CN1608661A

CN1608661A - Capsule preparation for treating gynecological diseases and preparation process thereof

Info

Publication number: CN1608661A
Application number: CN 200410022634
Authority: CN
Inventors: 穆润华; 谌贻洪
Original assignee: Guiyang Jirentang Pharmaceutical Co ltd
Current assignee: Guiyang Jirentang Pharmaceutical Co ltd
Priority date: 2004-05-25
Filing date: 2004-05-25
Publication date: 2005-04-27
Anticipated expiration: 2024-05-25
Also published as: CN1289110C

Abstract

The invention relates to a capsule preparation for treating gynecological diseases and a preparation process thereof, wherein the capsule preparation is prepared from honeysuckle stem, suberect spatholobus stem, east Asian tree fern rhizome, dandelion, motherwort herb, plantain herb and the like; the process provided by the invention has the characteristics of simple production process, stable product quality and good capsule quality stability, and because no auxiliary material is used in the formula, no auxiliary material containing no medicinal component exists in the effective ingredients of the medicament, so that the administration dosage can be reduced, and the administration of patients is facilitated; because the sugar-free health care product does not contain sugar, all patients can use the health care product conveniently without contraindications; the preparation is more convenient to take and carry, and the product can be preserved and stored for a longer time; provides more and better choices for treating patients with pelvic inflammation.

Description

Capsule preparations and the preparation technology thereof for the treatment of gynecological disease

Technical field: the present invention is a kind of capsule preparations and preparation technology thereof who treats gynecological disease, belongs to the technical field of medicine.

Background technology: pelvic infecton refers to the general name of the Lymph nodes such as pelvic cavity internal reproductive organ and pelvic cavity connective tissue, pelvic peritoneum, be one of gynaecology's common disease, illness rate reaches 40% in the women of child-bearing age, rural women's illness rate reaches 60%, the trend that increasingly increases of reproductive disease rises the pelvic infecton incidence of disease gradually in recent years, and special population women illness rate reaches 80%. Pelvic infecton can be divided into acute and chronic two kinds. Acute pelvitis of pelvic cavity is mainly caused by pathogen, also can without typical acute inflammation history, when Abwehrkraft des Koepers is relatively poor, show acute attack; Chronic pelvic inflammatory disease often fails appropriately thoroughly to treat for acute pelvitis of pelvic cavity, and patient's physique is relatively poor, due to the course of disease is delayed. Clinical manifestation can have different from range size because of the weight of inflammation, patient often has high heat, shiver with cold, poor appetite and hypogastralgia, menstruation increases and leucorrhea increasing, during the ovarian function infringement menstrual disorder can be arranged, fallopian tube adhesion can cause infertile when blocking, also can with digestive system, urinary system symptom, have a strong impact on patient's life, study, work and mood.

Antibiotic, immunopotentiator and physiotherapy are now mainly adopted in the treatment of pelvic infecton; The normal curative effect of alone antibiotic etc. treatments is not satisfied, and often due to illness kitchen range hyperplasia adhesion, and local absorption is bad, bacterial resistance and the course of disease is prolonged, and side effect is many, or causes flora imbalance, is difficult to eradicate focus; Because the pelvic infecton incidence of disease is high, market capacity is very big. " PENYANJING KELI " preparation that this class disease of a kind of special for treating is arranged in the prior art; It has certain therapeutic action to our described disease; But there is a larger problem in it: be exactly the auxiliary material that has added sucrose in this granular preparation of preparation, limited some patients' use, particularly diabetic as the preparation that contains sugar and obviously just should not use this product; This product is owing to containing sugar part, so the time limit of preserving is also shorter in the formulation in addition; Rotten situation also occurs easily; The problem that prepared method more complicated, needs solve is many.

Goal of the invention: the object of the invention is to: provide a kind of capsule preparations and preparation technology thereof who treats gynecological disease, this product

The preparation technology who can effectively treat this class gynaecology common disease of pelvic infecton, provides simultaneously is simple, reliable, and production cost is cheaper; The present invention consists of like this: the capsule preparations for the treatment of gynecological disease, to calculate according to components by weight percent, and it is mainly by 1500～2000 parts of caulis loniceraes, 1500～2000 parts of reticulate millettias, 1500～2000 parts of rhizoma cibotii; 500～750 parts of dandelions, 500～750 parts of motherworts, 500～750 parts of Asiatic plantains, 300～500 parts of the radix paeoniae rubrathe, 300～500 parts of Ligusticum wallichiis are prepared from. Prescription is accurately: it makes 1000 capsules with caulis lonicerae 1667g reticulate millettia 1667g rhizoma cibotii 1667g dandelion 666.7g motherwort 666.7g, Asiatic plantain 666.7g radix paeoniae rubrathe 400g Ligusticum wallichii 400g. The preparation technology of capsule preparations: be cut into suitable size after medicinal material taken by weighing, boiling is extracted 2～4 times, adds the water yield of 6～12 times of medicinal materials at every turn, decocts 1.5～3 hours at every turn, filter, filtrate is concentrated in right amount, spray-drying or drying under reduced pressure, get dry extract, be ground into fine powder, filled capsules. Concrete method is: medicinal material is cut into suitable size, and boiling is extracted 2～4 times, adds the water yield of 6～12 times of medicinal materials at every turn, the each decoction 1.5～3 hours filters, and it is 1.05～1.30 (90 ℃) that filtrate is concentrated into relative density, adding ethanol is 45～75% to containing the alcohol amount, stir evenly, left standstill the leaching supernatant 12～48 hours, be concentrated into thick paste behind the Recycled ethanol, spray-drying or drying under reduced pressure are ground into fine powder, are filled to capsule.

