CN112656850B - Veterinary ephedra, apricot kernel, gypsum and licorice sustained-release granules and preparation method thereof - Google Patents

Abstract

The invention discloses veterinary ephedra, apricot kernel, gypsum and licorice sustained-release particles and a preparation method thereof, wherein the particles comprise the following components in parts by weight: 40-60 parts of dry extract powder of ephedra, apricot kernel, gypsum and licorice, 15-25 parts of hydroxypropyl methylcellulose, 5-15 parts of glyceryl behenate and 10-20 parts of glucose; the raw material medicaments of the ephedra, apricot kernel, gypsum and licorice dry extract powder comprise: 500 to 700 portions of ephedra, 1000 to 3300 portions of gypsum, 500 to 700 portions of bitter apricot seed and 300 to 600 portions of liquorice; the preparation method of the veterinary ephedra, apricot kernel, gypsum and licorice sustained-release granules comprises the following steps: extracting semen Armeniacae amarum and Glycyrrhrizae radix with ethanol, mixing the residue with herba Ephedrae and Gypsum Fibrosum, extracting with water, concentrating the filtrate with film evaporator, spray drying, adding the rest materials, mixing, granulating, drying, and mixing. The ephedra, almond, gypsum and licorice granules have obvious slow release characteristic in vitro release, and the flavor and the quality of the product are greatly improved.

Description

Veterinary ephedra, apricot kernel, gypsum and licorice sustained-release granules and preparation method thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to veterinary ephedra, apricot kernel, gypsum and licorice sustained-release granules and a preparation method thereof.

Background

Ma xing Shigan Tang is derived from the Jing Fang in Shang Han Lun (treatise on Cold-induced diseases) written by Sheng Zhang Zhong Jing and comprises herba Ephedrae, semen Armeniacae amarum, gypsum Fibrosum, and Glycyrrhrizae radix. Has the effects of pungent and cool exterior syndrome dispersing, lung heat clearing and asthma relieving, and is clinically used for treating the symptoms of external infection of wind evil and pathogenic heat obstructing the lung. In the case of fighting against the new coronavirus pneumonia (CoVID-19), three famous medicines play an important role, wherein the golden flower influenza clearing granules, the honeysuckle plague clearing capsules/granules, the dampness and toxin eliminating prescriptions, the lung ventilating and toxin eliminating prescriptions and the lung clearing and toxin expelling decoctions are prepared by cutting the Maxingshigan decoction as a basic prescription, and the application and good clinical effects of the Maxingshigan decoction are shown. The veterinary drug Chinese herbal medicine prescription preparation such as the Maxingshigan tablet, the Maxingshigan powder, the Maxingshigan oral liquid, the Maxingshigan injection, the Maxingshigan granule and the like can also be added and modified. The Maxingshigan granules are recorded in the Chinese medicinal rolls of 2017 edition from veterinary drug quality Standard.

The bitter apricot seeds are the essential drug for treating cough and asthma, and the substance basis of the pharmacological actions of relieving cough, relieving asthma, resisting ulcer, enhancing immunity and the like is mainly amygdalin. The intestinal bacteria can hydrolyze amygdalin into phenylethanatonitrile, and then decompose the phenylethanatonitrile into free hydrocyanic acid to inhibit respiratory center, thereby achieving the effects of relieving cough and relieving asthma. However, amygdalin, an enzyme capable of hydrolyzing amygdalin, is contained in amygdalin. Under certain temperature and humidity, the activity of amygdalin is increased, the damage to amygdalin is accelerated, and the content of amygdalin can be influenced by storage environment and cold water feeding. In the prior art, processing methods such as damp heat (such as heating and boiling), dry heat (such as frying), boiling water feeding and the like are usually adopted, but the methods have the problems of complicated process, labor hour consumption and low safety, and amygdalin after processing is lost to a certain extent.

The Glycyrrhrizae radix mainly contains triterpene saponin (such as glycyrrhizic acid and glycyrrhetinic acid), flavone (such as liquiritin and isoliquiritin), and Glycyrrhrizae radix polysaccharide. Modern pharmacological experiments show that glycyrrhizic acid and glycyrrhetinic acid have the effects of resisting inflammation, relieving cough, eliminating phlegm, resisting pathogenic microorganisms and the like, and the glycyrrhiza polysaccharide has the function of immunoregulation.

