CN118903008B - A kind of amitriptyline spray and its preparation method and application - Google Patents
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Abstract
The invention relates to amitriptyline spray and a preparation method and application thereof, and belongs to the technical field of medicines. The amitriptyline spray takes water as a solvent, and comprises the following components of 30-100 g/L amitriptyline hydrochloride, 0.5-4 g/L disodium ethylenediamine tetraacetate, 40-60 mL/L dimethyl sulfoxide and 5-15 mL/L ethylparaben solution. The amitriptyline spray prepared by the invention can relieve and treat neuropathic pain, and has the advantages of stable property, good skin absorbability, high pain relieving speed, high pain relieving strength, lasting pain relieving effect, no toxic or side effect and convenient use.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to amitriptyline spray and a preparation method and application thereof.
Background
Neuropathic pain (neuropathicpain, NP) is a chronic pain caused by primary injury, dysfunction or various diseases of the somatic nervous system, the causes of which mainly include diabetic neuropathy, drug-induced neuropathy, traumatic nerve injury, shingles, adverse reactions of cancer chemotherapeutics, etc., and can be classified into central neuropathic pain and peripheral neuropathic pain according to the initial onset site, clinically manifested as spontaneous burning pain, tingling sensation, and with induced pain, and is usually manifested as sustained and repeated attacks when light touch or cold, and is a common symptom of somatic nervous system diseases.
At present, the treatment of NP is still troublesome clinically, the pain symptoms can not be controlled in a short time by the existing treatment means, the repeated attack of NP can not be improved, and the existing treatment medicaments also have the defects of low pain relieving strength, poor treatment effect, more side effects and the like, so that the clinical prevention and treatment of NP are extremely challenging. Amitriptyline in tricyclic antidepressants (TRICYCLIC ANTIDEPRESSANT, TCA) is useful in the treatment of diabetic peripheral neuropathy, postherpetic neuralgia, and neuropathic pain following central stroke, by blocking reuptake between serotonin and norepinephrine neurotransmitters. However, it has been found that oral administration of amitriptyline produces a central effect, resulting in the occurrence of numerous adverse drug events (adverse drug event, ADE) such as severe chest pain, accelerated heartbeat, syncope, abnormal bleeding, disturbance of consciousness, delirium, auditory hallucination, visual hallucination, and the like, and even an anticholinergic response, postural hypotension, and toxic liver damage.
No amitriptyline preparation capable of stably and effectively relieving and/or treating neuropathic pain and low in toxic and side effects exists in the prior art.
Disclosure of Invention
The invention aims to provide amitriptyline spray and a preparation method and application thereof, and aims to solve the problems of low pain relieving strength, poor treatment effect and more side effects in the process of treating neuropathic pain in the prior art.
In order to achieve the above object, the present invention provides the following technical solutions:
The invention provides an amitriptyline spray which takes water as a solvent and comprises the following components of 30-100 g/L amitriptyline hydrochloride, 0.5-4 g/L disodium ethylenediamine tetraacetate, 40-60 mL/L dimethyl sulfoxide and 5-15 mL/L ethylparaben solution.
Preferably, the amitriptyline spray takes water as a solvent, and comprises the following components of 40-60 g/L amitriptyline hydrochloride, 1-3 g/L disodium ethylenediamine tetraacetate, 45-55 mL/L dimethyl sulfoxide and 8-12 mL/L ethylparaben solution.
Preferably, the amitriptyline spray takes water as a solvent and comprises the following components of 50g/L amitriptyline hydrochloride, 2g/L disodium ethylenediamine tetraacetate, 50mL/L dimethyl sulfoxide and 10mL/L ethylparaben solution.
Preferably, the ethyl hydroxybenzoate solution takes absolute ethyl alcohol as a solvent and comprises the following components in concentration of 30-60 g/L of ethyl hydroxybenzoate and 300-600 mL/L of glycerol.
Preferably, the amitriptyline spray comprises one of amitriptyline water spray, amitriptyline Lin You spray and amitriptyline gel spray.
The invention also provides a preparation method of the amitriptyline spray, which comprises the following steps of mixing and dissolving amitriptyline hydrochloride, disodium ethylenediamine tetraacetate, dimethyl sulfoxide, ethylparaben solution and water to obtain the amitriptyline spray.
The invention also provides application of the amitriptyline spray in preparation of medicines for relieving and/or treating neuropathic pain.
