阅读说明：本技术 一种治疗关节疼痛、腰腿酸痛制剂的制备方法 (Preparation method of preparation for treating arthralgia and soreness of waist and lower extremities ) 是由 黄大权 唐新 邓春霞 于 2019-11-27 设计创作，主要内容包括：本发明公开了一种治疗关节疼痛、腰腿酸痛制剂的制备方法,将制川乌、制草乌、防已、防风、续断、牛膝、桂枝、威灵仙、老鹳草的提取清膏置填充有D101大孔树脂的层析柱柱顶,乙醇洗脱,收集洗脱液浓缩成浸膏；将浸膏加入海藻酸钠溶液中,搅拌制成水相；取液体石蜡和聚山梨酯加热混匀制得油相；将水相缓慢加入油相中,迅速降温后加入异丙醇,静置,过滤,分离,取固体物真空干燥,得微囊；取微囊加入助剂,混匀,压片,包衣,即得。本发明可明显提高制剂的稳定性、有效性,药物释放稳定、平缓,明显降低药物的毒副作用,提高药物生物利用度。该制备方法的工艺简单、容易操作、生产成本低,容易实现工业化生产,具有良好的推广前景。(The invention discloses a preparation method of a preparation for treating arthralgia and soreness and pain in waist and lower extremities, which comprises the steps of placing extract of prepared radix aconiti, prepared radix aconiti kusnezoffii, radix stephaniae tetrandrae, radix sileris, radix dipsaci, radix achyranthis bidentatae, cassia twig, radix clematidis and geranium wilfordii into the top of a chromatographic column filled with D101 macroporous resin, eluting with ethanol, collecting eluent and concentrating into extract; adding the extract into sodium alginate solution, and stirring to obtain water phase; heating and uniformly mixing liquid paraffin and polysorbate to prepare an oil phase; slowly adding the water phase into the oil phase, rapidly cooling, adding isopropanol, standing, filtering, separating, and vacuum drying solid to obtain microcapsule; adding adjuvant into the microcapsule, mixing, tabletting, and coating. The invention can obviously improve the stability and the effectiveness of the preparation, has stable and smooth drug release, obviously reduces the toxic and side effect of the drug and improves the bioavailability of the drug. The preparation method has the advantages of simple process, easy operation, low production cost, easy realization of industrial production and good popularization prospect.)

1. A preparation method of a preparation for treating arthralgia and soreness and pain in waist and lower extremities is characterized by comprising the following steps:

(1) 100 parts of processed radix aconiti, 100 parts of processed radix aconiti kusnezoffii, 100 parts of radix stephaniae tetrandrae, 100 parts of radix sileris, 100 parts of radix dipsaci, 100 parts of radix achyranthis bidentatae, 100 parts of cassia twig, 100 parts of radix clematidis and 100 parts of geranium are respectively taken according to the prescription amount, water is added for 2-3 times, the water amount is 6-8 times of the total weight of the medicinal materials each time, the extraction time is 2-3 hours, decoction liquids are merged and filtered, and the filtrate is decompressed and concentrated into clear paste with the relative density of 1.10-1.20;

(2) placing the fluid extract on the top of a chromatographic column filled with D101 macroporous resin, eluting with 55-65% ethanol, collecting eluate 4 times the volume of the fluid extract, recovering ethanol, and concentrating to obtain extract with relative density of 1.30-1.35 at 65 deg.C;

(3) placing sodium alginate in a batching pot, adding water, heating at 80-90 deg.C to dissolve sodium alginate to obtain 20% sodium alginate solution, adding the extract, stirring to make the extract fully dissolved in sodium alginate solution to obtain water phase; placing liquid paraffin in a mixing pot, adding polysorbate 80, heating to 80-90 deg.C, mixing, and making into oil phase;

(4) controlling the temperature of the oil phase at 75-80 deg.C, stirring, slowly adding the water phase into the oil phase, and stirring for 10min to obtain suspension; cooling the suspension to 20-30 ℃, adding isopropanol accounting for 3-5% of the total volume of the suspension, and standing for 18-24h to obtain standing liquid; filtering the standing solution, separating solid phase and liquid phase, and vacuum drying the solid to obtain microcapsule;

