WO2018086498A1 - Pharmaceutical composition and application thereof - Google Patents

Abstract

A pharmaceutical composition, comprising a pharmaceutical active ingredient consisting of dexmedetomidine hydrochloride and ketamine hydrochloride. The pharmaceutical composition of the present invention has a synergistic effect, and the effect is particularly prominent when used for children's sedation before examination, so that different examinations of sick children can be effectively accomplished. The pharmaceutical composition has a sedation success rate up to 96% or more, fast onset of action, and strong recovery controllability. In addition, the pharmaceutical composition has small side effect, leads to no obvious adverse effect, and causes no emergence agitation due to normal heart rate and blood pressure, and therefore shows high safety.

Description

Pharmaceutical composition and application thereof Technical field

The present invention relates to a pharmaceutical composition, and more particularly to a sedative pharmaceutical composition.

Background technique

Pre-examination sedation, especially before sedation in children, is an urgent problem in clinical practice. The use of safe and effective drugs is the key to ensuring the smooth completion of various tests.

At present, the commonly used pre-intestinal sedative drugs in China are oral chloral hydrate or midazolam orally, luminal sodium intramuscular injection. The efficacy and use of these sedative drugs have the following problems: (1) chloral hydrate oral preparation: It is the most commonly used sedative for children before the clinic. Because of its very bitter taste, many children refuse to take it or cause vomiting after taking it. The risk of aspiration is increased and even life-threatening. In addition, hydrated chloral metabolites are active and sometimes cause wake delay; at the same time, the first-pass effect of the drug is obvious, the sedative effect is uncertain, often leading to sedation failure, and many children often need to repeatedly use drugs. (2) Midazolam oral agent: the sedative effect is not good, the success rate is only 60-75%. (3) luminal sodium intramuscular injection: the success rate of sedation is about 80%, but accompanied by painful stimulation, causing harm to the child.

Dexmedetomidine hydrochloride is a dextrorotatory isomer of medetomidine. It is a derivative of imidazole and is a highly selective α2 receptor agonist. Its chemical name is (+)-4-(S). -[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole hydrochloride, which acts on the α2 receptor in the cerebral nucleus of the brainstem and produces a good sedative effect. The bioavailability of medetomidine is 81.8% (72.6–92.1%), so adults and children can have a significant sedative effect after nasal instillation of dexmedetomidine, and have no inhibitory effect on the respiratory center; /kg dexmedetomidine is sedated, it is easy to be awakened by external stimuli, the wake-up rate can reach about 50%, leading to sedation failure; a larger dose of dexmedetomidine hydrochloride (> 2ug / kg) nasal drops, can produce heartbeat Too slow.

Ketamine is an NMDA receptor antagonist with analgesic sedative and sympathetic stimulating effects, but generally it requires a large dose, which is likely to cause an increase in blood pressure and arousal during awakening.

Summary of the invention

It is an object of the present invention to provide a sedative pharmaceutical composition having a high success rate and few side effects.

The object of the present invention is achieved by the following technical solutions:

A pharmaceutical composition comprising a pharmaceutically active ingredient consisting of dexmedetomidine hydrochloride and ketamine hydrochloride. During the research, the inventors found that the pharmaceutical composition can produce a significant synergistic effect, and the pharmaceutical composition is used for various examinations with high success rate of sedation, and almost no arousal by external stimulation during the sedation of the drug, no Significant side effects.

Preferably, in the pharmaceutical composition provided by the present invention, the mass ratio of dexmedetomidine hydrochloride to ketamine hydrochloride is from 1 to 5:500 to 3,000.

More preferably, the mass ratio of dexmedetomidine hydrochloride to ketamine hydrochloride in the pharmaceutical composition of the present invention is 2:1000.

The use of the above pharmaceutical composition for the preparation of a sedative.

The present invention also provides a sedative drug comprising the pharmaceutical composition of the present invention as provided above and a pharmaceutically acceptable adjuvant.

The sedative drug of the present invention may be an aerosol, a nasal spray, a powder, a sublingual tablet, an injection, an oral solution, an oral tablet, a capsule or the like.

Preferably, the sedative drug provided by the present invention is a nasal spray.