The invention has the following technical effects and advantages:
The amitriptyline spray prepared by the invention can relieve and treat neuropathic pain, has the advantages of stable property, good skin absorbability, high pain relieving speed, high pain relieving strength, lasting pain relieving effect, convenient use and the like, and has no obvious stain left. Animal experiments show that the amitriptyline spray provided by the invention has effects within 10 minutes after spraying, the analgesic time can last for 3-4 hours, long-term administration is beneficial to promoting the repair of injured nerves, and all model mice have no common side effects after amitriptyline administration.
Drawings
FIG. 1 is an amitriptyline hydrochloride standard curve;
FIG. 2 is a liquid chromatogram of a control and a test, wherein A is a liquid chromatogram of the control and B is a liquid chromatogram of the test;
FIG. 3 is a diagram of a mouse model of neuropathic pain, wherein the left diagram is a schematic diagram of the mouse model of neuropathic pain, and the right diagram is a real photograph of the mouse model of neuropathic pain;
FIG. 4 is a mechanical pain threshold measurement of mice;
FIG. 5 shows the results of a cold pain response assay in mice;
FIG. 6 shows the results of a thermal pain response assay in mice;
Fig. 7 is a schematic diagram of a measurement part of the motor nerve conduction velocity of a mouse, in which S 1 is a stimulation electrode at a ischium notch of the mouse, S 2(R1) is a stimulation electrode at an ankle joint of the mouse or a double needle recording electrode at an ankle joint of the mouse, R 2 is a double needle recording electrode at a first inter-bone muscle of a toe of the mouse, and E is a reference electrode.
FIG. 8 shows the results of measuring the motor nerve conduction velocity in mice.
Detailed Description
The invention provides an amitriptyline spray which takes water as a solvent and comprises the following components of 30-100 g/L, preferably 40-60 g/L, more preferably 50g/L of amitriptyline hydrochloride, 0.5-4 g/L, preferably 1-3 g/L, more preferably 2g/L of disodium ethylenediamine tetraacetate, 40-60 mL/L, preferably 45-55 mL/L, more preferably 50mL/L of dimethyl sulfoxide, 5-15 mL/L, preferably 8-12 mL/L, and more preferably 10mL/L of ethylparaben solution.
In the invention, the ethyl hydroxybenzoate solution takes absolute ethyl alcohol as a solvent and comprises the following components in concentration of 30-60 g/L, preferably 50g/L, and 300-600 mL/L, preferably 500mL/L, of glycerin.
In the invention, the amitriptyline spray comprises one of amitriptyline water spray, amitriptyline Lin You spray and amitriptyline gel spray.
The invention also provides a preparation method of the amitriptyline spray, which comprises the following steps of mixing and dissolving amitriptyline hydrochloride, disodium ethylenediamine tetraacetate, dimethyl sulfoxide, ethylparaben solution and water to obtain the amitriptyline spray.
The preparation method comprises the following steps of sequentially adding amitriptyline hydrochloride, disodium ethylenediamine tetraacetate, dimethyl sulfoxide and ethylparaben solution into water, dissolving and uniformly mixing to obtain the amitriptyline spray.
The invention also provides application of the amitriptyline spray in preparation of medicines for relieving and/or treating neuropathic pain.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
The tested mice are C57BL/6J mice, the week-old mice are 6-8 weeks, the weight of the mice is 20-25 g, and the mice are purchased from Liaoning long biotechnology Co Ltd;
In the experimental equipment of the present invention, the Ugo basic cold/hot combination board was purchased from shanghai pure biotechnology limited.
EXAMPLE 1 preparation of amitriptyline spray
(1) Dissolving 50g of ethylparaben in a proper amount of absolute ethyl alcohol, adding 500mL of glycerol, uniformly mixing, and then using absolute ethyl alcohol to fix the volume to 1000mL to obtain a ethylparaben solution with the mass concentration of 5%;
(2) Dissolving 50g of amitriptyline hydrochloride in a proper amount of pure water to obtain amitriptyline hydrochloride solution;
(3) Sequentially adding 2g of disodium ethylenediamine tetraacetate, 50mL of dimethyl sulfoxide and 10mL of 5% mass concentration ethyl hydroxybenzoate solution into amitriptyline hydrochloride solution, completely dissolving and uniformly mixing, then fixing the volume to 1000mL by using pure water, and bottling to obtain amitriptyline spray.
EXAMPLE 2 preparation of amitriptyline spray
(1) Dissolving 60g of ethylparaben in a proper amount of absolute ethyl alcohol, adding 600mL of glycerol, uniformly mixing, and then using absolute ethyl alcohol to fix the volume to 1000mL to obtain a ethylparaben solution with the mass concentration of 6%;
(2) Dissolving 30g of amitriptyline hydrochloride in a proper amount of pure water to obtain amitriptyline hydrochloride solution;
(3) Sequentially adding 0.5g of disodium ethylenediamine tetraacetate, 60mL of dimethyl sulfoxide and 5mL of 6% mass concentration ethyl hydroxybenzoate solution into amitriptyline hydrochloride solution, completely dissolving and uniformly mixing, then fixing the volume to 1000mL by using pure water, and bottling to obtain amitriptyline spray.