(5) weighing the following raw materials in parts by weight: 100 parts of microcapsules, 25-30 parts of hydroxypropyl methyl cellulose, 9-10 parts of lactose, 35-40 parts of microcrystalline cellulose, 8-10 parts of sodium dodecyl sulfate, 8-10 parts of polyvinylpyrrolidone and 1 part of superfine silica gel powder, uniformly mixing, pressing into plain tablets and coating with a film.

2. The method for preparing the preparation for treating arthralgia and soreness of waist and legs as claimed in claim 1, wherein the water content of the microcapsule is less than or equal to 6%.

3. The method for preparing the preparation for treating arthralgia and soreness of waist and legs as claimed in claim 1, wherein the stirring speed in steps (3) and (4) is 1500-2000 rpm.

4. The preparation method of the preparation for treating arthralgia and soreness of waist and legs according to claim 1, wherein the vacuum drying temperature in step (4) is 60-70 ℃ for 10-12 hours.

5. The preparation method of the preparation for treating arthralgia and soreness of waist and legs according to claim 1, wherein the tablet weight of step (5) is 0.30-0.35 g.

6. The preparation method of the preparation for treating arthralgia and soreness of waist and legs according to claim 1, wherein the mass ratio of the fluid extract obtained in the step (2) to the D101 macroporous resin is 5: 1.

7. The preparation method of the preparation for treating arthralgia and soreness of waist and legs according to claim 1, wherein the mass ratio of the extract to the sodium alginate in the step (3) is 1: 1; the mass ratio of the extract to the liquid paraffin to the polysorbate is 1:1.2:6.

8. A tablet prepared by the preparation method of the preparation for treating arthralgia and soreness of waist and lower extremities according to claim 1, wherein the content range of the tablet is as follows: the total aconitine content is less than or equal to 20 ug/tablet, and tetrandrine content is greater than or equal to 3.0 mg/tablet.

Technical Field

The invention relates to a preparation method of a preparation for treating arthralgia and soreness and pain in waist and lower extremities.

Background

Rheumatism ostalgia is caused by invasion of wind-cold-dampness evil into human body, and after the wind-cold-dampness evil invades the human body, tendons and vessels are blocked and blocked, pain is caused by obstruction, therefore, the red swelling pain is often caused at the joints, periosteum, muscles and other parts of the human body, the main symptoms are joint pain, morning stiffness (the joints are sticky and stiff after the patient gets morning or has a rest for a long time, and can be relieved or disappeared after the patient moves), joint swelling and tenderness (the joints with pain are signs of synovitis or surrounding soft tissue inflammation, and the degrees of the joint are different due to different degrees of inflammation) and joint swelling pain (the finger joints lose normal shapes and the moving range of the finger joints are limited, for example, the knees can not be completely straightened, the metacarpophalangeal joints of the hands have ulnar deviation, the joints are dislocated, and the like), of the above symptoms, morning stiffness is most prominent in rheumatoid arthritis and can last for hours, with shorter duration in other arthritis; joint swelling and tenderness can be caused by joint cavity effusion or synovial hypertrophy; joint swelling and pain is associated with cartilage and bone destruction, and is common in rheumatoid arthritis. The rheumatism bone disease has the characteristics of slowness, wandering property, multiple occurrence, symmetry, fusibility, disability, positive test of serum rheumatoid factors, accelerated blood sedimentation in the activity period and the like.

97% of middle-aged and elderly people in China suffer from lumbar diseases, wherein complicated nerve type lumbar pain is high. In recent years, the trend of youth is shown, the disease incidence of people under 40 years old is up to more than 25%, and the traditional Chinese medicine considers that the disease belongs to the category of 'bone flaccidity' in the traditional Chinese medicine, and the disease can not nourish bones and marrow, and can not nourish kidney yin and essence due to kidney deficiency and essence deficiency.