The preparation technology of this capsule preparations is all right: medicinal material is cut into suitable size or is ground into meal, with 45～75% ethanol percolations, collect percolate, be concentrated into thick paste behind the Recycled ethanol, spray-drying or drying under reduced pressure are ground into fine powder, are filled to capsule. Concretely: medicinal material is cut into suitable size, adds 45～75% alcohol refluxs and extract 2～4 times, each 1～2 hour, filter, be concentrated into thick paste behind the filtrate recycling ethanol, spray-drying or drying under reduced pressure are ground into fine powder, are filled to capsule.

Adopt reduced vacuum dry among the present invention, its technical conditions are: vacuum 0.07～0.08Mpa, 70～75 ℃, 24 hours.

We's all cards of controlling are to accumulate the long-pending part of the body cavity below the umbilicus, housing the bladder, kidneys and bowels because of the malicious stagnant heat that wets, and the visitor fights mutually with qi and blood in born of the same parents, causes qi and blood stagnation, and a loss on transmission is appointed in punching, and the delay mistake is controlled thereby fallen ill, and prolonged illness is unbroken, injures the liver kidney; Evil quadrature is striven, and is disharmony between ying and wei, and evil poison is stopped up Sheng, thus see irregular menstruation, fever with aversion to cold, it is lossless to have a headache, or little sweat; The stagnation of blood stasis and heat part of the body cavity below the umbilicus, housing the bladder, kidneys and bowels, then hypogastralgia tenderness; Wet turbid making a bet causes profuse leukorrhea, and look yellow is or white, or red double mutually in vain; The liver kidney is impaired, then the pain in the back burnout; Dominance of heat in the interior then the polydipsia constipation urinate red, red tongue with yellowish and greasy fur, slippery and rapid pulse or big vast number; Prolonged illness is unbroken, and impairment of yin is breathed hard, and then tongue is light, and arteries and veins is thin. Control suitable clearing heat and promoting diuresis, and the blood vein relaxing, adjusting meridian and stopping leukorrhea, blood-activating analgetic. Caulis lonicerae, dandelion, Asiatic plantain removing damp-heat in the side, the toxin expelling diuresis; Reticulate millettia, Ligusticum wallichii, motherwort are enriched blood and invigorate blood circulation, promote qi circulation opening warp, adjusting meridian and stopping leukorrhea; Rhizoma cibotii, the filling liver kidney of red spoon, the cool blood of removing summer-heat, the loose stasis of blood, spasmolysis, pain relieving. All medicines share, and play altogether clearing heat and promoting diuresis, enrich blood and invigorate blood circulation, adjusting meridian and stopping leukorrhea, the merit of blood stasis removing analgesic; Be suitable for various acute and chronic gynaecological imflammations.

Medicine provided by the invention is with the pure traditional Chinese medicine of eight flavors, and formulation composition is rigorous, the Chinese medicine of existing heat clearing and inflammation relieving, loose stasis of blood spasmolysis, the promoting flow of qi and blood circulation, adjusting meridian and stopping leukorrhea, the again product of useful gas righting, clearing heat and promoting diuresis in the side. Asiatic plantain, caulis lonicerae, dandelion, red spoon pharmacological evaluation and clinical practice prove broad-spectrum antiseptic Chinese medicine, to causing the main pathogens of pelvic infecton, has stronger inhibitory action such as staphylococcus aureus, Escherichia coli, shigella dysenteriae, hemolytic streptococcus etc.; Caulis lonicerae, red spoon have stronger antiinflammatory action, and the permeability and the inflammation that reduce capillary are oozed out; Pharmacology proves: blood-activating and stasis-removing has the blood circulation of the pelvic cavity of improvement and histotrophic nutrition state, improves metabolism, promotes inflammation to absorb, and eliminates the effect of connective tissue adhesion. High heat, shiver with cold, poor appetite, hypogastralgia, menstrual disorder, the menstruation that acute and chronic pelvic infecton and pelvic infecton are caused increases, can cause the infertile preferably curative effect that all has when leucorrhea increasing and fallopian tube adhesion obstruction. This product prescription avirulence composition is without the incompatibility of eighteen imcompatible pairs, 15 fears. It is simple that technique provided by the invention has production technology, and constant product quality is conducive to the characteristics of control of product quality. Capsule quality stability provided by the invention is good, owing to do not use auxiliary material in the side, so do not contain the auxiliary material of medicine composition in effective ingredient, can reduce taking dose like this, facilitates patients; Because do not have sugar part, all patients can both conveniently use and need not avoid; This formulation is more convenient for taking and carrying, and product can be preserved, store the long time; For the treatment of Patients with Pelvic Inflammatory Disease provides more, better selection. The present invention can give full play to the characteristics that the capsule bioavilability is high, production technology is comparatively simple, product quality is controlled easily, production cost is lower, increased the types of drugs for the treatment of gynecological disease, enriched medical market, be convenient to the patient and select, satisfy the custom that applicable crowd takes capsule.

The side separates: 1, caulis lonicerae: have clearing heat and detoxicating, the effect of dispelling wind vein relaxing. Be used for the seasonal febrile diseases heating, toxic-heat and blood stasis, the carbuncle sore that swell, rheumatic fever numbness, redness and swelling of joints heat is bitterly. Clinical bacillary dysentery and the enteritis of being used for the treatment of.

2, reticulate millettia: have and enrich blood, invigorate blood circulation, the function of vein relaxing. Be used for irregular menstruation, the deficiency of blood is sallow, paralysis and numbness, the cards such as arthralgia due to wind-dampness.

3, rhizoma cibotii: have filling liver kidney, strong waist knee, the function of wines used as antirheumatic. Be used for soreness and weakness of waist and knees, weakness of the lower extremities, the cards such as arthralgia due to wind-dampness.

