8-1% citric acid, 1-2% sodium citrate, 0.1-0.5% preservative, and 0.1-0.5% sodium chloride, with the balance being water, wherein... The preservative is composed of methylparaben and propylparaben in a weight ratio of 9:

1.

5. The composition of claim 4, wherein, by weight-volume percentage, the first composition contains 1% nalbuphine hydrochloride, 0.94% citric acid, 1.26% sodium citrate, 0.2% preservative, and 0.2% sodium chloride, with the balance being water, wherein... The preservative is composed of methylparaben and propylparaben in a weight ratio of 9:

1.

6. The composition of claim 1, wherein the second composition contains 0.004-0.05% preservative by weight-volume percentage.

7. The composition of claim 6, wherein the second composition contains 0.005-0.01% preservative by weight-volume percentage.

8. The composition of claim 1, wherein the second composition contains 4-8% ketamine hydrochloride and 0.004-0.05% benzalkonium chloride by weight-volume percentage, with the balance being water.

9. The composition of claim 8, wherein the second composition contains 4% ketamine hydrochloride and 0.008% benzalkonium chloride by weight-volume percentage, with the balance being water.

10. A method for preparing the analgesic pharmaceutical composition according to any one of claims 1-9, comprising the following steps: (1) Weigh the required amounts of nalbuphine hydrochloride, citric acid, sodium citrate, sodium chloride, and preservative, add water for injection, stir at 30°C and 700 rpm until completely dissolved, add water for injection to make up the volume, filter through a 0.22 μm filter membrane, and fill the first composition into the front chamber of a dual-chamber syringe. (2) Weigh the required amounts of ketamine hydrochloride and benzalkonium chloride, add water for injection, and stir at 20-40℃ and 700rpm until completely dissolved. Add water for injection to make up the volume, filter through a 0.22μm filter membrane, and fill the rear chamber of a dual-chamber syringe to obtain the final product. The volume ratio of the anterior chamber to the posterior chamber is 0.8-10:

1. The drugs in the two chambers are mixed before use.

11. The preparation method according to claim 10, wherein the volume ratio of the front chamber to the rear chamber is 0.8-4:

1.

12. The preparation method according to claim 11, wherein the volume ratio of the front chamber to the rear chamber is 0.9-2:

1.

13. The preparation method according to claim 12, wherein the volume ratio of the front chamber to the rear chamber is (1.2-1.4):

1.

14. The use of the analgesic pharmaceutical composition according to any one of claims 1-9 or the analgesic pharmaceutical composition prepared by the preparation method according to any one of claims 10-13 in the preparation of analgesic pharmaceuticals.

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