Pain in the waist and lower extremities refers to the common conditions in the outpatient clinic of spinal and spinal surgery. The pain in the waist mainly includes strain pain (soft tissue pain), disc pain and rheumatic diseases. The leg pain mainly comprises lumbar disc herniation, arthritis, vascular diseases and rheumatic diseases.

At present, no effective treatment medicine exists for treating nerve type lumbar vertebra pain at home and abroad, and the traditional Chinese medicine mainly takes the effects of nourishing liver and kidney, dispelling wind-damp, relieving swelling and pain, relaxing muscles and stimulating blood circulation as main components and takes the existing Chinese herbal medicines as auxiliary components for treatment. Massage, fixed braking and manipulation are external forces, which only can temporarily relieve pain, but cannot achieve the purpose of treatment. While acupuncture and moxibustion can dredge meridians, activate blood and alleviate pain, it can only assist the nervous lumbar pain. The treatment mainly depends on drug therapy, and the closed therapy is that the drug is injected around pain points and nerve roots, but the closed therapy has great harm to human bodies and is not suitable for common use. Physical therapy is to act on human body (such as infrared ray, magnetism and electricity) through various physical factors, so as to achieve the purposes of diminishing inflammation, relieving pain and accelerating recovery, and is very effective in improving clinical symptoms, but has certain harm to human body. The operation treatment is mainly used for people who seriously affect life, work and rest, and is not effective through non-operation treatment. The operation changes the original tissue structure of human body, belonging to traumatic therapy. For example, some patients are easy to cause degeneration of other lumbar intervertebral discs or cause swelling or protrusion in different degrees after a period of operation, and are also easy to produce nerve adhesion or leg and foot numbness, lose consciousness, and especially easy to cause hyperosteogeny or unstable vertebrae. Therefore, the operation therapy can only be adopted when necessary, and the lumbar protrusion disease belongs to self-limiting or self-healing diseases to some extent, and the conservative therapy should be selected as much as possible.

The prescription of Fengshiling tablet is composed of nine traditional Chinese medicines of prepared radix aconiti, prepared radix aconiti kusnezoffii, radix stephaniae tetrandrae, radix sileris, teasel root, achyranthes, cassia twig, radix clematidis and geranium wilfordii. The earliest Fengshiling tablet prescription is loaded on the third volume of 50 pages of the health department medicine standard Chinese medicine prescription preparation with the standard code of WS3-B-0518-91, has the functions of expelling wind and removing cold, relaxing tendons and activating collaterals, and is used for treating anemofrigid-damp arthralgia, deadlimb, soreness and pain in waist and lower extremities. The preparation method of the ministerial standard comprises the following steps: taking 68g of prepared radix aconiti, 102g of prepared radix aconiti kusnezoffii, 136g of radix stephaniae tetrandrae, 68g of radix saposhnikoviae, 68g of radix dipsaci, 68g of radix achyranthis bidentatae, 68g of cassia twig, 68g of radix clematidis and 136g of geranium, adding water for decocting twice, 3 hours for the first time and 2 hours for the second time, combining the decoctions, filtering, concentrating the filtrate under reduced pressure to form thick paste, adding a proper amount of starch, uniformly mixing, preparing into granules, drying, pressing into 1000 tablets.

For example, Chinese patent CN105362424A discloses a rheumatism tablet and a preparation method thereof, which comprises the following steps: 80g of immature bitter orange, 180g of cortex periplocae, 240g of radix clematidis, 240g of parasitic loranthus and 145g of rhizoma atractylodis are extracted by a frontal carbon oxide supercritical extraction method, dried under reduced pressure, crushed into nano dry paste by a high-energy nano impact mill, and added with functional auxiliary materials (microcrystalline cellulose, hydroxypropyl cellulose, cross-linked carboxymethyl cellulose, magnesium aluminum silicate, sodium chloride, mannitol and maltodextrin) to prepare the rheumatism tablet (plain tablet), the disintegration time of the medicine is remarkably shortened, and the curative effect is remarkably superior to that of the rheumatism tablet sold in the market. However, the product is a plain tablet, is not protected by a coating layer, and the mannitol and other auxiliary materials have strong hygroscopicity, so that the phenomenon that the quality of a finished product is affected by the occurrence of specks and the like on the surface of the tablet due to easy moisture absorption in the storage process, and even some adverse reactions may be caused.

