阅读说明：本技术 一种泌淋制剂的制备方法 (Preparation method of stranguria-treating preparation ) 是由 窦啟玲 黄飞云 黄彩河 徐蓉 于 2019-10-24 设计创作，主要内容包括：本发明公开了一种泌淋制剂新的制备方法,一方面将头花蓼或头花蓼与酢浆草药材先用70%乙醇提取2小时后,药渣再与其余原料药加水煎煮后,所提取的浸膏再经过水沉除杂,另一方面在制剂成型过程中严格控制相对湿度,不仅改善了原有制剂中溶化性不好的问题,还提高了产品的稳定性和疗效。(The invention discloses a novel preparation method of a stranguria-treating preparation, which comprises the steps of firstly extracting polygonum capitatum or polygonum capitatum and creeping oxalis for 2 hours by 70% ethanol, then decocting medicinal residues and other raw material medicaments by adding water, and then carrying out water precipitation on the extracted extract to remove impurities, and on the other hand, strictly controlling relative humidity in the preparation forming process, so that the problem of poor dissolubility in the original preparation is solved, and the stability and curative effect of the product are improved.)

1. The preparation method of the stranguria treating preparation comprises the following raw material medicines in parts by weight: 450 parts of polygonum capitatum, 225 parts of plantain, 225 parts of creeping oxalis and 150 parts of chinarue; the method specifically comprises the following steps:

cutting herba Polygoni Capitati or herba Polygoni Capitati and herba Oxalidis Corniculatae, adding 6-10 times of 70% ethanol, reflux extracting for 1-3 hr, filtering, collecting residue, and recovering ethanol from filtrate to obtain ethanol extractive solution;

adding the rest raw materials into the residue after ethanol extraction, adding 6-10 times of water, decocting for 2-3 times (each time for 1-2 hr), mixing decoctions, filtering, concentrating the filtrate to relative density of 1.05-1.15, and addingThe alcohol extract is continuously concentrated into thick paste with the relative density of 1.25-1.35 for standby;

will be described in detail

controlling the relative humidity below 65 percent, and carrying out the following stepsAdding pharmaceutically acceptable medicinal adjuvants into the obtained dry extract powder, and making into various dosage forms.

2. The method according to claim 1, wherein the drying method is any one of vacuum drying, microwave drying, and spray drying.

3. The method of claim 2, wherein the vacuum drying method is vacuum belt drying.

4. The preparation method according to claim 1, wherein the dosage form is granules, capsules, tablets, pills, drop pills, syrups, oral solutions.

5. The preparation method according to claim 1, comprising the following steps:

cutting herba Polygoni Capitati, adding 8 times of 70% ethanol, reflux extracting for 1.5 hr, filtering, collecting residue, and recovering ethanol from filtrate to obtain ethanol extractive solution;

will be described in detailAdding 6 times of purified water into the extracted soft extract, stirring, refrigerating at 2-8 deg.C, standing for 24 hr, collecting supernatant, centrifuging, filtering to remove impurities, concentrating the medicinal liquid to relative density of 1.30, vacuum belt drying, and pulverizing to obtain dry extract powder;

6. The preparation method according to claim 1, comprising the following steps:

cutting herba Polygoni Capitati and herba Oxalidis Corniculatae, adding 10 times of 70% ethanol, reflux extracting for 2 hr, filtering, collecting residue, and recovering ethanol from filtrate to obtain ethanol extractive solution;

adding herba plantaginis and herba Boenninghauseniae into the residue after extracting herba Polygoni Capitati and herba Oxalidis Corniculatae with ethanol, decocting with 10 times of water for 2 times, each for 2 hr, mixing decoctions, filtering, concentrating the filtrate to relative densityWhen the degree is 1.10, adding the stepThe alcohol extract is continuously concentrated into thick paste with the relative density of 1.25 for standby;

will be described in detail

Technical Field

The invention relates to a preparation method of a stranguria-treating preparation, and belongs to the technical field of medicines.