Gypsum, gypsum Fibrosum, is the essential herb for clearing excess heat in the lung and stomach qi system. Modern pharmacological tests show that pure calcium sulfate has no antipyretic effect, and the antipyretic effect is related to calcium element and possibly trace elements in calcium element. The existing Maxingshigan granule medicine standard (preparation method) specifies that gypsum is decocted first for half an hour, but the gypsum is sulfate mineral and the main component is CaSO ₄ ·2H ₂ O, water solubility is low, so that the influence of the decoction time on the dissolution rate of the effective components is not great.

The herba Ephedrae mainly contains ephedrine, pseudoephedrine, volatile oil, polysaccharide, etc. Ephedrine is first isolated from ephedra in 1887 by the definition of the Japanese parent's well of chemistry, and the definite pharmacological action (similar to and lasting to the action of epinephrine, and the potency of the epinephrine is completely the same as that of a sympathetic stimulant) is discovered by modern pharmacology foundation people in China and professor Chenkehui of international famous pharmacologist, and is still widely applied to clinic at present. In the prior art, ephedra is usually decocted by water or extracted by acid water and an organic solvent, while ephedrine and pseudoephedrine are dissolved in hot water, but have volatility and are easy to lose when being extracted in an unsealed container, and the methods also have the problems of low extraction rate, environmental friendliness and high solvent recovery and treatment cost.

The ephedra, almond, gypsum and licorice common particles are clinically treated for several days when preventing and treating respiratory diseases (such as infectious bronchitis of chicken, mycoplasma pneumonia of swine and the like), and the administration frequency is frequent. Puerarin Schk (GSK) applied for the market of pseudoephedrine hydrochloride sustained-release capsules in 1982, most of the currently marketed pseudoephedrine-containing sustained-release preparations are compound pseudoephedrine hydrochloride sustained-release capsules, such as Bayer (BAYER) naproxen sodium pseudoephedrine sustained-release tablets and domestic Messangjin Schk pharmaceutical Limited compound pseudoephedrine hydrochloride sustained-release capsules.

Therefore, the development of the ephedra, almond and licorice granules which can maintain steady blood concentration, reduce the administration frequency, improve the transfer rate of active ingredients of the medicament and increase the animal administration compliance is urgently needed.

Disclosure of Invention

The invention mainly solves the technical problem of providing the veterinary ephedra, almond, gypsum and licorice sustained-release particles and the preparation method thereof, the sustained-release particles have obvious sustained-release characteristic in vitro release, the transfer rate of active ingredients is high, the flavor and the quality are greatly improved, and the compliance of animal medication is increased.

In order to solve the above problems, the present invention adopts a technical solution that:

the veterinary ephedra, apricot kernel, gypsum and licorice sustained-release granules comprise the following components in parts by weight:

40-60 parts of dry extract powder of ephedra, apricot kernel, gypsum and licorice, 15-25 parts of hydroxypropyl methylcellulose, 5-15 parts of glyceryl behenate and 10-20 parts of glucose;

the bulk drugs of the dry extract powder of ephedra, apricot kernel, gypsum and licorice comprise: 500 to 700 portions of ephedra, 1000 to 3300 portions of gypsum, 500 to 700 portions of bitter apricot seed and 300 to 600 portions of liquorice.

The usage of the components of the bulk drug of the ephedra, almond and gypsum dry extract powder is limited, and the usage of the components in the bulk drug of the ephedra, almond and gypsum dry extract powder is only expressed, and is irrelevant to the usage of the ephedra, almond and gypsum dry extract powder in the veterinary ephedra, almond and gypsum slow-release particles.

The inventor surprisingly finds that the hydroxypropyl methylcellulose, the glyceryl behenate and other components are matched, so that the sustained-release particle disclosed by the invention has an obvious sustained-release characteristic in vitro release.