Currently, the Fengshiling tablets sold in the market are products in the early nineties of the last century, but due to the limitation of conditions at the time, underground preparation technology and the like, the tablets are prepared only by simple decoction and concentration, most impurities cannot be removed, so that the prepared tablets have the problems of large dosage, dispersion (10 tablets each time and 2 times a day), long dissolution time, low bioavailability and the like after being taken, the effectiveness and stability of the medicine are greatly influenced, and the treatment effect is also directly influenced.

Moreover, the data show that the main active ingredients of the main ingredients of the prepared radix aconiti and the prepared radix aconiti kusnezoffii in the rheumatism tablet prescription are alkaloids such as aconitine and hypaconitine, and the rheumatism tablet has certain toxicity, can excite the vagus nerve, damage peripheral nerves, and mainly has the symptoms of poisoning of the nervous system and the circulatory system, and secondly has the symptoms of the digestive system. The clinical manifestations are numbness of mouth, tongue and limbs, and general tight sensation, which can decrease the autonomy of sinoatrial node by exciting vagus nerve, and cause the autonomy of translocation pacing point to increase, causing various arrhythmia and damaging cardiac muscle. Generally, 0.2mg (200ug) of pure aconitine can be poisoned by oral administration, and 3-5mg can be killed. Therefore, it is necessary to change the preparation process, improve the stability and effectiveness of the preparation, release the controlled release medicament at a high speed, reduce the toxic and side effects of the medicament, and improve the bioavailability of the medicament so as to meet various requirements of clinical treatment and household use, and particularly, the content of total aconitine in the preparation needs to be strictly controlled, so that the toxicity of the total aconitine is greatly reduced, and the safety and effectiveness of the administration of patients are ensured.

Disclosure of Invention

The invention aims to overcome the defects in the prior art and provides a rheumatism tablet, namely a preparation method of a preparation for treating arthralgia and soreness and pain in waist and lower extremities. The newly prepared preparation can obviously improve the stability and the effectiveness of the preparation, the release of the medicine is stable and smooth, the toxic and side effect of the medicine is obviously reduced, and the bioavailability of the medicine is improved. The preparation method has the advantages of simple process, easy operation, low production cost and easy realization of industrial production.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows:

the preparation method of the preparation for treating arthralgia, lumbocrural aching pain comprises the following steps:

(1) 100 parts of processed radix aconiti, 100 parts of processed radix aconiti kusnezoffii, 100 parts of radix stephaniae tetrandrae, 100 parts of radix sileris, 100 parts of radix dipsaci, 100 parts of radix achyranthis bidentatae, 100 parts of cassia twig, 100 parts of radix clematidis and 100 parts of geranium are respectively taken according to the prescription amount, water is added for 2-3 times, the water amount is 6-8 times of the total weight of the medicinal materials each time, the extraction time is 2-3 hours, decoction liquids are merged and filtered, and the filtrate is decompressed and concentrated into clear paste with the relative density of 1.10-1.20;

(2) placing the fluid extract on the top of a chromatographic column filled with D101 macroporous resin, eluting with 55-65% ethanol, collecting eluate 4 times the volume of the fluid extract, recovering ethanol, and concentrating to obtain extract with relative density of 1.30-1.35 at 65 deg.C;

(3) placing sodium alginate in a batching pot, adding water, heating at 80-90 deg.C to dissolve sodium alginate to obtain 20% sodium alginate solution, adding the extract, stirring to make the extract fully dissolved in sodium alginate solution to obtain water phase; placing liquid paraffin in a mixing pot, adding polysorbate 80, heating to 80-90 deg.C, mixing, and making into oil phase;

