CN115919858A - Analgesic pharmaceutical composition, preparation method and application thereof - Google Patents

Abstract

The invention relates to an analgesic composition, which consists of a first composition containing nalbuphine or a pharmaceutically acceptable salt thereof and a second composition containing ketamine or a pharmaceutically acceptable salt thereof, wherein the ratio of nalbuphine or a pharmaceutically acceptable salt thereof in the compositions is as follows: the molar ratio of ketamine or its pharmaceutically acceptable salt is 1:5-1. The invention scientifically screens the proportion of the ketamine and the nalbuphine, has the advantages of synergistic interaction, quick response, prolonged duration, good analgesic effect and the like, and obviously reduces the respiratory depression effect brought by the single use of the ketamine and the nalbuphine.

Description

A kind of analgesic pharmaceutical composition and its preparation method and its application

technical field

The invention relates to the field of medicine, in particular to an analgesic pharmaceutical composition, a preparation method thereof and an application thereof.

Background technique

Ketamine has sedative, hypnotic and analgesic effects and is widely used as an anesthetic drug in clinic, but it has a short duration of analgesia, and there are adverse reactions such as respiratory depression and circulatory excitation (or inhibition) when it is used rapidly in large doses. its clinical use. Nalbuphine is a new type of opioid receptor agonist-antagonist analgesic. It mainly stimulates the κ receptor to exert a central analgesic effect, and has a partial antagonistic effect on the μ receptor. It is often used for analgesia of moderate to severe pain. Similar to morphine. However, compared with morphine, nalbuphine has the advantages of less psychological and emotional impact on patients, less addiction, mild respiratory depression, and long duration of action (3-6h), but it has a slow onset of action, which affects the analgesic treatment of patients. and other defects. Therefore, it is necessary to develop a pharmaceutical composition with quick onset of action, prolonged duration of anesthesia, good analgesic effect, and few side effects, so as to meet the clinical demand for safe and effective medication.

Contents of the invention

The object of the present invention is to provide a kind of analgesic pharmaceutical composition, and described composition is made up of the first composition and the second composition of dual-chamber independent packaging, and the nalbuphine or its pharmaceutically acceptable salt in the composition : the molar ratio of ketamine or its pharmaceutically acceptable salt is 1:5-1:20, by mass volume percentage, the first composition is made of 0.1-10% nalbuphine or its pharmaceutically acceptable salt and Composed of a pharmaceutically acceptable carrier, the second composition is composed of 1-20% ketamine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and the pharmaceutically acceptable salt is selected from hydrochloride, Any one or combination of nitrates, phosphates, sulfates, acetates.

In the preferred technical scheme of the present invention, the molar ratio of nalbuphine or its pharmaceutically acceptable salt in the composition: ketamine or its pharmaceutically acceptable salt is 1:6-1:15, 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.

In the preferred technical scheme of the present invention, the molar ratio of nalbuphine or its pharmaceutically acceptable salt in the composition: ketamine or its pharmaceutically acceptable salt is 1:8-1:12, by mass volume percentage The first composition contains 0.8-1% of nalbuphine or its pharmaceutically acceptable salt, and the second composition contains 4-10% of ketamine or its pharmaceutically acceptable salt.

In a preferred technical solution of the present invention, the pharmaceutically acceptable carrier is selected from any one of preservatives, pH regulators, osmotic pressure regulators or a combination thereof.

In the preferred technical solution of the present invention, the preservative is selected from the group consisting of phenoxyethanol, propylparaben, methylisothiazolinone, methyl p-hydroxybenzoate, ethylparaben, p-hydroxybenzoic acid Propyl Ester, Sodium Benzoate, Potassium Sorbate, Benzoic Acid or Its Salts, Sorbic Acid or Its Salts, Benzalkonium Chloride, Parabens, Sodium Metabisulfite, Chlorhexidine, Sodium Citrate, Butylated Hydroxytoluene, Any one or combination of butyl hydroxyanisole, tocopherol, ethylenediaminetetraacetic acid, propyl gallate, quaternary ammonium compounds.

In the preferred technical solution of the present invention, the first composition contains 0.01-1% of preservative, and the preservative is composed of methyl p-hydroxybenzoate and propyl p-hydroxybenzoate.

In a preferred technical solution of the present invention, the first composition contains 0.05-0.5% of a preservative, and the preservative is composed of methyl p-hydroxybenzoate: propyl p-hydroxybenzoate at a mass ratio of 9:1.