4, dandelion: have clearing heat and detoxicating, the function of diuresis dissipating bind. Be used for acute mastitis, adenolymphitis, malignant boil carbuncle toxin, acute conjunctivitis, cold, fever, the diseases such as acute tonsillitis, hepatitis, cholecystitis, urinary tract infections; Dandelion preparation is to a certain extent like replacing antibiotic to use the effect that some disease is also shown broad-spectrum antibiotic; Effect from treatment virus flu, hepatitis etc. may also have antivirus action.

5, motherwort: motherwort has promoting blood circulation for regulating menstruation, removing blood stasis for promoting tissue regeneration, the function of inducing diuresis to reduce edema. Be used for irregular menstruation, dysmenorrhoea, postpartum blood stasis stomachache, ephritis edema, difficult urination, sore swollen toxin, traumatic injury.

6, Asiatic plantain: have reducing fever and causing diuresis, cool blood, the function of detoxifcation. Be used for bladder heat stagnation, difficult urination, under the stranguria with turbid discharge band, summer-heat and damp is rushed down dysentery, hematuria, bleeding from five sense organs or subcutaneous tissue, the hot hot eyes of liver, abscess of throat, carbuncle sore tumefacting virus.

7, red spoon: have clearing heat and cooling blood, the function of blood stasis removing analgesic. Be used for febrile virulent maculae, hematemesis and epistaxis, red eye, swell pain, liver-depressed hypochondrium pain through closing dysmenorrhoea, falls the cards such as macrolesion.

8, Ligusticum wallichii: have the promoting flow of qi and blood circulation. The function of wind-expelling pain-stopping. Clinical efficacy:

With ofloxacin capsule in contrast. In the 40 example observations with capsule for treating provided by the invention, chronic pelvic inflammatory disease treatment (8 a days) total effective rate course for the treatment of is 90.0%, obvious effective rate is 65.0%, symptom takes a turn for the better fast, satisfactory effect, significantly be better than alone antibiotic group, the patient of alone medicinal capsule for treating pelvic inflammatory disease treatment does not find the bad reactions such as times of defecation increases, dry throat, pharyngalgia, vomiting during medication.

Medicinal capsule for treating pelvic inflammatory disease treatment endoretention of damp heat, qi stagnation and blood stasis type chronic pelvic inflammatory disease 30 examples, the same period and a thousand pieces of gold sheet compare, and the result shows through clinical observation treatment: after the treatment group treatment, no matter be clinical cardinal symptom, Signs and laboratory examination all have obvious improvement. The clinical symptoms that chronic pelvic inflammatory disease belonged to endoretention of damp heat, qi stagnation and blood stasis type: unusual under soreness of waist pain, the band, treated effect is more than 80.00%. To clinical uterus and the attachment area tenderness is efficient reaches more than 82%. And conventional to leukorrhea, blood divides in vain, blood sedimentation has efficient reaching more than 85% after the unusual treatment, and is wherein especially obvious to reduce white count action, reaches 100%. But the attachment area due to chronic inflammation hyperblastosis adhesion is thickened, clinical therapeutic efficacy is efficient to reach 12.5%, this also meets the objective law of disease treatment development, chronic pelvic inflammatory disease is efficient reaches 93.33% for this product treatment, model case: (1) Wang, 34 years old, the worker of machinery plant. Sign: the high heat of shivering, temperature is 39.5 ℃, and abdominal pain refusing to pressure is face of acute ill, and yellowish leukorrhea increases, and is dirty smelly like purulence, ache of the spinal column, headache, n and V, drak urine, yellowish fur, slippery and rapid pulse. Gynecologial examination: the uterus is bigger, and tenderness is arranged. Laboratory examination: leucocyte is 15 * 10⁹/ L; B ultrasonic shows, has inflammatory to ooze out in the pelvic cavity. Be diagnosed as acute pelvitis of pelvic cavity. Use this product treatment 8 days, 3 tablets/times, 3 times on the one, first and second sky is used ofloxacin capsule, and the third body temperature drop is extremely normal, pain relief; Basic recovery from illness in the 5th day, leucocyte is down to normally, consolidates and uses this product 3 days, leaves hospital.

(2) Ni, 28 years old, certain machine-operated worker. Sign: readme is hypogastralgia repeatedly, rectal tenesmus, leucorrhea increasing, be everlasting tired after aggravation, normal low-heat to 38.5 ℃, lassitude hypodynamia, delay menstrual period. Gynecologial examination: retroposition of uterus, owe movable, left side attachment thickens, mild tenderness; Laboratory examination: leucocyte 12 * 10⁵/ L, B ultrasonic see the fast shape thing of inflammatory, have the edge unclear, the dark space of essence inequality, in closeer luminous point is arranged; Laparoscopy is seen obvious inflammation, adhesion. Be diagnosed as chronic pelvic inflammatory disease. Use this product treatment 30 days, 3 tablets/times, 3 times on the one, it is normal that sign is recovered, and face is red even, and menstrual period are normal.

The specific embodiment:

Embodiments of the invention 1: it is mainly by 1500 kilograms of caulis loniceraes, 1500 kilograms of reticulate millettias, 1500 kilograms of rhizoma cibotii; 500 kilograms of dandelions, 500 kilograms of motherworts, 500 kilograms of Asiatic plantains, 300 kilograms of the radix paeoniae rubrathe, Ligusticum wallichii 300 is prepared from. Be cut into suitable size after medicinal material taken by weighing, boiling is extracted 2 times, adds the water yield of 6 times of medicinal materials at every turn, the each decoction 1.5 hours filters, and it is 1.05～1.30 (90 ℃) that filtrate is concentrated into relative density, adding ethanol is 45% to containing the alcohol amount, stir evenly, left standstill the leaching supernatant 12 hours, be concentrated into thick paste behind the Recycled ethanol, spray-drying is ground into fine powder, is filled to capsule.