A nasal spray for sedation, which comprises the following raw materials of weight ratio, characterized in that: dexmedetomidine hydrochloride 0.002～0.01 parts, ketamine hydrochloride 1～5 parts, polyethylene glycol 400 0.01～0.05 a portion, 0.1 to 1.5 parts of sodium chloride, 0.03 to 0.16 parts of disodium edetate, 0.3 to 0.9 parts of benzyl alcohol, 0.02 to 0.18 parts of glycerin, and 0.01 to 3.9 parts of sodium hydrogencarbonate;

The method for preparing a nasal spray for sedation according to the present invention is characterized in that it is carried out as follows:

1. Take 2L of purified water in the liquid mixing tank, set the mixing speed to 60-80 rpm, slowly add the prescription amount of polyethylene glycol 400, and stir while adding PEG 400. Stir, spare;

2. After stirring for 20 minutes, dexmedetomidine hydrochloride, ketamine hydrochloride, glycerin, sodium chloride, disodium edetate, benzyl alcohol were added in sequence, and purified water was added until the volume of the solution was 8 L, and stirring was continued to dissolve. spare;

3. Under stirring, add sodium bicarbonate to adjust the pH of the solution to 5.0-7.0, add purified water to make the volume of the solution 10L, then filter with 0.22 micron microporous membrane and transfer to the appropriate ultrasonic function. In the container, set the ultrasonic frequency to 50KHZ, ultrasonic for 10 to 20 minutes, perform degassing treatment, and reserve;

4. After passing the intermediate product inspection, fill it into the sterilized spray bottle and add the bottle cap with the spray metering pump.

More preferably, the sedative drug provided by the present invention is administered in an amount of 1.1 mg/kg per time.

The invention has the following beneficial effects:

The pharmaceutical composition of the invention has synergistic effect, especially for sedation before child examination, and the effect is particularly prominent, so that the child can complete various examinations safely and effectively; the sedation success rate is as high as 96% or more, and the medicine has quick onset and wake up. At the same time, the side effects are small, no obvious adverse reactions, heart rate, blood pressure, etc. are normal, there is no awakening during the recovery period, and the safety is high.

DRAWINGS

Figure 1: HE staining micrograph of rat brain tissue; 1: control group CA1; 2: control group CA3; 3: experimental group CA1; 4: experimental group CA3.

Figure 2: Nissl staining micrograph of rat brain tissue; 1: control group CA1; 2: control group CA3; 3: experimental group CA1; 4: experimental group CA3.

detailed description

The present invention is specifically described by the following examples, and the following examples are intended to be illustrative of the present invention, and are not to be construed as limiting the scope of the present invention. The content makes some non-essential improvements and adjustments to the invention.

Example 1

A sedative drug comprising dexmedetomidine hydrochloride and ketamine hydrochloride and a pharmaceutically acceptable adjuvant, which is prepared as a nasal spray, and is prepared as follows:

Prescription composition:

1. Take 2L of purified water in HJBJ 1.5B.0 high-speed stirring liquid tank (equipment manufacturer: Shanghai Huiwei Electromechanical Equipment Co., Ltd.), set the mixing speed to 60-80 rev / min, slowly add the prescription amount of poly The diol 400 is stirred while being added, and after the addition of the polyethylene glycol 400 is completed, stirring is continued, and the solution is set aside;

2. After stirring for 20 minutes, dexmedetomidine hydrochloride, ketamine hydrochloride, glycerin, sodium chloride, disodium edetate, benzyl alcohol were added in sequence, and purified water was added until the volume of the solution was 8 L, and stirring was continued to dissolve. ,spare;

3. Under stirring, add sodium bicarbonate to adjust the pH of the solution to 5.0-7.0. The pH meter used is the Phs-3c acidity meter (equipment manufacturer: Shanghai Lei Magnetic Instrument Factory), and the remaining purified water is used after 0.22 micron. The microporous membrane is filtered and transferred to the EX-TE-30 multi-function extraction tank (equipment manufacturer: Shanghai Shunyi Experimental Equipment Co., Ltd.), and the ultrasonic frequency is set to 50KHZ, ultrasonic for 10 to 20 minutes, and degassing treatment is performed. spare;

4. After passing the intermediate product inspection, fill it with a YMGXS spray filling and capping machine into the sterilized spray bottle (equipment manufacturer: Shanghai Yiman Packaging Machinery Co., Ltd.), and add a cap with a spray metering pump. , labeling, packaging is available.

Example 2

A sedative drug comprising dexmedetomidine hydrochloride and ketamine hydrochloride and a pharmaceutically acceptable excipient, which is prepared by the following steps:

ingredient	Dosage (parts by weight)
Dexmedetomidine hydrochloride	0.005 parts
Ketamine hydrochloride	0.5 parts
Mannitol	3.7 copies
Sodium chloride	1.1 copies
Sterilized water for injection	Add to 2000ml

Preparation process:

1. Concentration: Add the above raw materials to HJBJ 1.5B.0 high-speed stirring liquid tank (equipment manufacturer: Shanghai Huiwei Electromechanical Equipment Co., Ltd.), then add 1/3 of the prescribed amount of sterile water for injection, stir and dissolve , rich in dosing;

2. Rare: take concentrated solution, add 0.1mol / L sodium bicarbonate solution, adjust the pH to 6.5 ~ 7.0, the pH meter used is Phs-3c acidity meter (equipment manufacturer: Shanghai Lei Magnetic Instrument Factory), stirring, Mix well, filter with 0.8μm filter, add activated carbon with a total volume of 0.1% to 0.3% by mass, adsorb decolorize, filter with 0.45μm filter, collect filtrate, add sterile water for injection to the prescription amount, After passing the intermediate product inspection, it can be;