In the preferred technical solution of the present invention, the pH of the first composition is 5-7, wherein the pH regulator is selected from 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, carbonic acid Potassium, 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 tartrate, potassium fumarate, fumaric acid or its hydrate, any one or combination thereof.

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

In the preferred technical solution of the present invention, the first composition contains 0.1-10% nalbuphine hydrochloride, 0.1-1% citric acid, 0.1-2% sodium citrate, 0.1-2% preservative 1% and 0.01-1% of sodium chloride, and the balance is water, wherein the preservative is composed of methyl p-hydroxybenzoate-propyl p-hydroxybenzoate in a mass ratio of 9:1.

In the preferred technical solution of the present invention, the first composition contains 0.5-5% nalbuphine hydrochloride, 0.5-5% citric acid, 0.5-5% sodium citrate, 0.05-5% preservative 0.8% and 0.05-0.8% of sodium chloride, and the balance is water, wherein the preservative is composed of methyl p-hydroxybenzoate-propyl p-hydroxybenzoate in a weight ratio of 9:1.

In the preferred technical solution of the present invention, the first composition contains 0.8-1% of nalbuphine hydrochloride, 0.8-1% of citric acid, 1-2% of sodium citrate, 0.1-1% of preservative 0.5% and 0.1-0.5% of sodium chloride, and the balance is water, wherein the preservative is composed of methyl p-hydroxybenzoate-propyl p-hydroxybenzoate in a weight ratio of 9:1.

In a preferred technical solution of the present invention, the second composition contains 0.001-0.1%, preferably 0.004-0.05%, and more preferably 0.005-0.01% of the preservative in terms of mass volume percentage.

In the preferred technical solution of the present invention, the second composition contains 5-10% of ketamine hydrochloride and 0.001-0.1% of benzalkonium chloride, and the balance is water.

In the preferred technical solution of the present invention, the second composition contains 4-8% of ketamine hydrochloride and 0.004-0.05% of benzalkonium chloride, and the balance is water.

In a preferred technical solution of the present invention, the first composition and the second composition are solutions, preferably injections.

In the preferred technical solution of the present invention, the first composition contains 1% nalbuphine hydrochloride, 0.94% citric acid, 1.26% sodium citrate, 0.2% preservatives and 0.2% sodium chloride by mass volume percentage, The remainder is water, wherein the preservative is composed of methyl p-hydroxybenzoate-propyl p-hydroxybenzoate in a weight ratio of 9:1.

In the preferred technical solution of the present invention, the second composition contains 4% of ketamine hydrochloride and 0.008% of benzalkonium chloride, and the balance is water.

In the preferred technical solution of the present invention, the mass ratio of nalbuphine or a pharmaceutically acceptable salt thereof: ketamine or a pharmaceutically acceptable salt thereof in the composition is 1:9.

In the preferred technical solution of the present invention, the mass ratio of nalbuphine or its pharmaceutically acceptable salt to ketamine or its pharmaceutically acceptable salt in the composition is 1:6.

In the preferred technical solution of the present invention, the mass ratio of nalbuphine or its pharmaceutically acceptable salt to ketamine or its pharmaceutically acceptable salt in the composition is 1:4.5.

Another object of the present invention is to provide a preparation method of analgesic pharmaceutical composition, said composition is made up of the first composition and the second composition of dual-chamber independent packaging, nalbuphine or its pharmaceutical composition in the composition The above acceptable salt: the molar ratio of ketamine or its pharmaceutically acceptable salt is 1:5-1:20, and the first composition is composed of 0.1-10% nalbuphine or its pharmaceutically acceptable salt. acceptable salt and a pharmaceutically acceptable carrier, the second composition is composed of 1-20% ketamine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and the pharmaceutically acceptable salt is selected from From hydrochloride, nitrate, phosphate, sulfate, acetate any one or its combination, described method comprises the following steps:

(1) Weigh the required amount of nalbuphine or its pharmaceutically acceptable salt, pH regulator, osmotic pressure regulator, preservative, add water for injection, stir at 30°C and 700rpm until completely dissolved, add Dilute to volume with water for injection, filter with 0.22um filter membrane, fill the prepared first composition into the front chamber of the double-chamber syringe;

(2) Weigh the required amount of ketamine or its pharmaceutically acceptable salt and preservative, add water for injection, place it at 20-40°C and 700rpm and stir until completely dissolved, add water for injection to volume, 0.22um Membrane filtration, the prepared second composition is filled into the back chamber of the double-chamber syringe, and the volume ratio of the front chamber and the back chamber is 0.8-10:1, and the medicines in the two chambers are mixed before use .