Background

At present, the stranguria caused by the accumulation of damp-heat such as urinary system infection, urgent micturition, odynuria, unclean urine and the like is a big problem which troubles a plurality of patients, if not taken into consideration, the inflammation is aggravated, and the normal functions of the urinary tract, the gonad, the accessory gonad and the external genitalia are influenced to different degrees, so that the body is more injured. In the prior art, a plurality of medicines for treating stranguria also exist, and stranguria treating granules and stranguria treating capsules are ideal medicines. The stranguria-treating granule is a pure Chinese medicinal preparation prepared from polygonum capitatum, plantain herb, creeping oxalis and chinarue herb according to the reasonable prescription of Miao nationality medication habits and the theory of traditional Chinese medicine, has the functions of clearing away heat and toxic materials and inducing diuresis for treating stranguria, and is used for difficult urination, painful urination, urinary tract infection and the like caused by damp-heat accumulation. CN02134098.6 discloses a common preparation method of the prior stranguria treating preparation, but the method always has the phenomena of poor dissolubility and excessive water content after long-time storage in the production process.

Disclosure of Invention

In view of the above problems, the present invention aims to provide a novel preparation method of a stranguria treating preparation with good dissolubility and higher stability.

The invention is realized by the following technical scheme: the preparation method of the stranguria treating preparation comprises the following raw material medicines in parts by weight: 450g of polygonum capitatum, 225g of plantain, 225g of creeping oxalis and 150g of chinarue; the method specifically comprises the following steps:

cutting herba Polygoni Capitati or herba Polygoni Capitati and herba Oxalidis Corniculatae, adding 6-10 times of 70% ethanol, reflux extracting for 1-3 hr, filtering, collecting residue, and recovering ethanol from filtrate to obtain ethanol extractive solution;

adding the rest raw materials into the residue after ethanol extraction, adding 6-10 times of water, decocting for 2-3 times (each time for 1-2 hr), mixing decoctions, filtering, concentrating the filtrate to relative density of 1.05-1.15, and addingThe alcohol extract is continuously concentrated into thick paste with the relative density of 1.25-1.35 for standby;

will be described in detail

Extracted ofAdding 4-8 times of purified water into the soft extract, stirring, refrigerating at 2-8 deg.C, standing for more than 24 hr, centrifuging the supernatant, removing impurities, concentrating the medicinal liquid to relative density of 1.25-1.35, drying, and pulverizing to obtain dry extract powder;

controlling the relative humidity below 65 percent, and carrying out the following stepsAdding pharmaceutically acceptable medicinal adjuvants into the obtained dry extract powder, and making into various dosage forms.

Preferably, the stranguria preparation specifically comprises the following steps:

cutting herba Polygoni Capitati, adding 8 times of 70% ethanol, reflux extracting for 1.5 hr, filtering, collecting residue, and recovering ethanol from filtrate to obtain ethanol extractive solution;

adding herba plantaginis, herba Oxalidis Corniculatae, and herba Boenninghauseniae into the residue after extracting herba Polygoni Capitati with ethanol, decocting with 8 times of water for 2 times, each time for 1.5 hr, mixing decoctions, filtering, concentrating the filtrate to relative density of 1.10, and adding into the above step

The alcohol extract is continuously concentrated into thick paste with the relative density of 1.30 for standby;

will be described in detail

Adding 6 times of purified water into the soft extract, stirring, refrigerating at 2-8 deg.C for 24 hr, centrifuging the supernatant, filtering to remove impurities, and collecting the medicinal liquidConcentrating to relative density of 1.30, vacuum belt drying, and pulverizing to obtain dry extract powder;

controlling the relative humidity below 65 percent, and carrying out the following steps

Adding appropriate amount of sucrose powder into the obtained dry extract powder, mixing, granulating, drying, grading, and packaging to obtain stranguria treating granule.

Preferably, the stranguria preparation specifically comprises the following steps:

cutting herba Polygoni Capitati and herba Oxalidis Corniculatae, adding 10 times of 70% ethanol, reflux extracting for 2 hr, filtering, collecting residue, and recovering ethanol from filtrate to obtain ethanol extractive solution;

adding herba plantaginis and herba Boenninghauseniae into the residue after ethanol extraction of herba Polygoni Capitati and herba Oxalidis Corniculatae, decocting with 8 times of water for 2 times, each time for 2 hr, mixing decoctions, filtering, concentrating the filtrate to relative density of 1.10, and adding into the above step

The alcohol extract is continuously concentrated into thick paste with the relative density of 1.25 for standby;

will be described in detailAdding 5 times of purified water into the extracted soft extract, stirring, refrigerating at 2-8 deg.C, standing for 24 hr, centrifuging the supernatant, removing impurities, concentrating the medicinal liquid to relative density of 1.25, and spray drying to obtain dry extract powder;

controlling the relative humidity below 65 percent, and carrying out the following steps

Adding appropriate amount of starch into the obtained dry extract powder, mixing, and making into capsule to obtain NILIN Capsule.