3. Potting: After passing the intermediate test, filter with 0.22μm filter to check visible foreign matter. After the bacterial endotoxin is qualified, use ALG-2 double-needle ampoule drawing and sealing machine (equipment manufacturer: Jishou Zhongcheng Pharmaceutical Machinery Factory) ) Filled into 2ml / support, sealed;

4. Sterilization: The filled Ampere semi-finished product is sent to the LDZM-80KCS high-pressure steam sterilization pot (equipment manufacturer: Shanghai Rongyan Instrument Co., Ltd.) for sterilization for 15 minutes at 121 °C, and the leak is checked according to the specified conditions;

5. Inspection: The foreign matter will be inspected after the sterilization, and the qualified samples will be outsourced, fully inspected, and stored in the warehouse.

Example 3

A sedative drug comprising dexmedetomidine hydrochloride and ketamine hydrochloride and a pharmaceutically acceptable adjuvant, which are prepared into tablets, which are obtained by the following steps:

Preparation process:

1. dexmedetomidine hydrochloride, ketamine hydrochloride, magnesium stearate, magnesium lauryl sulfate, carboxymethyl lake

Powdered sodium and starch are separately used WF-20B universal crusher (equipment manufacturer: Jiangyin Fuzhong Machinery Co., Ltd.

Division) crushed, passed through 80 mesh sieve, spare;

2. Mix dexmedetomidine hydrochloride, ketamine hydrochloride, magnesium lauryl sulfate, sodium carboxymethyl starch and starch in SYH-5 three-dimensional motion mixer (equipment manufacturer: Changzhou Guangbo Drying Equipment Co., Ltd.) , take out, put in a stainless steel tray, add 20% ethanol solution to make soft materials;

3. Take the above-mentioned soft material into WK-60 swing granulator (equipment manufacturer: Weifang North Pharmaceutical Equipment Manufacturing Co., Ltd.), granulate with 18 mesh sieve, and place the prepared granules on LON-5R- 7CRXH-0 hot air circulation oven (equipment manufacturer: Nanjing Longwu Machinery Co., Ltd.), set temperature 60 ° C, dry to granule moisture ≤ 3%, 18 mesh sieve whole grain;

4. Take the above granules, add magnesium stearate, and place it in a WK-60 swing granulator (equipment manufacturer: Weifang North Pharmaceutical Equipment Manufacturing Co., Ltd.) to mix evenly;

5. Tableting: Adjust the TP-1.5T single punching machine (equipment manufacturer: Changzhou Wangqun Pharmaceutical Machinery Co., Ltd.), press the tablet, set the film to 0.3g/piece, pay attention to control the loading;

6. Packaging is available.

Example 4 Sedation experiment

Experimental method: effects on spontaneous activity of mice: 30 mice, weighing 22-25 g, male and female, were randomly divided into 3 groups, namely the drug combination injection prepared in Example 2 (Specification: dexamethasone hydrochloride) Midea 0.1mg/ml, Ketamine hydrochloride 0.05g/ml, administered at 0.1ml/10g), dexmedetomidine hydrochloride injection (Specification: 2ml: 0.2mg, administered at 0.1ml/10g, source: Jiangsu Heng Rui Pharmaceutical Co., Ltd.), ketamine hydrochloride injection (specification: 2ml / 0.1g, administered dose of 0.1ml / 10g, source: Jiangsu Hengrui Pharmaceutical Co., Ltd.). Each experimental mouse was orally administered with the corresponding drug. Before the administration, the mice in each group were placed in a transparent small box, first adapted for 2 minutes, and then began to observe and record the walking and other activities of each group of mice. The number of cases was recorded for 10 minutes, and the number of activities before administration was obtained. Then, after administration according to the relevant dose, the mice were again placed in a transparent small box, and the same condition was first adapted for 2 minutes, and then each group of mice was observed and recorded. The number of walking and other activities, recorded for 10 minutes, calculate the spontaneous activity inhibition rate of each mouse, the formula is as follows:

Spontaneous activity inhibition rate = 100% × (number of spontaneous activities of mice before administration - number of spontaneous activities of mice after administration) / number of spontaneous activities of mice before administration

Effectiveness = 100% × effective inhibition of the number of mice / total number of mice

Note: The inhibition rate ≥ 50% is considered as effective inhibition.

At the same time, heart rate and blood pressure should be monitored during the experiment, and the phenomenon of agitation during the recovery period should be observed.

The test results are shown in the table below:

The experimental results show that the inhibition rate and the effective rate of the pharmaceutical composition of the present invention are significantly higher than those of the control group. Heart rate, blood pressure and recovery period The pharmaceutical composition of the present invention is superior to the control group.