(4) controlling the temperature of the oil phase at 75-80 deg.C, stirring, slowly adding the water phase into the oil phase, and stirring for 10min to obtain suspension; cooling the suspension to 20-30 ℃, adding isopropanol accounting for 3-5% of the total volume of the suspension, and standing for 18-24h to obtain standing liquid; filtering the standing solution, separating solid phase and liquid phase, and vacuum drying the solid to obtain microcapsule;

(5) weighing the following raw materials in parts by weight: 100 parts of microcapsules, 25-30 parts of hydroxypropyl methyl cellulose, 9-10 parts of lactose, 35-40 parts of microcrystalline cellulose, 8-10 parts of sodium dodecyl sulfate, 8-10 parts of polyvinylpyrrolidone and 1 part of superfine silica gel powder, uniformly mixing, pressing into plain tablets and coating with a film.

Preferably, the microcapsules have a moisture content of 6% or less.

Preferably, the stirring speed of the steps (3) and (4) is 1500-.

Preferably, the vacuum drying temperature of the step (4) is 60-70 ℃ and the time is 10-12 hours.

Preferably, the weight of the sheet of step (5) is 0.30 to 0.35 g.

Preferably, the mass ratio of the clear paste obtained in the step (2) to the D101 macroporous resin is 5: 1.

Preferably, the mass ratio of the extract to the sodium alginate in the step (3) is 1: 1; the mass ratio of the extract to the liquid paraffin to the polysorbate is 1:1.2:6.

The total aconitine content of the tablets prepared by the preparation method is less than or equal to 20 ug/tablet, and the tetrandrine content is more than or equal to 3.0 mg/tablet.

The source and the effect of the traditional Chinese medicinal materials adopted by the invention are as follows:

radix Aconiti Preparata is processed product of radix Aconiti (dried mother root of Aconitum carmichaeli Debx. of Ranunculaceae). Pungent, bitter and hot; is toxic. It enters heart, liver, kidney and spleen meridians. The same applies to Sichuan aconite root. Dispel wind and dampness, warm meridians and alleviate pain. Can be used for treating arthralgia due to wind-cold-dampness, arthralgia, psychroalgia of heart and abdomen, cold hernia, and pain due to anesthesia.

Radix Aconiti Kusnezoffii Preparata is processed product of radix Aconiti Kusnezoffii (dried root tuber of Aconitum kusnezoffii Reichb. of Ranunculaceae). Pungent, bitter and hot; is toxic. It enters heart, liver, kidney and spleen meridians. Dispel wind and dampness, warm meridians and alleviate pain. Can be used for treating arthralgia due to wind-cold-dampness, arthralgia, psychroalgia of heart and abdomen, cold hernia, and pain due to anesthesia.

Radix Stephaniae Tetrandrae is dried root of Stephania tetrandra S.Moore of Menispermaceae family. Bitter and cold. It enters bladder and lung meridians. Induce diuresis to alleviate edema, dispel wind to alleviate pain. Can be used for treating edema, loempe, dysuresia, eczema, skin sore, and rheumatalgia; hypertension is caused.

Ledebouriella root, a dried root of the plant Saposhnikovia divaricata (Turcz.) switzerland, of the family umbelliferae, schischchk. Pungent, sweet and warm. It enters bladder, liver and spleen meridians. Relieve exterior syndrome, dispel wind, subdue dampness and stop spasm. Can be used for treating common cold, headache, rheumatalgia, rubella, pruritus, and tetanus.

Radix Dipsaci is dried root of Dipsacus asperoides C.Y.Cheng et T.M.ai (or Dipsacus asper Wall) of Dipsacaceae. Bitter and pungent with mild warm nature. It enters liver and kidney meridians. Tonify liver and kidney, strengthen tendons and bones, continue fracture and stop metrorrhagia and metrostaxis. Can be used for treating soreness of waist and knees, rheumatalgia, metrorrhagia, fetal leakage, and traumatic injury. Jiu xue Duan is mainly used for arthralgia due to wind-dampness and traumatic injury. Salted xu Duan is mostly used for soreness and weakness of waist and knees.