EXAMPLE 3 preparation of amitriptyline spray
(1) Dissolving 30g of ethylparaben in a proper amount of absolute ethyl alcohol, adding 300mL of glycerol, uniformly mixing, and then using absolute ethyl alcohol to fix the volume to 1000mL to obtain a ethylparaben solution with the mass concentration of 3%;
(2) Dissolving 70g of amitriptyline hydrochloride in a proper amount of pure water to obtain amitriptyline hydrochloride solution;
(3) Sequentially adding 4g of disodium ethylenediamine tetraacetate, 40mL of dimethyl sulfoxide and 15mL of 3% mass concentration ethyl hydroxybenzoate solution into amitriptyline hydrochloride solution, completely dissolving and uniformly mixing, then fixing the volume to 1000mL by using pure water, and bottling to obtain amitriptyline spray.
EXAMPLE 4 preparation of amitriptyline spray
(1) Dissolving 50g of ethylparaben in a proper amount of absolute ethyl alcohol, adding 500mL of glycerol, uniformly mixing, and then using absolute ethyl alcohol to fix the volume to 1000mL to obtain a ethylparaben solution with the mass concentration of 5%;
(2) Dissolving 40g of amitriptyline hydrochloride in a proper amount of pure water to obtain amitriptyline hydrochloride solution;
(3) Sequentially adding 1g of disodium ethylenediamine tetraacetate, 55mL of dimethyl sulfoxide and 8mL of 5% mass concentration ethyl hydroxybenzoate solution into amitriptyline hydrochloride solution, completely dissolving and uniformly mixing, then fixing the volume to 1000mL by using pure water, and bottling to obtain amitriptyline spray.
EXAMPLE 5 preparation of amitriptyline spray
(1) Dissolving 50g of ethylparaben in a proper amount of absolute ethyl alcohol, adding 500mL of glycerol, uniformly mixing, and then using absolute ethyl alcohol to fix the volume to 1000mL to obtain a ethylparaben solution with the mass concentration of 5%;
(2) Dissolving 60g of amitriptyline hydrochloride in a proper amount of pure water to obtain amitriptyline hydrochloride solution;
(3) And sequentially adding 3g of disodium ethylenediamine tetraacetate, 45mL of dimethyl sulfoxide and 12mL of 5% mass concentration ethyl hydroxybenzoate solution into the amitriptyline hydrochloride solution, completely dissolving and uniformly mixing, then fixing the volume to 1000mL by using pure water, and bottling to obtain the amitriptyline spray.
Comparative example 1 preparation of amitriptyline spray adjuvant
(1) Dissolving 50g of ethylparaben in a proper amount of absolute ethyl alcohol, adding 500mL of glycerol, uniformly mixing, and then using absolute ethyl alcohol to fix the volume to 1000mL to obtain a ethylparaben solution with the mass concentration of 5%;
(2) 2g of disodium ethylenediamine tetraacetate, 50mL of dimethyl sulfoxide and 10mL of 5% mass concentration ethyl hydroxybenzoate solution are subjected to constant volume to 1000mL by pure water, and the mixture is bottled after uniform mixing, so as to obtain the amitriptyline spray adjuvant.