Embodiments of the invention 2: it is mainly by 2000 kilograms of caulis loniceraes, 2000 kilograms of reticulate millettias, and 2000 kilograms of rhizoma cibotii, 750 kilograms of dandelions, 750 kilograms of motherworts, 750 kilograms of Asiatic plantains, 500 kilograms of the radix paeoniae rubrathe, 500 kilograms of Ligusticum wallichiis are prepared from. Be cut into suitable size after medicinal material taken by weighing, boiling is extracted 4 times, adds the water yield of 12 times of medicinal materials at every turn, the each decoction 3 hours filters, and it is 1.05～1.30 (90 ℃) that filtrate is concentrated into relative density, adding ethanol is 75% to containing the alcohol amount, stir evenly, left standstill the leaching supernatant 48 hours, be concentrated into thick paste behind the Recycled ethanol, drying under reduced pressure is ground into fine powder, is filled to capsule.

Embodiments of the invention 3: mainly by caulis lonicerae 1900 grams, reticulate millettia 1600 restrains for it, rhizoma cibotii 1600 grams, and dandelion 500 grams, motherwort 650 grams, Asiatic plantain 650 grams, the radix paeoniae rubrathe 350 restrains, and Ligusticum wallichii 400 is restrained standby forming. Medicinal material is cut into suitable size or is ground into meal, add 75% alcohol reflux and extract 4 times, each 2 hours, filter, be concentrated into thick paste behind the filtrate recycling ethanol, drying under reduced pressure is ground into fine powder, is filled to capsule.

Embodiments of the invention 4: it is mainly by 1800 kilograms of caulis loniceraes, 1900 kilograms of reticulate millettias, 1800 kilograms of rhizoma cibotii; 600 kilograms of dandelions, 600 kilograms of motherworts, 650 kilograms of Asiatic plantains, 400 kilograms of the radix paeoniae rubrathe, 400 kilograms of Ligusticum wallichiis are prepared from. Medicinal material is cut into suitable size or is ground into meal, add 45% alcohol reflux and extract 2 times, each 1 hour, filter, be concentrated into thick paste behind the filtrate recycling ethanol, spray-drying is ground into fine powder, is filled to capsule.

Embodiments of the invention 5: caulis lonicerae 1667g, reticulate millettia 1667g, rhizoma cibotii 1667g, dandelion 666.7g, motherwort 666.7g, Asiatic plantain 666.7g, radix paeoniae rubrathe 400g, Ligusticum wallichii 400g, boiling 3 times, add 10 times of water gagings (increase when for the first time adding water medicinal material amount 1.4 times) at every turn, the each decoction 2 hours, soaked first 2.5 hours when decocting for the first time, collecting decoction, filter, it is 1.20 (90 ℃) that filtrate is concentrated into relative density, add ethanol and make that to contain alcohol amount be 65%, stir evenly, left standstill 12 hours, the leaching supernatant, be concentrated into thick paste behind the Recycled ethanol, (vacuum 0.07～0.08Mpa) is ground into fine powder to drying under reduced pressure, be filled to 1000 capsules, and get final product.

For the production of this medicine, the applicant has carried out a series of engineer testing

(1) chopping of crude drug: consider that modern production all extracts with multi-function extractor, the tank internal pressure is larger, medicinal material active ingredient is easy to fried, but also be easy to well-donely, therefore, can improve recovery rate though medicinal material is meticulous, but cause filtration difficulty, be unfavorable for the process operations such as filtration, so the medicinal material appropriateness is cut little extraction, feed intake in clean medicinal material amount. Reticulate millettia, rhizoma cibotii, the radix paeoniae rubrathe, Ligusticum wallichii section, caulis lonicerae, motherwort are cut into segment, and dandelion, Asiatic plantain suitably cut little for subsequent use.

(2) the water extract-alcohol precipitation condition is selected

This product major function is clearing heat and promoting diuresis, and the blood vein relaxing, adjusting meridian and stopping leukorrhea. Be used for damp invasion of lower energizer, leukorrhea, pelvic infecton are seen above patient. Main extraction process is water extraction, alcohol precipitation process, and water soluble ingredient contained in the component should be mainly the compositions such as glycoside, organic acid, water-soluble alkaloid. Because some composition is difficult to measure or is that two kinds and two or more component are common in the component, be difficult to determine the transfer case of active ingredient, so in the extraction process examination, plan as evaluation index, is carried out the effects with the extracted amount of active ingredient Paeoniflorin in solid content (dried cream) extracted amount and the red spoon.

(1), instrument and reagent

High performance liquid chromatograph: Shimadzu LC-10A_TVP，SPD-6A _VPUV-vis detector, CLASS-_VP(ver 6.12) chromatographic work station; CTO-10AS_VPThe chromatographic column insulating box

Shimadzu AY120 type (scale division value 0.1mg) electronic balance, Shimadzu AUW220 type (scale division value 0.01mg) electronic balance;

CH-250 type ultrasonic cleaner (Beijing innovation moral ultrasonic electronic research institute); 800 type desk centrifuges (Shanghai Surgical Operation Equipment Factory). Electric-heated thermostatic water bath (Tianjin Tai Site Instr Ltd.);

Methyl alcohol, acetonitrile are chromatographically pure, and water is double distilled water; All the other reagent are pure for analyzing

Paeoniflorin reference substance (for assay): be purchased from Nat'l Pharmaceutical ﹠ Biological Products Control Institute, lot number 0736-200116

(2), water absorption rate is measured

Draw fixed prescription, ratio takes by weighing medicinal material and adds 10 times of water gagings, soaks, and observes 1 time every 30 minutes, to the whole saturating hearts of medicinal material, the time is 90 minutes as a result, filters to the greatest extent, claims wet dregs of a decoction weight. The medicinal material water absorption rate is calculated as by following formula:

The medicinal material water absorption rate is 140.5%.