Achyranthis radix is dried root of Achyranthus bidentis Blume. Bitter, sour and neutral. It enters liver and kidney meridians. Tonify liver and kidney, strengthen tendons and bones, dispel blood stasis and dredge meridians, and draw blood to descend. Can be used for treating soreness of waist and knees, weakness of tendons and bones, amenorrhea, abdominal mass, and vertigo due to liver-yang.

Cassia twig, a dried twig of Cinnamomum cassia Cassia Presl of Lauraceae. Pungent, sweet and warm. It enters heart, lung and bladder meridians. Induce sweating to relieve muscles, warm and dredge meridians, strengthen yang to transform qi, and smooth the flow of qi. Can be used for treating wind-cold type common cold, abdominal psychroalgia, blood cold amenorrhea, arthralgia, phlegm retention, edema, palpitation, and galloping.

Radix Clematidis is dried root and rhizome of Clematis chinensis Osbeck, Clematis hexapetala pall or Clematis manshurica rupr of Ranunculaceae. Pungent, salty and warm. It enters bladder meridian. Dispel wind and dampness, dredge collaterals and alleviate pain. Can be used for treating rheumatic arthralgia, numbness of limbs, spasm of muscles and tendons, difficulty in flexion and extension, and choking throat.

Geranium, is a dry aerial part of Geranium wild, Geranium Wilfordii Maxodii Maxim or Geranium carolina L. Pungent, bitter and mild. It enters liver, kidney and spleen meridians. Dispel wind-damp, unblock collaterals, check diarrhea and alleviate diarrhea. Can be used for treating rheumatalgia, numbness, spasm, soreness of bones and muscles, and diarrhea and dysentery.

Due to the adoption of the technical scheme, the invention has the following beneficial effects:

1. on the basis of the original rheumatism tablet medicinal material extraction process, the preparation process of the medicinal material extract is optimized, the purification process of macroporous resin to the medicinal material extract is added, most impurities are effectively removed, the auxiliary material consumption is greatly reduced, and the toxic and side effects of the impurities on a human body can be effectively reduced.

2. The method of the invention can obviously reduce the hygroscopicity of the preparation after microencapsulating the medicinal material extract and pressing the medicinal material extract into a film-coated tablet, so that the medicament is not easy to be affected with damp and deteriorated during the production and storage processes, and the stability and the effectiveness of the rheumatism tablet can be improved.

3. The method of the invention has certain sustained and controlled release performance after the extract is microencapsulated, the release degree is obviously reduced compared with the commercially available rheumatism tablet, the drug release is slow and stable, the inactivation of the drug in the stomach can be prevented or the irritation to the stomach can be reduced, and the bioavailability of the drug can be improved.

4. The invention takes sodium alginate as the wall material of the microcapsule, has wide raw material source, low price, good water solubility and emulsibility, and can better perform inclusion on the medicament.

5. The dosage of the preparation obtained by the method is reduced from 10 tablets/time of currently marketed Fengshiling tablets to 5 tablets/time, and the dosage of the preparation is reduced from 2 times of daily administration to 1 time, so that the physical burden of a patient is relieved.

6. Through detection, the content range of the preparation obtained by the method is as follows: the total aconitine content is less than or equal to 20 ug/tablet, and tetrandrine content is not less than 3.0 mg/tablet, so as to effectively reduce aconitine content.

7. The method has the advantages of simple process, easy operation, low energy consumption, time saving, low production cost and easy realization of industrial production.

Drawings

Fig. 1 is a drug release profile.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail below with reference to preferred embodiments. It should be noted, however, that the numerous details set forth in the description are merely for the purpose of providing the reader with a thorough understanding of one or more aspects of the present invention, which may be practiced without these specific details. Unless otherwise indicated, the percentages of the amount of ethanol in the present invention are volume percentages, and v/v represents the volume ratio of the solution.