In a specific embodiment of the invention, the components of the veterinary ephedra, apricot kernel, gypsum and licorice sustained-release granules comprise the following components in parts by weight: 45-55 parts of dry extract powder of ephedra, apricot kernel, gypsum and licorice, 20-25 parts of hydroxypropyl methylcellulose, 10-15 parts of glyceryl behenate and 15-20 parts of glucose; preferably, the following components are used: 50 parts of ephedra, almond, gypsum and licorice dry extract powder, 25 parts of hydroxypropyl methylcellulose, 10 parts of glyceryl behenate and 15 parts of glucose;

further, the bulk drugs of the dry extract powder of ephedra, apricot kernel, gypsum and licorice comprise: 600 to 700 portions of ephedra, 1300 to 3300 portions of gypsum, 500 to 600 portions of bitter apricot kernel and 400 to 600 portions of liquorice; preferably, the method comprises the following steps: 650 parts of ephedra, 3100 parts of gypsum, 600 parts of bitter apricot seed and 520 parts of liquorice.

The components of the veterinary ephedra, apricot kernel, gypsum and licorice sustained-release granules also comprise 2-30 parts of flavoring agent and/or 6-60 parts of sour agent; preferably 2 to 15 parts of flavoring agent and/or 10 to 30 parts of sour agent, more preferably 7 parts of flavoring agent and/or 18 parts of sour agent;

further, the flavoring agent is edible essence, preferably fresh milk essence;

further, the sour agent is fumaric acid.

The common granules in the market have poor mouthfeel, and the proper amount of the sour agent and the flavoring agent are added, so that the flavor and the quality of the sustained-release granules are greatly improved, and the compliance of animal medication can be increased after the sustained-release granules are matched with other components for synergistic interaction.

The invention also provides a preparation method of the particle, which comprises the following steps:

(1) Extracting semen Armeniacae amarum and Glycyrrhrizae radix with alcohol or alcohol water solution, performing solid-liquid separation, and concentrating the extractive solution to obtain ethanol extractive solution;

(2) Extracting the dregs after the alcohol extraction in the step (1), ephedra and gypsum by water, carrying out solid-liquid separation, and concentrating the extracting solution to obtain a water extraction concentrated solution;

(3) Uniformly mixing the ethanol extract concentrate and the water extract concentrate, and then performing spray drying to obtain dry extract powder of the ephedra, apricot kernel, gypsum and licorice;

(4) Mixing the dry extract powder with the rest raw materials, and granulating.

In the specific embodiment of the invention, the ephedra is prepared by freezing and crushing ephedra medicinal materials; further, the conditions of freezing in the freezing pulverization are as follows: freezing at-25 deg.c to-40 deg.c for 10-30 min, preferably at-30 deg.c to-35 deg.c for 15-25 min.

In a specific embodiment of the present invention, the average particle size of the ephedra is 150 to 250 μm, preferably 170 to 190 μm;

the average grain diameter of the bitter almond and the liquorice is 300 to 900 mu m, preferably 820 to 880 mu m

The particle size D (v, 0.9) of the gypsum is less than or equal to 15um, and further less than or equal to 10um.

The gypsum is crushed by adopting airflow crushing.

The invention adopts the freezing and crushing technology to process the ephedra herb to increase the brittleness of the medicinal materials, and the inventor finds that the ephedra herb can retain volatile components after being frozen and crushed; furthermore, when the particle sizes of the ephedra herb, the bitter apricot seed and the liquorice are in the range limited by the invention, the transfer rate of the effective components of the medicine can be improved; the gypsum is pulverized by airflow pulverization, so that the dissolution of effective components such as calcium ions, trace elements and the like can be increased, and the operation process of 'decocting firstly' is omitted by directly feeding the gypsum powder.

The gypsum is crushed by adopting airflow crushing.

In a specific embodiment of the invention, the extraction mode in the step (1) is heating reflux extraction; further, the extraction time in the step (1) is 1-5 h, preferably 2h; further, the extraction times in the step (1) are 1 to 3 times, and preferably 2 times;

further, soaking the bitter apricot seeds and the liquorice in an extraction solvent before heating reflux extraction; furthermore, the time for soaking the bitter apricot seeds and the liquorice is 0.5 to 2 hours, and the optimal time is 1 hour.

The extraction time of the invention is the time of single extraction.