(3), the investigation of extraction process by water condition

We intend adopting orthogonal test to the water consumption in the extraction process by water, decoct number of times, decocting time, technological parameters such as soak time when extracting are for the first time investigated.

Take by weighing 9 parts of medicinal materials by formula rate respectively, every part of 117g (caulis lonicerae 25g, reticulate millettia 25g, rhizoma cibotii 25g, dandelion 10g, motherwort 10g, Asiatic plantain 10g, red spoon 6g, Ligusticum wallichii 6g, wherein contain Paeoniflorin 91.2mg in the red spoon), carry out orthogonal test (wherein each test amount of water first time should be considered the medicinal material water absorption rate, has both increased by 1.405 times of water gagings of medicinal material amount). Orthogonal test factor table and result are as follows:

The factor level table

Level	Factor
	Factor				A: amount of water (doubly amount)	B: decoct number of times	C: decocting time (hour)	D: decoct for the first time soak time (hour)
	1	8	2	1	A: amount of water (doubly amount)	B: decoct number of times	C: decocting time (hour)	D: decoct for the first time soak time (hour)	0
2	1	8	2	1	10	3	2	1.5	0
2	3	12	4	3	10	3	2	1.5	2.5

Orthogonal Experiment and Design table and result

Numbering	Factor				Evaluation index
	Factor				Evaluation index				A	B	C	D	Solid content		Paeoniflorin extracted amount (mg)
	Solid content amount (g)	Solid yield (%)	Concentration among the 100ml (mg/ml)	Average extracted amount (mg)									Solid content		Paeoniflorin extracted amount (mg)
	Solid content amount (g)	Solid yield (%)	Concentration among the 100ml (mg/ml)	Average extracted amount (mg)	1	1	1	1					1	14.9692	12.794	0.500	50.0
2	1	2	2	2	1	1	1	1	21.2688	18.178	0.613	61.3	1	14.9692	12.794	0.500	50.0
2	1	2	2	2	3	1	3	3	21.2688	18.178	0.613	61.3	3	25.2488	21.580	0.577	57.7
4	2	1	2	3	3	1	3	3	18.4036	15.729	0.586	58.6	3	25.2488	21.580	0.577	57.7
4	2	1	2	3	5	2	2	3	18.4036	15.729	0.586	58.6	1	18.2942	15.636	0.511	51.1
6	2	3	1	2	5	2	2	3	22.2720	19.035	0.595	59.5	1	18.2942	15.636	0.511	51.1
6	2	3	1	2	7	3	1	3	22.2720	19.035	0.595	59.5	2	18.2644	15.610	0.541	54.1
8	3	2	1	3	7	3	1	3	20.2102	17.273	0.634	63.4	2	18.2644	15.610	0.541	54.1
8	3	2	1	3	9	3	3	2	20.2102	17.273	0.634	63.4	1	22.7626	19.455	0.576	57.6
K ₁	52.552	44.133	49.102	47.885	9	3	3	2	∑Y＝155.29 CT＝2679.4426				1	22.7626	19.455	0.576	57.6
K ₁	52.552	44.133	49.102	47.885	K ₂	50.400	51.087	53.362					52.823
K ₃	52.338	60.070	52.826	54.582	K ₂	50.400	51.087	53.362					52.823
K ₃	52.338	60.070	52.826	54.582	R	2.152	15.937	4.260					6.697
SS	0.9370	42.5601	3.5893	8.0365	R	2.152	15.937	4.260					6.697
SS	0.9370	42.5601	3.5893	8.0365	K ₁	169.0	162.7	172.9					158.7			∑Y＝513.3 CT＝29275.21
K ₂	169.2	175.8	177.5	174.9	K ₁	169.0	162.7	172.9					158.7
K ₂	169.2	175.8	177.5	174.9	K ₃	175.1	174.6	162.9	179.7
R	6.1	13.1	14.6	21	K ₃	175.1	174.6	162.9	179.7
R	6.1	13.1	14.6	21	SS	8.0067	12.1533	37.1467	80.72

Annotate: solid content is measured and Paeoniflorin is measured

Solid content is measured: extract is concentrated into small size, and then constant volume shakes up in the 100ml volumetric flask, the accurate absorption in the evaporating dish that 50ml puts constant weight, and water-bath volatilizes, and in 105 ℃ of dryings 5 hours, weighs, and is calculated as follows solid content amount and solid yield.

Solid content amount (g)=(claim weight-evaporating dish weight) * 2

The mensuration of Paeoniflorin: with reference to " condition under Chinese pharmacopoeia version in 2000 one the 125th page " red spoon ", the 402nd page of " Bezoar pill for lowering blood pressure " assay item is measured.

Chromatographic condition: chromatographic column: Hypersil C (ODS₂) post, 5 μ m, 250 * 4.6mm, post number: 2108265 (Dalian Yi Lite scientific instrument companies); Detect wavelength: 230nm; Column temperature: 30 ℃; Mobile phase: acetonitrile-water (12: 88), flow velocity: 1.0ml/min.

The preparation of reference substance solution: it is an amount of, accurately weighed that the phosphorus pentoxide of learning from else's experience is dried to the Paeoniflorin reference substance of constant weight, adds methyl alcohol and make the solution that every 1ml contains Paeoniflorin 36.8 μ g, and get final product.