Compared with the prior art, the invention has the beneficial effects that: provides a new extraction and preparation method of the stranguria treating preparation, can improve the dissolubility (dissolubility) and stability of the product, can also improve the curative effect, and has simple operation and convenient extraction.

The extraction and preparation method of the invention is improved on the basis of the existing extraction method, and the specific method is as follows: extracting herba Polygoni Capitati or herba Polygoni Capitati and herba Oxalidis Corniculatae with ethanol under reflux, decocting the residue and other rest materials in water for 2 times, mixing the ethanol extractive solution and water extract, concentrating to obtain soft extract, and precipitating with water to remove impurities, so as to improve solubility (solubility) of the extract in syrup, oral liquid, and granule, and prevent precipitation, and to ensure qualified and stable water content in granule and capsule, the relative humidity in the environment is controlled below 65%. On one hand, the invention solves the problems of poor dissolubility and excessive water content in the existing product production process, and on the other hand, the polygonum capitatum and/or the creeping oxalis are extracted by alcohol and then by water, so that the gallic acid content can be increased, the total flavone content can be increased, and the curative effect can be improved.

To illustrate the contents and advantages of the present invention, the following tests were also conducted in the present invention, which are intended to illustrate the present invention and in no way limit the scope of the present invention.

Experiment 1: the extraction method comprises the following steps:

the experimental method and the results are as follows by taking gallic acid, total flavone and the paste yield as investigation indexes:

s-1: weighing 900g of polygonum capitatum, 450g of plantain, 450g of creeping oxalis and 300g of boenninghausenia, adding 8 times of water, decocting for 2 times, each time for 1.5 hours, combining the decoctions, filtering, concentrating the filtrate into thick paste with the relative density of 1.30, drying in vacuum, and weighing to obtain the traditional Chinese medicine composition;

s-2: weighing 900g of polygonum capitatum, adding 70% ethanol which is 8 times the weight of the polygonum capitatum, performing reflux extraction for 1.5 hours, filtering, reserving medicine residues, and recovering ethanol from filtrate to obtain ethanol extract for later use; weighing 450g of plantain herb, 450g of creeping oxalis and 300g of chinarue, adding into polygonum capitatum dregs, adding 8 times of water, decocting for 2 times, each time for 1.5 hours, combining decoctions, filtering, adding polygonum capitatum alcohol extract when the filtrate is concentrated to the relative density of 1.10, continuously concentrating to thick paste with the relative density of 1.30, vacuum drying and weighing to obtain the medicine;

s-3: weighing 900g of polygonum capitatum and 450g of creeping oxalis, adding 70% ethanol with the amount of 8 times of that of the polygonum capitatum, refluxing and extracting for 1.5 hours, filtering, and recovering ethanol from the filtrate to obtain ethanol extract for later use; weighing 450g of plantain herb and 300g of chinarue, adding into the polygonum capitatum and creeping oxalis herb residues, adding 8 times of water, decocting for 2 times, each time for 1.5 hours, combining the decoctions, filtering, concentrating the filtrate until the relative density is 1.10, adding the polygonum capitatum and creeping oxalis alcohol extract, continuously concentrating to thick paste with the relative density of 1.30, vacuum drying, and weighing to obtain the traditional Chinese medicine preparation;

s-4: weighing 900g of polygonum capitatum, 450g of plantain, 450g of creeping oxalis and 300g of boenninghausenia, adding 70% ethanol which is 8 times the amount of polygonum capitatum, refluxing and extracting for 1.5 hours, filtering, reserving medicine residues, and recovering ethanol from filtrate to obtain ethanol extract for later use; decocting the residue with 8 times of water for 2 times, each for 1.5 hr, mixing decoctions, filtering, concentrating the filtrate to relative density of 1.10, adding ethanol extractive solution, concentrating to soft extract with relative density of 1.30, vacuum drying, and weighing;

TABLE 1 optimization results table of extraction method

As a result: from the above table, it can be seen that the increase of alcohol extraction on the basis of the original water extraction process can improve the yield of dry paste, and the content of gallic acid can also be increased by more than 60%, and particularly, after the increase of the alcohol extraction process, the content of total flavonoids is increased by 2 times; in addition, experiments show that the results of alcohol extraction of the polygonum capitatum or the polygonum capitatum and the creeping oxalis are not greatly different from the results of alcohol extraction and water extraction of all the medicinal materials, the extraction cost is limited, and finally, the polygonum capitatum or the polygonum capitatum and the creeping oxalis are preferably only subjected to alcohol extraction and then subjected to a water extraction process with the other medicinal materials.