In a specific embodiment of the present invention, in the step (1), the alcohol is selected from one or more of ethanol, propylene glycol, glycerol, isopropanol and n-butanol, preferably ethanol; further, the extraction solvent in the step (1) is selected from an aqueous alcohol solution, wherein the volume fraction of the alcohol in the aqueous alcohol solution is 50-70%, and preferably 60%; further, the mass ratio of the extraction solvent to the mixture of bitter apricot seed and liquorice is 6-12: 1, preferably 8 to 10.

In a specific embodiment of the invention, the extraction mode in the step (2) is reflux extraction; further, the extraction time in the step (2) is 1-5 h, preferably 2h; further, the extraction times in the step (2) are 1 to 3 times, preferably 2 times;

further, the mass ratio of the water to the mixture of the medicine dregs, the ephedra herb and the gypsum in the step (2) is 6-12, preferably 10-12;

further, the extract to be extracted is soaked in the extraction solvent before the reflux extraction in the step (2); further, the soaking time in the step (2) is 0.5 to 2 hours; the number of extraction is 1 to 3 times, preferably 2 times.

In the specific embodiment of the invention, the relative density of the alcohol extract concentrate and the water extract concentrate is 1-1.2, preferably 1.05-1.1.

The step of heating reflux alcohol extraction after soaking the bitter apricot seeds and the liquorice is understood as that the bitter apricot seeds and the liquorice are respectively soaked and alcohol extracted, or the bitter apricot seeds and the liquorice are respectively soaked and then mixed and alcohol extracted, or the bitter apricot seeds and the liquorice are mixed and soaked and then alcohol extracted.

The invention firstly uses ethanol with proper concentration to extract the liquorice and the bitter almond, thereby avoiding the influence of gypsum on glycyrrhizic acid, inhibiting the activity of the bitter almond enzyme, increasing the transfer rate of the effective components of the liquorice and the dissolution of the medicinal substances of the bitter almond, namely amygdalin and bitter almond fatty oil; the bitter apricot seeds and the liquorice which are extracted by alcohol are further extracted by water with the ephedra herb and the gypsum, so that the extraction rate of fat-soluble effective components can be increased, the traditional compatibility theory of the traditional Chinese medicine of the ephedra herb, the almond, the ephedra herb and the gypsum is followed, and the effective components of the liquorice, the bitter apricot seeds, the ephedra herb and the gypsum are reserved; the product quality and the production efficiency can be improved by adopting centrifugal purification and reduced pressure concentration of a falling film evaporator.

The invention has the beneficial effects that:

(1) The sustained-release granules have low loss rate of volatile components, high transfer rate and effective components, obvious sustained-release characteristic in vitro release, increased animal drug compliance, and greatly improved flavor and quality.

(2) The invention has simple preparation process and good repeatability and is suitable for industrial production.

Drawings

Fig. 1 is a graph showing the release profile of ephedrine in four dissolution media in the present ephedra-gypsum sustained release granule.

Fig. 2 is a release curve of glycyrrhizic acid in four dissolution media in the ephedra, apricot, gypsum and licorice sustained-release granules.

FIG. 3 is the release profile of ephedrine in four dissolution media in the general granules of Maxingshigan.

Fig. 4 is the release curve of glycyrrhizic acid in four dissolution media in the common granules of ephedra, apricot, gypsum and licorice.

Wherein, the comparative example in fig. 3 and 4 is comparative example 4 in the embodiment of the present invention.

Detailed Description

The technical solutions of the present invention are described clearly and completely below, and it is obvious that the described embodiments are some, not all embodiments of the present invention. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.

Example 1

(1) 650g of ephedra herb is frozen and crushed into powder with the average grain diameter of 170-190 mu m, 600g of bitter apricot seed and 520g of liquorice are mixed and crushed into powder with the average grain diameter of 820-880 mu m, 3100g of gypsum is crushed by air flow, and the grain size distribution d (v, 0.9) is 9.271um.

(2) Soaking semen Armeniacae amarum and Glycyrrhrizae radix in 10 times of 60% ethanol for 1 hr, heating and reflux-extracting for 2 hr (stirring, the same as below), hot-filtering, adding 8 times of 60% ethanol into the residue, heating and reflux-extracting for 2 hr, hot-filtering, and keeping the residue; centrifuging the filtrate at high speed, filtering the filtrate under pressure by a plate-and-frame filter press, and concentrating the filtrate by a falling film evaporator under reduced pressure until the relative density of the liquid medicine is 1.05-1.10 (at the temperature of 55-70 ℃), thus obtaining the bitter almond and liquorice alcohol extract concentrated solution.