Experimental example 1 determination of the content of active ingredient of amitriptyline spray
(1) Solution preparation:
preparing a methanol-water-triethylamine solution, namely mixing 60mL of methanol, 0.3mL of triethylamine and 40mL of water, and regulating the pH to 3.1 by phosphoric acid to obtain the methanol-water-triethylamine solution;
Preparing a test product, namely taking 1mL of amitriptyline spray prepared in the embodiment 1, adding a methanol-water-triethylamine solution to a constant volume of 50mL to obtain a test product stock solution, and taking 1mL of the test product stock solution, and adding the methanol-water-triethylamine solution to a constant volume of 50mL to obtain the test product;
Preparing a reference substance, namely mixing 10mg of amitriptyline hydrochloride standard substance with methanol, performing ultrasonic dissolution for 10min, adding the methanol to a volume of 25mL to obtain a reference substance stock solution, and adding 1mL of the reference substance stock solution into a methanol-water-triethylamine solution to a volume of 10mL to obtain the reference substance;
(2) Drawing an amitriptyline hydrochloride standard curve, namely respectively diluting the control stock solution prepared in the step (1) to control gradient solutions with the concentration of 0.816mg/mL, 1.631mg/mL, 3.263mg/mL, 6.525mg/mL, 13.050mg/mL and 26.100mg/mL by using a methanol-water-triethylamine solution, carrying out liquid chromatography detection on the control gradient solutions with the concentrations, wherein the liquid chromatography condition is that octadecylsilane bonded silica gel is used as a filler, the methanol-water-triethylamine solution prepared in the step (1) is used as a mobile phase of the liquid chromatography, the liquid chromatography wavelength is 240nm, the sample injection volume is 2 mu L, calculating the peak area of the control gradient solutions with the concentrations according to an external standard method, and drawing the amitriptyline hydrochloride standard curve, wherein the result is shown in figure 1;
(3) And (3) measuring the amitriptyline hydrochloride content in the amitriptyline spray, namely adopting the liquid chromatography condition in the step (2) to carry out liquid chromatography detection on the test sample and the control sample prepared in the step (1), and calculating the peak area and the amitriptyline hydrochloride content according to an external standard method, wherein the result is shown in figure 2.
The result shows that the regression equation of the amitriptyline hydrochloride standard curve is y= 3.0755x-0.3957 (R 2 =0.9999), the linear regression relation is adopted, the linear range is 0.816-26.100 mg/mL, and according to the calculation result, the amitriptyline hydrochloride content in the amitriptyline hydrochloride spray is 5.0157%.
Experimental example 2 modeling and administration of mice
(1) The method comprises the steps of molding, namely selecting 28 adult male C57BL/6J mice to be divided into 4 groups, namely an experiment group A, an experiment group B, a control group and a blank group, wherein 7 mice are respectively used, injecting 50mg/kg of pentobarbital sodium into the experiment group A, the experiment group B and the control group mice by an intraperitoneal injection method, then placing the mice in a prone position, cleaning superficial mouse hairs near the right femur of the mice, disinfecting by iodophors, exposing subcutaneous muscles by longitudinally cutting an incision of 8mm in the rear middle of the right femur, blunt-separating the muscles by using hemostats to expose sciatic nerves, loosely ligating four chromium intestines around the sciatic nerves, and spacing the chromium intestines by 1mm to obtain a neuropathic pain model (CCI model), wherein the blank group mice are not subjected to sciatic nerve ligation treatment, as shown in figure 3. The CCI model is mainly characterized in that the ischial nerve is damaged to a certain extent by moderately ligating the ischial nerve, further the remote nerve fiber is affected, and the mechanical compression of the chromium intestine to the nerve forms chronic inflammatory response, so that the characteristics of neuropathic pain and inflammatory pain are simulated, and meanwhile, the chronic inflammatory response is accompanied by endoneurial edema, focal ischemia and axonal degeneration. Returning the sciatic nerve to position after the operation is finished, arranging muscles and suturing the wound;
(2) Dosing the amitriptyline spray of example 1 was sprayed 3 times per day, 4 sprays (1.5 mL) each time, for 2 weeks near the right femur of mice of experimental group a and experimental group B, wherein the amitriptyline spray was sprayed once more 0.5h before the behavioral and nerve conduction index measurements were performed on mice of experimental group a and mice of experimental group B, the amitriptyline spray adjuvant of comparative example 1 was sprayed near the right femur of mice of control group, 3 times per day, 4 sprays (1.5 mL) each time, for 2 weeks total, and the mice of the blank group were not dosed.