Experiment 2: and (3) testing the dissolubility:

extracting thick paste: weighing 1800g of polygonum capitatum, adding 70% ethanol which is 8 times the weight of the polygonum capitatum, performing reflux extraction for 1.5 hours, filtering, reserving medicine residues, and recovering ethanol from filtrate to obtain ethanol extract for later use; weighing 900g of creeping oxalis, 900g of plantain herb and 600g of boenninghausenia herb, adding into the polygonum capitatum dregs, adding 8 times of water, decocting for 2 times, each time for 1.5 hours, merging the decoctions, filtering, concentrating the filtrate to the relative density of 1.10, adding the polygonum capitatum alcohol extract, and continuously concentrating to the thick paste with the relative density of 1.30 for later use;

screening by a water sedimentation process:

w-1: directly taking the thick paste, vacuum drying, adding a proper amount of sugar powder, and preparing the stranguria treating granules W1;

w-2: adding 4 times of purified water into the thick paste, performing water precipitation for 24 hours, concentrating the supernatant into thick paste, vacuum drying, adding a proper amount of sugar powder, and preparing the stranguria treating granules W2;

w-3: adding 6 times of purified water into the thick paste, performing water precipitation for 24 hours, concentrating the supernatant into thick paste, vacuum drying, adding a proper amount of sugar powder, and preparing the stranguria treating granules W3;

w-4: adding 8 times of purified water into the thick paste, performing water precipitation for 24 hours, concentrating the supernatant into thick paste, vacuum drying, adding a proper amount of sugar powder, and preparing the stranguria treating granules W4;

w-5: adding ethanol into the soft extract to make ethanol content reach 40%, precipitating with ethanol for 24 hr, collecting supernatant, recovering ethanol, concentrating into soft extract, vacuum drying, adding appropriate amount of sugar powder, and making into stranguria treating granule W5;

w-6: adding ethanol into the soft extract to make the ethanol content reach 60%, precipitating with ethanol for 24 hr, collecting supernatant, recovering ethanol, concentrating into soft extract, vacuum drying, adding appropriate amount of sugar powder, and making into stranguria treating granule W6;

w-7: adding 6 times of purified water into the soft extract, precipitating with water, refrigerating at 2-8 deg.C, standing for 24 hr, collecting supernatant, concentrating into soft extract, vacuum drying, adding appropriate amount of sugar powder, and making into stranguria treating granule W7;

the solubility was used as an index to investigate the effect of different purification methods on solubility, and the results are shown in table 2:

table 2: comparison table of solubility of the present invention and commercially available stranguria treating granules

As a result: as can be seen from the table, the original process has poor solubility, and the solubility is obviously improved after the extracted thick paste is subjected to water precipitation or alcohol precipitation. Through tests, when water is precipitated, 6 times of water is properly added, less water is used, layering is not easy, more water is used, concentration is troublesome, and when water is precipitated, the water can be refrigerated at the temperature of 2-8 ℃ for 24 hours, so that the layering effect is better. In addition, the solubility of both alcohol precipitation concentrations can be improved, but the yield of dry paste after alcohol precipitation is low, and the cost of alcohol precipitation is higher than that of water precipitation, so that water precipitation purification is finally selected.

Experiment 3: examination of hygroscopicity of particles

In order to ensure the stability of the particles, whether the particles are easy to absorb moisture is examined, and the critical relative humidity is measured by the following specific method: an appropriate amount of the particles of example 1 was weighed, and the particles having a thickness of about 2mm were placed on the bottom of a flat weighing bottle having a constant weight, accurately weighed, placed in a desiccator containing supersaturated solutions of different salts having different relative humidities (RH%) as shown in the following table, and kept in a constant temperature incubator at 25 ℃ for 72 hours, and then weighed to calculate the percentage of moisture absorption. The results are shown in Table 3

Table 3 examination of hygroscopicity of granules

The moisture absorption rate% in the table is plotted as ordinate and the relative humidity RH% is plotted as abscissa, the tangents at the two ends of the curve in the plot are plotted, and the abscissa corresponding to the intersection of the two tangents is the critical relative humidity, as shown in fig. 1.