(3) Taking the dregs of the bitter apricot kernels and the liquorice extracted by the alcohol in the step (2), adding 12 times of purified water into the dregs of the alcohol, ephedra and gypsum, soaking for 2 hours, heating and refluxing for extracting for 2 hours, synchronously collecting aromatic water by using an oil-water separator, filtering while hot, adding 10 times of purified water into the dregs of the alcohol, heating and refluxing for extracting for 2 hours, synchronously collecting aromatic water by using the oil-water separator, filtering while hot, centrifuging the filtrate at a high speed, filtering by using a plate-and-frame filter press under pressure, and concentrating by using a falling film type film evaporator under reduced pressure until the relative density of the liquid medicine is 1.05-1.10 (at the temperature of 55-70 ℃), thus obtaining the concentrated water extract.

(4) And (3) putting the alcohol extraction concentrated solution of the bitter apricot kernels and the liquorice prepared in the step (2) and the water extraction concentrated solution prepared in the step (3) into a suitable container, stirring with a stirring paddle (the rotating speed is 200 rpm), and carrying out centrifugal spray drying under the conditions that the liquid medicine temperature is 60-70 ℃, the air inlet temperature is 170-180 ℃, the air outlet temperature is 80-90 ℃ and the rotating speed of an atomizer is 27000rpm to obtain dry extract powder.

(5) Taking the dry extract powder prepared in the step (4), adding 487g of hydroxypropyl methylcellulose, 260g of glyceryl behenate, 439g of glucose and 18g of fumaric acid, uniformly mixing, preparing a soft material by using 80% ethanol, extruding and granulating by using a rotary granulator, placing wet granules in a boiling granulator, controlling the air inlet temperature to be 60-80 ℃, keeping the material temperature to be 45 +/-5 ℃, drying until the moisture of the granules is 3.0-4.0%, granulating by using a swing granulator, adding 7g of edible fresh milk essence, placing in a double-cone mixer for total mixing, and subpackaging to obtain the finished product.

Example 2

(1) Taking 600g of ephedra herb, freezing and crushing the ephedra herb into powder with the average grain diameter of 170-190 mu m, mixing 570g of bitter apricot seed and 400g of liquorice, and crushing the mixture into powder with the average grain diameter of 820-880 mu m; 1300g of gypsum are pulverized by air flow, and the particle size distribution d (v, 0.9) of the gypsum is 5.683um.

(2) Adding 12 times of 70% ethanol into the semen Armeniacae amarum and Glycyrrhrizae radix, soaking for 1 hr, heating and reflux extracting for 2 hr (stirring, the same as below), hot filtering, adding 10 times of 70% ethanol into the residue, heating and reflux extracting for 1 hr, hot filtering, and keeping the residue; centrifuging the filtrate at high speed, filtering the filtrate under pressure by a plate-and-frame filter press, and concentrating the filtrate by a falling film evaporator under reduced pressure until the relative density of the liquid medicine is 1.10-1.15 (at the temperature of 55-70 ℃), thus obtaining the bitter almond and liquorice alcohol extract concentrated solution.

(3) Taking dregs of the bitter apricot kernels and the liquorice which are subjected to alcohol extraction in the step (2), ephedra and gypsum, adding 12 times of purified water, soaking for 2 hours, heating and refluxing for 2 hours, synchronously collecting aromatic water by using an oil-water separator, filtering while the dregs are hot, adding 12 times of purified water into the dregs of the medicinal dregs, heating and refluxing for 2 hours, synchronously collecting aromatic water by using an oil-water separator, filtering while the dregs are hot, centrifuging the filtrate at high speed, pressurizing and filtering by using a plate-and-frame filter press, and concentrating under reduced pressure by using a falling film type film evaporator until the relative density of the liquid medicine is 1.10-1.15 (at the temperature of 55-70 ℃), thus obtaining an aqueous extract concentrated solution.