The preparation of need testing solution: the accurate extract 2ml of constant volume in 100ml that draw, add methanol constant volume in the 25ml volumetric flask, shake up, with the membrane filtration of 0.45 μ m, get subsequent filtrate as need testing solution.

Determination method is accurate reference substance solution and each 10 μ l of need testing solution of drawing respectively, injects high performance liquid chromatograph, measures, and calculates extracted amount (mg) with following formula:

The solid content variance analysis

Source of error	SS	F	F	P
Source of error	SS	F	F	P	B	42.5601	2	45.4215	＜0.05
C	3.5893	3.8305	＞0.05		B	42.5601		45.4215	＜0.05
C	3.5893	3.8305	＞0.05	D	8.0365	8.5773		＞0.05
Error (A)	0.9370			D	8.0365	8.5773		＞0.05

^*F _0.05(2，2)＝19.00；F _0.01(2，2)＝99.00

The variance analysis of Paeoniflorin extracted amount

Source of error	SS	F	F	P
Source of error	SS	F	F	P	B	12.1533	2	1.5789	＞0.05
C	37.1467	4.6395	＞0.05		B	12.1533		1.5789	＞0.05
C	37.1467	4.6395	＞0.05	D	80.72	10.082		＞0.05
Error (A)	8.0067			D	80.72	10.082		＞0.05

^*F _0.05(2，2)＝19.00；F _0.01(2，2)＝99.00

The result shows: take the solid content amount as index, the primary and secondary of each factor effect is B＞D＞C＞A, and factor B has a significant impact, with A₁B ₃C ₂D ₃Technique is good, being more or less the same of 1,2,3 level affects of factor A; The K of factor B₃Value is apparently higher than K₁、K ₂ 2,3 level affects of factor C, D are suitable; Take Paeoniflorin as index, the primary and secondary of each factor effect is D＞C＞B＞A, factor A, B, C, D there are no significant the impact, with A₂B ₂C ₂D ₃Technique is good.

(4), the investigation of alcohol precipitation process condition

Get 1.5 times of recipe quantity medicinal material 351g (caulis lonicerae 75g, reticulate millettia 75g, rhizoma cibotii 75g, dandelion 30g, motherwort 30g, Asiatic plantain 30g, radix paeoniae rubrathe 18g, Ligusticum wallichii 18g) by above-mentioned extraction process by water A₂B ₂C ₂D ₃Test, constant volume was in 500ml after water extraction liquid was concentrated. Fetch water respectively 4 parts of extracts, every part of 100ml is concentrated into different relative densities, add ethanol, make that to contain alcohol amount be 65%, stir hold over night, filter, filtrate was flung in the evaporating dish that is transferred to constant weight behind the ethanol, and water-bath volatilizes, in 105 ℃ of dryings 5 hours, weigh, the peace following formula calculates solid content amount and solid yield:

Solid content amount (g)=(claim weight-evaporating dish weight) * 5

Paeoniflorin content is measured: get dry solid content 0.2g, precise weighing is put in the 50ml conical flask, adds methyl alcohol 25ml, weighs, ultrasonic processing 1 hour is taken out, and lets cool, and supplies the weight that subtracts mistake with methyl alcohol, shake up, filter with 0.45 μ m filter membrane, get the subsequent filtrate sample introduction and measure, be calculated as follows:

Extracted amount (mg)=content (%) * solid content amount

The result is as follows:

Numbering	Relative density	Solid content		Paeoniflorin
		Solid content		Paeoniflorin		Solid content amount (g)	Solid yield (%)	Paeoniflorin content (%)	Paeoniflorin extracted amount (mg)
		1	1.15	19.2045	5.471	Solid content amount (g)	Solid yield (%)	Paeoniflorin content (%)	Paeoniflorin extracted amount (mg)	0.6012	115.46
2	1.20	1	1.15	19.2045	5.471	19.0225	5.420	0.6391	121.59	0.6012	115.46
2	1.20	3	1.25	17.4538	4.9725	19.0225	5.420	0.6391	121.59	0.6257	109.21
4	1.30	3	1.25	17.4538	4.9725	16.4062	4.674	0.5718	93.81	0.6257	109.21

According to above result, be concentrated into relative density as 1.20 take water extraction liquid, adding ethanol is that 65% effect is best to containing the alcohol amount. Relative density is low, and to make water extraction liquid get volume larger, and it is large to consume amount of alcohol, and cost increases; When relative density was high, water extraction liquid was feeding-up, and the alcohol precipitation effect is bad.

(3) preparations shaping technical study

1, determining of specification: according to above test, the dry extract of extraction process (solid content) recovery rate is about 5.4%. Calculate (medicinal material amounts to 234g, makes 10 bags of particles) by recipe quantity, the dry extract that obtains behind the water extract-alcohol precipitation should be about 12.636g; Can be made into 30 capsules, every is 0.4212g, considers the fluctuation of Chinese medicine quality, determines that product specification provided by the invention is every 0.4g (every is equivalent to crude drug 7.8g), once takes 3.