In the preferred technical solution of the present invention, the volume ratio of the front chamber to the back chamber is 0.8-4:1, preferably 0.9-2:1, more preferably (1.2-1.4):1.

Another object of the present invention is to provide the application of the pharmaceutical composition of the present invention in the preparation of analgesic drugs.

Unless otherwise stated, when the present invention relates to the percentage between liquid and liquid, said percentage is volume/volume percentage; When the present invention relates to the percentage between liquid and solid, said percentage is volume/weight percentage; When referring to percentages between solids and liquids, said percentages are weight/volume percentages; the remainder are weight/weight percentages.

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

1. The present invention scientifically mixes ketamine and nalbuphine and packs them independently in double chambers to avoid infection caused by the combination before use, and the prepared pharmaceutical composition has quick onset of action, doubled duration of action, and analgesic effect Good, accurate dosage, reduced drug dosage (≥50%) and drug cost (≥30%), significantly reduced side effects such as respiratory depression, convenient for clinical use, easy to operate, and more economical medication, and it is suitable for moderate to severe pain accompanied by massive bleeding , fractures and other injuries, unstable circulation, and emotional irritability patients, can exert a strong analgesic effect and post-traumatic stress disorder treatment effect.

2. The preparation method of the present invention has the advantages of simple operation, significantly shortened production cycle, significantly reduced production cost, and is suitable for large-scale industrial production.

Description of drawings

Fig. 1 Comparative study of the paw withdrawal latency of the test group 1-3, the control group 1-4, and the blank group.

Fig. 2 Comparative study on respiratory rate of test group 1-3, control group 1-4, and blank group.

Fig. 3 Comparative study of minute ventilation of test group 1-3, control group 1-4, and blank group.

Detailed ways

The present invention is illustrated below with reference to examples. However, the present invention is not limited to the Examples.

The preparation of embodiment 1 nalbuphine hydrochloride injection

The composition of nalbuphine hydrochloride injection is:

The preparation of nalbuphine hydrochloride injection comprises the steps:

Weigh the required amount of nalbuphine hydrochloride, citric acid, sodium citrate, sodium chloride, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, stir and dissolve at 30°C and 700rpm , add water for injection to make the volume to 20ml, and filter the prepared medicinal solution twice through a 0.22μm filter membrane to obtain the product.

The preparation of embodiment 2 ketamine hydrochloride injection

Ketamine hydrochloride injection consists of:

Ketamine Hydrochloride 1000mg

Benzalkonium Chloride 2mg

The preparation of ketamine hydrochloride injection comprises the steps:

Weigh the required amount of ketamine hydrochloride and benzalkonium chloride, stir and dissolve them at 40°C and 700rpm, add water for injection to make the volume to 25ml, and filter the prepared medicinal solution twice through a 0.22μm filter membrane, Instantly.

Embodiment 3 Preparation of analgesic pharmaceutical composition of the present invention

The preparation of analgesic pharmaceutical composition of the present invention comprises the following steps:

1) Fill 2.1 ml of ketamine hydrochloride injection prepared in Example 2 into the front chamber of the dual-chamber syringe at 18-25°C and a filling speed of 30-40 tubes/min;

2) Fill 1.2 ml of nalbuphine hydrochloride injection prepared in Example 1 into the rear chamber of the dual-chamber syringe at 18-25° C. and a filling speed of 30-40 tubes/min, to obtain final product.

Embodiment 4 Preparation of analgesic pharmaceutical composition of the present invention

The preparation of analgesic pharmaceutical composition of the present invention comprises the following steps:

1) Fill 2.1 ml of ketamine hydrochloride injection prepared in Example 2 into the front chamber of the dual-chamber syringe at 18-25°C and a filling speed of 30-40 tubes/min;

2) Fill 1.75ml of 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 tubes/min, to obtain final product.

Embodiment 5 Preparation of analgesic pharmaceutical composition of the present invention

The preparation of analgesic pharmaceutical composition of the present invention comprises the following steps:

1) Fill 2.1 ml of ketamine hydrochloride injection prepared in Example 2 into the front chamber of the dual-chamber syringe at 18-25°C and a filling speed of 30-40 tubes/min;

2) Fill 2.3ml of nalbuphine hydrochloride injection prepared in Example 1 into the rear chamber of the dual-chamber syringe at 18-25°C and a filling speed of 30-40 tubes/min, to obtain final product.