(4) And (3) putting the ethanol extract concentrated solution of the bitter almonds and the liquorice prepared in the step (2) and the water extract concentrated solution prepared in the step (3) into a suitable container, stirring the mixture by using a stirring paddle (the rotating speed is 100 rpm), and carrying out centrifugal spray drying on the mixture under the conditions that the liquid medicine temperature is 50-60 ℃, the air inlet temperature is 150-160 ℃, the air outlet temperature is 75-85 ℃ and the rotating speed of an atomizer is 32000rpm to obtain dry extract powder.

(5) Taking the dry extract powder prepared in the step (4), adding 430g of hydroxypropyl methylcellulose, 72g of glyceryl behenate and 187g of glucose, uniformly mixing, preparing a soft material by using 50% ethanol, extruding and granulating by using a rotary granulator, placing wet granules in a boiling granulator, controlling the air inlet temperature to be 60-70 ℃, keeping the material temperature to be 45 +/-5 ℃, drying until the moisture of the granules is 3.0-4.0%, finishing granules by using a swing granulator, adding 10g of edible cream essence, placing in a double-cone mixer, totally mixing, and subpackaging to obtain the finished product.

Comparative example 1

Compared with the embodiment 1, the crushing mode of the ephedra medicinal material is replaced by the normal-temperature continuous crushing.

Taking appropriate amount of powder at different positions randomly, placing in a stainless steel barrel, adding 6 times of water, stirring, and connecting with volatile oil detector and reflux condenser tube. Adding water from the upper end of the condensation tube to fill the scale part of the volatile oil detector and overflow into the stainless steel barrel. Slowly heating to boil with an electromagnetic oven, keeping slightly boiling for about 5 hours, reading the volatile oil amount, and calculating the yield of the volatile oil, wherein the results are shown in table 1.

TABLE 1 influence of different pulverizing methods of herba Ephedrae on the retention rate of volatile oil

As can be seen from Table 1, the content of volatile oil in Ephedra herb can be significantly retained by freeze-pulverization.

Comparative example 2

Weighing 100g of ephedra, bitter apricot seed and liquorice with different particle size specifications, extracting according to the steps (1), (2) and (3) in the embodiment 1 respectively, combining the extracting solutions, adjusting each medicine liquid to 5000ml by water, uniformly stirring, taking a proper amount of the extracting solution, measuring the contents of ephedrine, amygdalin and glycyrrhizic acid, and calculating the transfer rate according to the actually measured contents of the medicinal materials, wherein the results are shown in a table 2.

TABLE 2 measurement results of transfer rates of effective components in medicinal material extract solutions with different particle diameters

According to Table 2, the average particle size of the Chinese ephedra is optimally selected to be 170-190 μm; the average grain size of the bitter almond is 820-880 mu m, the transfer rate of the bitter almond in the extractive solution of 340-380 mu m is not very different, the coarser the grain size, the less impurities dissolved out after decoction and the high crushing efficiency, therefore, the average grain size of the bitter almond is selected to be 820-880 mu m; the average particle diameter of the licorice is preferably 340 to 380 μm. But in order to simplify the process operation steps, the liquorice and the bitter apricot seeds can be selected to be mixed and crushed, and the average grain diameter of the mixed powder of the liquorice and the bitter apricot seeds is controlled to be 820 to 880 mu m.

Comparative example 3

Compared with the example 1, the prescription of the slow release granules of the ephedra, which is the main active ingredient ephedrine in the prescription of the ephedra, is selected as evaluation indexes in four different dissolution media, namely 0.1mol/L HCl, acetic acid-sodium acetate buffer (pH4.5), phosphate buffer (pH6.8) and purified water. Recipes 1-5 are designed as shown in Table 3.

The final product was prepared according to the recipe composition of table 3, referring to the procedure of example 1. Precisely weighing a proper amount of finished products, taking 0.1mol/L HCl, acetic acid-sodium acetate buffer solution (pH4.5), phosphate buffer solution (pH6.8) and purified water as dissolution media respectively according to a dissolution rate and release rate determination method (second method of general rule 931), taking 10ml of solution respectively after 1h, 2h, 4h, 6h, 8h, 10h and 12h by adopting the method with the volume of the dissolution media being 900ml and the rotating speed being 75 revolutions per minute, supplementing the dissolution media with the same temperature and volume in time, and filtering to obtain the subsequent filtrate as a test solution. Injecting into a liquid chromatograph, and calculating the release degree by peak area according to an external standard method. The results are shown in Table 4.