2, the preparation of dried cream powder

By above-mentioned selected extraction process, get 50 times of recipe quantity medicinal materials (amounting to 11700g), wherein caulis lonicerae 2500g, reticulate millettia 2500g, rhizoma cibotii 2500g, dandelion 1000g, motherwort 1000g, Asiatic plantain 1000g, red spoon 600g, Ligusticum wallichii 600g, carry out water extract-alcohol precipitation, be concentrated into thick paste, drying under reduced pressure (vacuum 0.07～0.08Mpa, 70～80 ℃) gets dry extract, pulverize, cross 60 mesh sieves. The result is as follows:

Title	Weight (g)	Remarks
Title	Weight (g)	Remarks	Caulis lonicerae	2500	Add 10 times of water gagings (increase 1.4 times of medicinal material amount when for the first time adding water, soaked 2.5 hours) decoction 3 times at every turn, decocted 2 hours at every turn; Being concentrated into relative density and being 1.20 adds ethanol and makes and contain the alcohol amount and reach 65%. Recycled ethanol is concentrated into thick paste, drying under reduced pressure.
Reticulate millettia	2500		Caulis lonicerae	2500
Reticulate millettia	2500	Rhizoma cibotii	2500
Dandelion	1000	Rhizoma cibotii	2500
Dandelion	1000	Motherwort	1000
Asiatic plantain	1000	Motherwort	1000
Asiatic plantain	1000	Red spoon	600
Ligusticum wallichii	600	Red spoon	600
Ligusticum wallichii	600	Total dried cream powder amount	637.47	Moisture is 3.52%
Paeoniflorin content (%)	0.638	Total dried cream powder amount	637.47

2, the hygroscopicity of medicinal powder is investigated with mobile

(1) mensuration of hydroscopicity: the glass drier that the bottom is filled the sodium chloride supersaturated solution is put into 25 ℃ constant incubator, constant temperature 24 hours, and its internal relative humidity (RH) is constant in 75%. Add an amount of medicinal powder in the measuring cup of dry constant weight, the about 2mm of thickness, precise weighing are placed in the glass drier of sodium chloride supersaturated solution (25 ℃), open the weighing bottle cap; Regularly weighing is calculated as follows hydroscopicity:

The result is as follows:

Medicinal powder hydroscopicity (%)

Time (h)	0	4	8	12	24	48	72
Time (h)	0	4	8	12	24	48	72	Medicinal powder weight (g)	3.4208	3.5381	3.6695	3.7430	3.8394	3.9349	3.9756
Hydroscopicity (%)		3.43	7.27	9.42	12.24	15.03	16.22	Medicinal powder weight (g)	3.4208	3.5381	3.6695	3.7430	3.8394	3.9349	3.9756

The result shows: the extract powder hygroscopicity increases in time and increases, particularly in rear 10 hours of drying hygroscopicity increase very fast, so should fill as early as possible when producing.

(2) medicinal powder critical relative moisture (CRH) is measured

Get the measuring cup of 7 dry constant weights, put into respectively medicinal powder, thickness is about 2mm, accurately weighed weight postposition fills respectively in the glass drier of supersaturated solution of 7 kinds of variable concentrations sulfuric acid solutions and different salt, open the weighing bottle cap, in 25 ℃ of insulating boxs, keep weighing after 84 hours, be calculated as follows medicinal powder moisture absorption percentage:

The result is as follows:

The moisture absorption percentage (%) of medicinal powder under the different relative humidity

	Sulfuric acid concentration (%)			The supersaturated solution of various salt
	Sulfuric acid concentration (%)			The supersaturated solution of various salt				54	48	44	NaBr	NaCl	NaI	NaNO ₃
	RH(％)(25℃)	29.55	40.52	48.52	57.70	75.28	84.26	54	48	44	NaBr	NaCl	NaI	NaNO ₃	92.48
0 hour medicinal powder heavy (g)	RH(％)(25℃)	29.55	40.52	48.52	57.70	75.28	84.26	3.2475	3.0004	3.3782	3.4037	3.1054	3.1237	3.1726	92.48
0 hour medicinal powder heavy (g)	84 hours medicinal powder heavy (g)	2.3595	3.1275	3.5474	3.6715	3.6202	3.8146	3.2475	3.0004	3.3782	3.4037	3.1054	3.1237	3.1726	4.0304
Medicinal powder hydroscopicity (%)	84 hours medicinal powder heavy (g)	2.3595	3.1275	3.5474	3.6715	3.6202	3.8146	3.45	4.23	5.01	7.87	16.58	22.12	27.04	4.0304

The drafting of sucting wet curve: the moisture absorption percentage in the above table is ordinate, and relative humidity is the abscissa mapping, and is as follows:

Make the tangent line at upper figure curve two ends, the corresponding abscissa of two points of intersection of tangents is critical relative moisture (CRH). This product medicinal powder critical relative moisture is 50%. So when production this product, the relative humidity of medicinal powder packing workshop condition should be controlled in 50%, to reduce moisture to the impact of medicine stability, guarantee product quality.

(3) mensuration at angle of repose

Adopt the fixed funnel method to measure: funnel to be fixed on the graph paper of horizontal positioned, suitable height (3cm), carefully medicinal powder is poured in the uppermost funnel along hopper walls, until the medicinal powder apex partis petrosae termination that forms on the graph paper contacts bottom bell mouth, measure the conical base diameter, be calculated as follows out angle of repose α:

The result is as follows:

Cone high (cm)	Cone radius (cm)	Angle of repose (degree)
Cone high (cm)	Cone radius (cm)	Angle of repose (degree)	3.53	3.17	42.01°

The result shows that the angle of repose of this product medicinal powder is little, and the medicinal powder good fluidity is easy to packing.

4, filling experiment

(1) selection of capsule: rule of thumb, every 0.4g specification generally should be selected capsule No. 0, and through filling experiment, loading amount stability meets the requirements, and the result is as follows:

Medicinal powder amount (g)	290
Medicinal powder amount (g)	290	Loading amount specification (g/ grain)	0.4
Filled capsules amount (grain)	653	Loading amount specification (g/ grain)	0.4
Filled capsules amount (grain)	653	Content uniformity	0.401～0.454
Average particle heavy (g)	0.42	Content uniformity	0.401～0.454

So adopt capsule charge No. 0.