Experimental example 1 the analgesic effect research of pharmaceutical composition of the present invention

Select 80 male SD rats with SPF grade and a body weight of 180-220 g. During the test, the test animals are allowed to eat and drink freely, 5/cage. The experimental animals were randomly divided into 8 groups, 10 in each group. The test drug was injected intramuscularly to the test animals in accordance with 0.4ml.

Test group 1: the pharmaceutical composition of embodiment 3, the injection dosage is 1.0mg/kg with nalbuphine hydrochloride;

Test group 2: the pharmaceutical composition of embodiment 4, the injection dosage is 1.5mg/kg with nalbuphine hydrochloride;

Test group 3: the pharmaceutical composition of embodiment 5, the injection dosage is 2.0mg/kg with nalbuphine hydrochloride;

Matched group 1: the nalbuphine injection of embodiment 1, the injection dosage is 1.0mg/kg with nalbuphine hydrochloride;

Matched group 2: the nalbuphine injection of embodiment 1, the injection dosage is 1.5mg/kg with nalbuphine hydrochloride;

Matched group 3: the nalbuphine injection of embodiment 1, the injection dosage is 2.0mg/kg with nalbuphine hydrochloride;

Control group 4: the ketamine injection of embodiment 2, the injection dose is based on 9 mg/kg of ketamine;

Blank group: 0.9% sodium chloride injection.

2. Drug analgesic efficacy experiment

Using the rear foot incision pain model, the rats were placed in an anesthesia box and given sevoflurane until the righting reflex disappeared. Disinfect the left hind paw with povidone iodine, and make an incision about 1 cm long from the proximal 0.5 cm of the sole to the toe. After cutting the skin, use ophthalmic tweezers to pick up the plantar muscles and cut them longitudinally to keep the muscles starting and ending and attached intact , After pressing to stop the bleeding, suture the skin with thin thread. Rats were injected intramuscularly with each group of drugs 5 minutes after they woke up. When administering the drug, grasp the tail of the rat with one hand and lift it up, and place it on a table or cage with a rough surface. The assistant grasps the tail of the rat with one hand and pulls it back, and grasps the skin of the head and neck with the thumb and index finger of the left hand. The rat was lifted by grasping the skin of the back of the upper body of the rat with the palm of the hand. The operator grasps one hind limb of the rat with one hand, sterilizes the injection site with an alcohol cotton ball, and then takes the syringe with the other hand (the needle is a No. 5 needle), at an angle of 60° to the muscle, and quickly penetrates into the muscle, withdrawing without reflux substance, inject the liquid medicine. After the injection, press the eye of the needle with a dry cotton ball for a while to prevent bleeding (note: the administration volume should be controlled at 0.2ml/100g). 30min before the model preparation, 15min, 2h, 4h, and 6h after the drug injection, the thermal pain threshold of the rats was measured, and the thermal pain threshold was measured by the hot plate pain measurement method. To measure the latent period of foot and record it. The changes in the thermal pain threshold of the rats before and after administration were compared within the group, and the thermal pain threshold of the rats in each group was compared between the groups.

Effect of drugs on respiratory depression in rats: Adjust the parameters of the respiratory module of the whole body plethysmography system, and a continuous airflow (2L/min) is introduced into the box to maintain a constant temperature and humidity in the box. The rats were put into a circular plexiglass box for 60 minutes to fully adapt to the detection environment until the breathing was stable. One rat was placed in each glass box. The baroreceptor device is used to sense the air pressure change in the cavity caused by the rat's breathing, and the collected signal is converted through the signal acquisition system. Ponemah data acquisition and analysis system was used to record the respiratory parameters and process the corresponding data. After the intramuscular injection of the drug to the rats in each group, the respiratory conditions of the rats were observed within 1 hour.

The time values and pain scores of each group are expressed as mean ± standard deviation, and p<0.05 indicates a significant difference. One-way analysis of variance was used to compare the data between groups, and paired t-test was used for pairwise comparison, and repeated measures analysis of variance was used for comparison within groups. Respiratory parameters of rats were expressed as mean ± standard deviation, and differences between groups were compared by two-way ANOVA, and Bonferron i post-test, P<0.05 indicated a significant difference.

The results are shown in Figures 1-3. Compared with the control group 3 and the blank group, the paw withdrawal latency of the test group 3 was significantly longer after 1 hour of administration, and there was still a significant analgesic effect, with a significant difference (p<0.05), compared with the blank group , the combined drug did not increase the risk of respiratory depression side effects.

The above description of the specific embodiments of the present invention does not limit the present invention, and those skilled in the art can make various changes or deformations according to the present invention, as long as they do not depart from the spirit of the present invention, all should belong to the scope of protection of the claims of the present invention.