TABLE 3 formulations 1 to 5

TABLE 4 determination of in vitro Release of ephedrine in 0.1mol/L HCl for formulations 1-5

As can be seen from Table 4, the ephedrine in the formulas 1 and 2 has a fast release rate in the 0.1mol/L HCl dissolution medium, the release rate in the first four hours reaches more than 75%, while the release rate in the 8 th hour reaches more than 75%, so that the glyceryl behenate added in the formula 3 is matched with other components, so that the obtained sustained-release granules have a proper release characteristic. The average accumulated release degrees of ephedrine in formula 4 without hypromellose and formula 5 without glucose are lower (71.7% and 57.2% respectively) in 12h, i.e. the release is not complete, which indicates that hypromellose, glyceryl behenate and glucose have synergistic effect in the formula.

Comparative example 4

Weighing 650g of ephedra, 3100g of gypsum, 600g of bitter apricot seed and 520g of liquorice, directly feeding decoction pieces, decocting for 2 times, mixing decoctions, standing, filtering, concentrating under reduced pressure to obtain clear paste, adding 3600g of dextrin, granulating and drying to obtain the traditional Chinese medicine composition.

The finished granules in example 1 and comparative example 4 were subjected to the measurement of transfer rate of active ingredients and the evaluation of flavor and taste, and the test results are shown in table 5 below.

Table 5 comparison of the quality of the finished products of example 1 and comparative example 4

As can be seen from Table 5, the product prepared by the invention has good taste, the transfer rates of the active ingredients of amygdalin, glycyrrhizic acid and ephedrine are obviously improved, and the effectiveness of clinical medication is ensured.

The release profiles of the effective substances glycyrrhizic acid and ephedrine in the products of example 1 and comparative example 4 in four different dissolution media of 0.1mol/L HCl, acetic acid-sodium acetate buffer (pH 4.5), phosphate buffer (pH 6.8) and purified water were determined. Precisely weighing a proper amount of finished products, taking 0.1mol/L HCl, acetic acid-sodium acetate buffer solution (pH4.5), phosphate buffer solution (pH6.8) and purified water as dissolution media respectively according to a dissolution rate and release rate determination method (second method of general rule 931), taking 10ml of solution respectively after 1h, 2h, 4h, 6h, 8h, 10h and 12h by adopting the method with the volume of the dissolution media being 900ml and the rotating speed being 75 revolutions per minute, supplementing the dissolution media with the same temperature and volume in time, and filtering to obtain the subsequent filtrate as a test solution. Injecting into a liquid chromatograph, and calculating the release degree by peak area according to an external standard method. The results are shown in FIGS. 1 to 4.

From the results shown in fig. 1 to 4, it can be known that the ephedra, apricot kernel and licorice root granules prepared in comparative example 4 release drugs basically and completely in four different dissolution media within 3 hours, while the ephedra, apricot kernel and licorice root sustained release granules prepared in example 1 release slowly, and the accumulated release degree of the effective components ephedrine and glycyrrhizic acid at each time point meets the requirements of sustained release preparations, and is expected to be popularized in clinical application.

The ephedra, bitter apricot seed, liquorice and other effective components in the ephedra, bitter apricot seed, liquorice sustained-release granules provided by the invention have high transfer rate, and the in vitro release has obvious sustained-release characteristics, so that the animal medication compliance is increased.

Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims (13)

1. The veterinary ephedra, apricot kernel, gypsum and licorice sustained-release granule is characterized by comprising the following components in parts by weight:

40-60 parts of dry ephedra almond gypsum extract powder, 15-25 parts of hydroxypropyl methylcellulose, 5-15 parts of glyceryl behenate and 10-20 parts of glucose;

the bulk drugs of the dry extract powder of ephedra, apricot kernel, gypsum and licorice are as follows: 500 to 700 parts of ephedra, 1000 to 3300 parts of gypsum, 500 to 700 parts of bitter apricot kernel and 300 to 600 parts of liquorice;

the average particle size of the ephedra is 170 to 190 mu m;

the average grain size of the bitter apricot seeds and the liquorice is 820 to 880 mu m.