Experimental example 3 determination of the behavioral index of mice
(1) The mechanical pain threshold measurement of mice, namely, before molding, molding and dosing of each group of mice in experimental example 2, placing each group of mice in a metallic mesh-bottomed organic glass cage (10 multiplied by 10 cm), measuring the mechanical pain threshold of each group of mice by using a 37450 type Ugo basile claw tactile tester when the mice are adapted to the environment for 15min and are in a quiet state, specifically, controlling a mechanical needle to vertically stimulate the skin in the midfoot of each group of mice from bottom to top, setting the stimulation force in 20s to gradually rise from 0g to 10g, stopping stimulation and recording the stimulation pressure value when each group of mice has rapid paw withdrawal reaction, measuring 3 times, 5min each time interval, and taking the average value of the 3 times of the stimulation pressure value as the mechanical pain threshold, wherein the result is shown in figure 4;
(2) The cold pain response of the mice is measured by adopting Ugo basic cold/hot combination boards to carry out cold pain response after the administration of the mice in each group of experimental example 2 is finished, specifically, the temperature of the cold board is reduced to 5+/-0.5 ℃, the cold board is isolated from the external environment by using a glass fiber board to keep constant temperature;
(3) The mice thermal pain response measurement, namely, after the end of the administration of each group of mice in experimental example 2, carrying out thermal pain response by adopting a Ugo basic cold/hot combined board, specifically, heating a hot plate to 55+/-0.5 ℃, and isolating the hot plate from the external environment by using a glass fiber board so as to keep constant temperature;
(4) Measurement of motor nerve conduction velocity of Mice (MNCV) after the end of administration of each group of mice in Experimental example 2, pulse stimulation was performed on each group of mice, specifically, stimulation was performed at room temperature of 20.+ -. 0.5 ℃ and at a temperature of 37 ℃ by using a stimulation electrode S 1/S2 at the ischial notch and ankle joint of each group of mice, stimulation and recording was performed at the ankle joint and the first inter-bone muscle of the toe by using a double needle recording electrode R 1/R2, and a reference electrode E was placed between electrode S 1 and electrode S 2/R1 and between electrode S 2/R1 and electrode R 2 at a distance of 1cm from electrode S 2/R1, as shown in FIG. 7; the method comprises the steps of giving single pulse square wave stimulation with wave width of 0.1ms to each group of mice, gradually increasing the stimulation intensity, recording biphasic compound action potential from an electrode R 1/R2, then gradually reducing the stimulation intensity, gradually disappearing the recorded biphasic compound action potential, repeatedly adjusting the stimulation intensity, taking the stimulation intensity when the compound action potential appears or disappears as a stimulation threshold value and recording, taking a 1.5-time stimulation threshold value as the stimulation intensity, taking a potential value between a peak value and a peak valley of the biphasic compound action potential as a wave amplitude value every 2 times of stimulation interval, recording the time from the stimulation beginning to the action potential as the conduction time of an excitation signal, repeatedly measuring for 10 times and calculating an average value, measuring the distance from the stimulation electrode to the recording electrode of each group of mice to the position and the direction of the ischial nerve passing through after the state of enough natural limb and the spinal column of Fang Lazhi, and calculating MNCV, wherein the result is shown in fig. 8;
MNCV the formula MNCV = distance from the stimulating electrode to the recording electrode/conduction time.
The result shows that the amitriptyline spray disclosed by the invention can be sprayed on a neuropathic pain model mouse to improve the symptom of neuropathic pain of the mouse, the pain relieving time can last for 3-4 hours, and no toxic or side effect is caused. It is explained that the amitriptyline spray provided by the invention can rapidly exert analgesic effect when being administered to a neuropathic pain model mouse, and long-term administration is helpful for promoting the repair of injured nerves, and no possible skin injury caused by the amitriptyline spray is found in the administration process, and no related side effects possibly occurring in oral amitriptyline disclosed in the amitriptyline product specification disclosed in the prior art are found.
From the above examples, the present invention provides an amitriptyline spray, and a preparation method and application thereof. The amitriptyline spray prepared by the invention can relieve and treat neuropathic pain, and has the advantages of stable property, good skin absorbability, high pain relieving speed, high pain relieving strength, lasting pain relieving effect, no toxic or side effect and the like.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (6)
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| US4370324A (en) * | 1980-09-17 | 1983-01-25 | Bernstein Joel E | Method and composition for treating and preventing irritation of the eyes |
| US4505909A (en) * | 1980-09-17 | 1985-03-19 | Bernstein Joel E | Method and composition for treating and preventing irritation of the eyes |
| US4788189A (en) * | 1988-02-29 | 1988-11-29 | Glazer Howard I | Method to treat smoking withdrawal symptoms by potentiated central noradrenergic blocking |
| CN103848814A (en) * | 2012-12-06 | 2014-06-11 | 山东亨利医药科技有限责任公司 | Substituted indole ketone derivative as tyrosine kinase inhibitor |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4370324A (en) * | 1980-09-17 | 1983-01-25 | Bernstein Joel E | Method and composition for treating and preventing irritation of the eyes |
| US4505909A (en) * | 1980-09-17 | 1985-03-19 | Bernstein Joel E | Method and composition for treating and preventing irritation of the eyes |
| US4788189A (en) * | 1988-02-29 | 1988-11-29 | Glazer Howard I | Method to treat smoking withdrawal symptoms by potentiated central noradrenergic blocking |
| CN103848814A (en) * | 2012-12-06 | 2014-06-11 | 山东亨利医药科技有限责任公司 | Substituted indole ketone derivative as tyrosine kinase inhibitor |
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