Claims (10)

1. An analgesic pharmaceutical composition, said composition is made up of the first composition and the second composition of double-chamber independent packaging, nalbuphine or its pharmaceutically acceptable salt in composition: ketamine or its The molar ratio of the pharmaceutically acceptable salt is 1:5-1:20, and the first composition is composed of 0.1-10% nalbuphine or its pharmaceutically acceptable salt and pharmaceutically acceptable The carrier composition, the second composition is made up of 1-20% ketamine or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier, and described pharmaceutically acceptable salt is selected from hydrochloride, nitrate, phosphoric acid Any one or combination of salts, sulfates, acetates. 2. the composition as claimed in claim 1, the mol ratio of nalbuphine or its pharmaceutically acceptable salt in composition: ketamine or its pharmaceutically acceptable salt is 1:6-1:15, according to In terms of 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. 3. The composition according to any one of claims 1-2, nalbuphine or its pharmaceutically acceptable salt in the composition: the mol ratio of ketamine or its pharmaceutically acceptable salt is 1:8- 1:12, by mass volume percentage, the first composition contains 0.8-1% of nalbuphine or a pharmaceutically acceptable salt thereof, and the second composition contains ketamine or a pharmaceutically acceptable salt thereof 4-10% %. 4. The composition according to any one of claims 1-3, wherein the pharmaceutically acceptable carrier is selected from any one or a combination of preservatives, pH regulators, osmotic pressure regulators. 5. The composition according to any one of claims 1-4, said preservative is selected from the group consisting of phenoxyethanol, methyl propylparaben, methylisothiazolinone, methyl p-hydroxybenzoate, nipagin Parkin Ethyl Ethyl, Propyl Paraben, Sodium Benzoate, Potassium Sorbate, Benzoic Acid or Its Salts, Sorbic Acid or Its Salts, Benzalkonium Chloride, Parabens, Sodium Metabisulfite, Chlorhexidine, Sodium citrate, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol, ethylenediaminetetraacetic acid, propyl gallate, any one of quaternary ammonium compounds or a combination thereof. 6. the composition as described in any one of claim 1-5, contains preservative 0.01-1% in the first composition, and described preservative is made up of methyl p-hydroxybenzoate and propyl p-hydroxybenzoate . 7. the composition as described in any one of claim 1-6, by mass volume percentage, contain nalbuphine hydrochloride 0.1-10%, citric acid 0.1-1%, sodium citrate in the first composition 0.1-2%, preservative 0.1-1% and sodium chloride 0.01-1%, and the balance is water, wherein, the preservative consists of methyl p-hydroxybenzoate-propyl p-hydroxybenzoate according to the mass ratio of 9:1 composition. 8. The composition according to any one of claims 1-7, in terms of mass volume percentage, the second composition contains 5-10% of ketamine hydrochloride and 0.001-0.1% of benzalkonium chloride, and the balance is water. 9. the preparation method of the analgesic pharmaceutical composition as described in any one of claim 1-8, described composition is made up of the first composition and the second composition of two-chamber independent packaging, the Nabu in composition The molar ratio of morphine or a pharmaceutically acceptable salt thereof: ketamine or a pharmaceutically acceptable salt thereof is 1:5-1:20, and the first composition consists of 0.1-10% nalbuphine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, the second composition is composed of 1-20% ketamine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, the pharmaceutically acceptable Accepted salt is selected from any one or combination of hydrochloride, nitrate, phosphate, sulfate, acetate, and described method comprises the following steps: (1) Weigh the required amount of nalbuphine or its pharmaceutically acceptable salt, pH regulator, osmotic pressure regulator, preservative, add water for injection, stir at 30°C and 700rpm until completely dissolved, add Dilute to volume with water for injection, filter through a 0.22um filter membrane, fill the prepared first composition into the front chamber of the double-chamber syringe; (2) Weigh the required amount of ketamine or its pharmaceutically acceptable salt and preservative, add water for injection, place it at 20-40°C and 700rpm and stir until completely dissolved, add water for injection to volume, 0.22um Membrane filtration, the prepared second composition is filled into the back chamber of the double-chamber syringe, and the volume ratio of the front chamber and the back chamber is 0.8-10:1, and the medicines in the two chambers are mixed before use . 10. The application of the analgesic pharmaceutical composition according to any one of claims 1-8 or the analgesic pharmaceutical composition prepared by the preparation method according to claim 9 for the preparation of analgesic medicine.

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