2. The granule according to claim 1, consisting of the following components in parts by weight:

45 to 55 parts of dry ephedra almond gypsum extract powder, 20 to 25 parts of hydroxypropyl methylcellulose, 10 to 15 parts of glyceryl behenate and 15 to 20 parts of glucose;

the bulk drugs of the dry extract powder of ephedra, apricot kernel, gypsum and licorice are as follows: 600 to 700 parts of ephedra, 1300 to 3300 parts of gypsum, 500 to 600 parts of bitter almond and 400 to 600 parts of liquorice.

3. The granule according to claim 2, characterized by consisting of the following components in parts by weight: 50 parts of dry extract powder of ephedra, apricot kernel, gypsum, 25 parts of hydroxypropyl methylcellulose, 10 parts of glyceryl behenate and 15 parts of glucose;

the ephedra, apricot kernel, gypsum and licorice dry extract powder comprises the following raw material medicaments: 650 parts of ephedra, 3100 parts of gypsum, 600 parts of bitter apricot seed and 520 parts of liquorice.

4. The granules according to any one of claims 1 to 3, wherein the veterinary ephedra and gypsum sustained-release granules further comprise 2 to 30 parts of flavoring agent and/or 6 to 60 parts of sour agent; the flavoring agent is edible essence;

the sour agent is fumaric acid.

5. A process for producing the granule according to any one of claims 1 to 4, which comprises the steps of:

(1) Extracting semen Armeniacae amarum and Glycyrrhrizae radix with alcohol or alcohol water solution, performing solid-liquid separation, and concentrating the extractive solution to obtain ethanol extractive solution;

(2) Extracting the dregs, ephedra and gypsum after alcohol extraction in the step (1) with water, carrying out solid-liquid separation, and concentrating the extracting solution to obtain a water extraction concentrated solution;

(3) Uniformly mixing the ethanol extract concentrate and the water extract concentrate, and then performing spray drying to obtain dry extract powder of the ephedra, the almond, the gypsum and the liquorice;

(4) Mixing the dry extract powder with the rest raw materials, and granulating.

6. The preparation method according to claim 5, wherein the herba Ephedrae is prepared by freezing and pulverizing herba Ephedrae; the freezing conditions in the freezing and crushing are as follows: freezing for 10 to 30min at the temperature of minus 25 to minus 40 ℃.

7. The preparation method according to claim 5, wherein the average particle size of the ephedra is 170 to 190 μm; the average grain size of the bitter almond and the liquorice is 820 to 880 mu m; the particle size D (v, 0.9) of the gypsum is less than or equal to 15um.

8. The method according to claim 5, wherein the extraction in the step (1) is a heating reflux extraction; the extraction time in the step (1) is 1 to 5 hours; the number of extraction times in the step (1) is 1 to 3.

9. The method of claim 8, wherein the almond and the licorice are soaked in the extraction solvent before the heating reflux extraction; the soaking time of the bitter apricot seeds and the liquorice is 0.5 to 2h.

10. The preparation method according to claim 5, wherein the alcohol in step (1) is one or more selected from ethanol, propylene glycol, glycerol, isopropanol, and n-butanol; the extraction solvent in the step (1) is selected from an alcohol aqueous solution, wherein the volume fraction of alcohol in the alcohol aqueous solution is 50-70%; the mass ratio of the extraction solvent to the mixture of bitter apricot seed and licorice is 6 to 12:1.

11. the method according to claim 5, wherein the extraction in the step (2) is reflux extraction; the extraction time in the step (2) is 1 to 5h; the extraction times in the step (2) are 1 to 3;

and (3) the mass ratio of the water to the mixture of the medicine residue, the ephedra and the gypsum in the step (2) is 6 to 12.

12. The method according to claim 11, wherein the extract to be extracted is soaked in the extraction solvent before the reflux extraction in the step (2); the soaking time in the step (2) is 0.5 to 2h; the extraction times are 1 to 3.

13. The preparation method according to claim 5, wherein the relative density of the ethanol concentrated solution and the water concentrated solution is 1 to 1.2.

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