As shown in fig. 1, the critical relative humidity of the granules is slightly greater than 65%, i.e. the environmental humidity should be controlled below 65% during granulation and packaging.

Experiment 4: and (3) inspecting the stability of the stranguria treating preparation:

accelerated stability tests were carried out according to the guidelines of the stability tests of the raw material drugs and the formulations in the "Chinese pharmacopoeia (fourth part) of the 2015 edition, and the test results are shown in Table 4:

table 4: expedition result table of accelerated stability test of stranguria treating preparation

As a result: as can be seen from the table, the gallic acid content of the stranguria preparation is higher by about 60 percent compared with that of the commercially available stranguria granule, and the stranguria preparation is more stable than the commercially available stranguria granule in terms of moisture, and the results of the products meet the requirements through accelerated test investigation.

In order to enable a person of ordinary skill in the art to better understand the present invention, the applicant conducted a series of animal experimental studies to prove the effects of the present invention:

the purpose of the test is as follows: the influence of the stranguria preparation on experimental acute pyelonephritis of rats is examined

60 SD rats with the weight of 200-250 g are anesthetized by intraperitoneal injection of pentobarbital sodium 3Omg/kg, fixed in prone position, cut at the back side, and the right kidney is fully exposed, and a 0.25 mL BCG (4 mL BCG) syringe with the volume of 0.25 mL is adopted^#Needle) at the renal parenchyma, part 3, inoculation 10⁷·mL^-150. mu.l of the bacterial suspension. And after operation, the seeds are placed in a metabolism cage for independent feeding. A fresh urine sample 24 h after the operation is collected, the number of leucocytes in the urine sample is counted under a microscope by using a blood cell counting plate, and the number of leucocytes in the urine sample per cubic millimeter is more than 100, so that the bacterial nephritis model is considered to be successful. The model mice were randomly divided into 6 groups according to the number of leukocytes and sex in urine: the commercially available Neisseria gonorrhoeae granule group, the groups of examples 1 to 3 of the present invention, the norfloxacin group and the model group were used together with a normal control group (those not infected with bacteria). After the animals are grouped, the corresponding tested drugs are administered by intragastric administration, the equal-volume normal saline is administered to the model group, and the drugs are continuously administeredAnd 7 d, a medicine. Collecting urine samples before administration every day, and counting the number of leucocytes in the urine samples; urine samples of 1, 2, 3, 5 and 7 days after administration were collected from each group of animals and urine Protein (PRO), occult Blood (BLD), ketone body (KET), Bilirubin (BIL) and Urobilinogen (URO) were analyzed by a Japanese MA-4210 type urine analyzer. The results of the urinalysis were converted to score values according to the following criteria: "-" score 1, "+" score 2, "+ + +" score 3, "+ + + + + + + + +" score 4, "+ + + + + + + + + + + + + + + + +" score 5, and the average score value for each group was determined. Statistical analysis is carried out by adopting a non-parameter method; the counting treatment of leucocyte in urine adopts t test to compare the difference between the administration group and the model group. The statistical processing is carried out by adopting computer SPSS software. The results are shown in tables 5 to 7.

TABLE 5 Effect of stranguria-treating preparation on urine leukocytes of rat with pyelonephritis

TABLE 6 Effect of drench preparation on PRO, BLD, KET, BIL, URO urine of rat on day 2

TABLE 7 Effect of drench preparation on PRO, BLD, KET, BIL, URO urine in rat on day 3

As can be seen from Table 5, the rat bacterial nephritis in the experiment can be recovered by itself, but the recovery of the stranguria preparation group is obviously better than that of the model group, and particularly the recovery of 3 example groups of the invention is better than that of the commercially available stranguria granule group; secondly, as can be seen from tables 6-7, the stranguria preparation can significantly reduce the amount of occult blood in urine of rats with bacterial nephritis, and the effect of the 3 example groups of the invention is better than that of the commercially available stranguria granule group. The stranguria treating preparation has certain treatment effect on experimental bacterial nephritis rats, and the curative effect is superior to that of the stranguria treating granules sold on the market.

Drawings

Fig. 1 is a graph of critical relative humidity of stranguria treating granules.

The abscissa in the figure represents the relative humidity of the environment and the ordinate represents the moisture absorption rate of the particles.

Detailed Description