Example 5 Neurotoxicity experiment

experimental method:

I. Experimental animals and grouping

Thirty mice, weighing 22-25 g, half male and half female, were randomly divided into two groups (n=10): control (N) group and experiment (D) group.

2. Mode of administration and dosage

In the experiment (D) group, a mixture of dexmedetomidine hydrochloride (0.1 ml/10 g) and ketamine hydrochloride (0.1 ml/10 g) was intranasally instilled. In the control (N) group, the same volume of physiological saline was intranasally instilled.

3. Collection and processing of specimens

On the next day, the newborn rats were perfused with 4% PFA, and then the rats were decapitated and the brain tissue of the newborn rats was quickly separated. The brain tissue was removed and perfused with 4% PFA. After dehydration and paraffin embedding, paraffin sections were prepared. For HE staining and Nissl staining.

4. Pathological observation of brain tissue

HE staining

The paraffin section was dewaxed by xylene, and the gradient (100%, 95%, 80%, 70%) was hydrated with alcohol. After rinsing with distilled water, it was stained with hematoxylin for 10 min, washed with tap water for 1 min, and separated by 1% hydrochloric acid ethanol solution. The blue liquid returned to blue, rinsed with water, stained with 0.5% eosin alcohol for 1 min, dehydrated with ascending gradient alcohol (80%, 95%, 100%), transparent with xylene, and observed under the light microscope of neutral gum seal. Take photos with the CA3 area.

2. Nissl staining

Paraffin sections were deparaffinized by xylene, preheated at 57 ° C for 1% toluidine blue for 60 min, washed with ddH 2 O for 3 times, differentiated with 95% ethanol, decolorized, and mirrored until the background was clear. Dehydrated ethanol and xylene were transparent. The CA1 and CA3 regions of the hippocampus of the rat brain were observed under a light microscope with a neutral gum seal and photographed.

Experimental results: HE staining is shown in Figure 1. Nissl staining is shown in Figure 2;

Conclusion: It can be seen from the results that the experimental group has no neurotoxic effect.

Claims (8)

1. A pharmaceutical composition comprising a pharmaceutically active ingredient consisting of dexmedetomidine hydrochloride and ketamine hydrochloride.
2. The pharmaceutical composition according to claim 1, wherein the mass ratio of dexmedetomidine hydrochloride to ketamine hydrochloride is from 1 to 5:500 to 3,000.
3. The pharmaceutical composition according to claim 1, wherein the mass ratio of dexmedetomidine hydrochloride to ketamine hydrochloride is 2:1000.
4. A pharmaceutical composition according to claim 1, 2 or 3, wherein the pharmaceutical composition is used in the preparation of a sedative.
5. A pharmaceutical composition according to Claim 1, 2 or 3, which comprises said pharmaceutical composition and a pharmaceutically acceptable adjuvant.
6. A pharmaceutical composition according to claim 5, wherein the pharmaceutical composition is an aerosol, a nasal spray, a powder, a sublingual tablet, an injection, an oral solution, an oral tablet or a capsule. Agent.
7. A pharmaceutical composition according to claim 6, wherein the nasal spray comprises the following raw materials in a weight ratio: 0.002 to 0.01 parts of dexmedetomidine hydrochloride, 1 to 5 parts of ketamine hydrochloride, and poly The ethylene glycol 400 is 0.01 to 0.05 parts, the sodium chloride is 0.1 to 1.5 parts, the disodium edetate is 0.03 to 0.16 parts, the benzyl alcohol is 0.3 to 0.9 parts, the glycerin is 0.02 to 0.18 parts, and the sodium hydrogencarbonate is 0.01 to 3.9 parts.
8. A method for preparing a nasal spray, characterized in that it is carried out as follows:

   A. Take 2L of purified water in the liquid mixing tank, set the mixing speed to 60-80 rev / min, slowly add the prescription amount of polyethylene glycol 400, while stirring, after the polyethylene glycol 400 is added, continue Stir, spare;

   B. After stirring for 20 minutes, dexmedetomidine hydrochloride, ketamine hydrochloride, glycerin, sodium chloride, disodium edetate, and benzyl alcohol were sequentially added, and purified water was added until the volume of the solution was 8 L, and stirring was continued to dissolve. spare;

   C. Under stirring, add sodium bicarbonate to adjust the pH of the solution to 5.0-7.0, add purified water to make the volume of the solution 10L, then filter it with a 0.22 micron microporous membrane and transfer it to a suitable container with ultrasonic function. Set the ultrasonic frequency to 50KHZ, ultrasonic for 10 to 20 minutes, perform degassing treatment, and reserve;

   D. After passing the intermediate product inspection, fill it into the sterilized spray bottle and add the bottle cap with the spray metering pump.

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