(2) packing environmental requirement: according to test, regulation this product packing environment temperature should be controlled at about 25 ℃, and humidity is no more than 50%.

(4) pilot scale research

On the basis of lab scale research, carry out trial production in three batches, every batch feeds intake by 12000 capsules. Carry out in strict accordance with the GMP standard in the production, further determined preparation technology. The product of middle trial production is through check, and indices meets the target level of product quality of working out.

Lot number				20031201	20031202	20031203
Lot number				20031201	20031202	20031203	Raw material (kg)	Caulis lonicerae		20	20	20
Reticulate millettia		20	20	20				Caulis lonicerae		20	20	20
Reticulate millettia		20	20	20	Rhizoma cibotii			20	20	20
Dandelion		8	8	8	Rhizoma cibotii			20	20	20
Dandelion		8	8	8	Motherwort			8	8	8
Asiatic plantain		8	8	8	Motherwort			8	8	8
Asiatic plantain		8	8	8	Red spoon			4.8	4.8	4.8
Ligusticum wallichii		4.8	4.8	4.8	Red spoon			4.8	4.8	4.8
Ligusticum wallichii		4.8	4.8	4.8	Amount of water (kg) when Extraction parts extracts			2900	2900	2900
It is 1.20 o'clock weight (kg) that water extraction liquid is concentrated into relative density				32.0	Amount of water (kg) when Extraction parts extracts			2900	2900	2900	31.8	31.6
				32.0	Add alcohol amount (kg)			56	55	55	31.8	31.6
Dried cream powder amount (kg)				4.85	Add alcohol amount (kg)			56	55	55	4.95	5.02
Dried cream powder amount (kg)				4.85	Filled capsules amount (0.42g/ grain) (grain)			11256	11456	11850	4.95	5.02
Theoretical capsule output (grain)				12000				11256	11456	11850
Theoretical capsule output (grain)				12000			Yield rate (%)			93.8	95.47	98.75
Proterties							Yield rate (%)			93.8	95.47	98.75
Proterties							Differentiate (1)～(3)
Check	Average particle heavy (g)			0.4201	0.4205	0.4202	Differentiate (1)～(3)
	Average particle heavy (g)			0.4201	0.4205	0.4202	Content uniformity		Up to specification	Up to specification	Up to specification
	Moisture (%)			4.6	4.5	4.6	Content uniformity		Up to specification	Up to specification	Up to specification
	Moisture (%)			4.6	4.5	4.6	Disintegration time limited (min)		15	14.5	15
	Microorganism checking			Up to specification	Up to specification	Up to specification	Disintegration time limited (min)		15	14.5	15
	Microorganism checking			Up to specification	Up to specification	Up to specification	The sweet approximately assay of Chinese herbaceous peony	Content (%)	0.612	0.672	0.628
	Every content (mg/ grain)	2.571	2.824	2.640				Content (%)	0.612	0.672	0.628

Above-mentioned middle trial production result shows that the every technical parameter of product is stable, and quality meets the requirements. Illustrate that technique is reasonable, it is feasible to stablize, be suitable for batch production.

The applicant has carried out experiment relatively with capsule provided by the invention and the curative effect of existing commercially available granule:

	Capsule	Granule	The result
	Capsule	Granule	The result	Specification	0.3g/ grain	The 12g/ bag
Dose	3 tablets/times, 3 times on the one	1 bag/time, 3 times on the one	Capsule can reduce taking dose.	Specification	0.3g/ grain	The 12g/ bag
Dose	3 tablets/times, 3 times on the one	1 bag/time, 3 times on the one	Capsule can reduce taking dose.	The preparation method	Need not the auxiliary materials such as Icing Sugar, need not granulation process, technique is simple	Add about 90% Icing Sugar, the operations such as drying that need to granulate, technique is comparatively complicated
	(1) observe among the patient in treatment 50 examples, 32 examples of fully recovering, produce effects 9 examples, effective 8 examples, invalid 1 example, effectively total	(1) in 60 routine patients for the treatment of, 28 examples of fully recovering, produce effects 8 examples, effective 15 examples, no effect 9, total effective rate is	The capsule granule that is better than evident in efficacy	The preparation method

Curative effect

Rate is during 40 examples of 98% (2) treatment are observed, chronic pelvic inflammatory disease treatment (8 a days) total effective rate course for the treatment of is 90.0%, obvious effective rate is 65.0%, symptom takes a turn for the better fast, satisfactory effect, significantly be better than alone antibiotic group, the patient of alone this product treatment, during medication, do not find the bad reactions such as times of defecation increases, dry throat, pharyngalgia, vomiting, this product cooperates with Western medicine such as antibiotic, has synergy, can improve curative effect, certain gynaecology of front three hospital of Shorten the Treatment Process (3) uses this product treatment endoretention of damp heat June to September, qi stagnation and blood stasis type chronic pelvic inflammatory disease 30 examples, the same period and medicine a thousand pieces of gold sheet compare, and the result shows through clinical observation treatment: after the treatment group treatment, no matter be clinical cardinal symptom, Signs and laboratory examination all have obvious improvement. The clinical symptoms that chronic pelvic inflammatory disease belonged to endoretention of damp heat, qi stagnation and blood stasis type: unusual under soreness of waist pain, the band, treated effect is more than 80.00%. To clinical uterus and the attachment area tenderness is efficient reaches more than 82%. And conventional to leukorrhea, blood divides in vain, blood sedimentation has efficient reaching more than 85% after the unusual treatment, and is wherein especially obvious to reduce white count action, reaches 100%. But the attachment area due to chronic inflammation hyperblastosis adhesion is thickened, and clinical therapeutic efficacy is efficient to reach 12.5%, and this also meets the objective law of disease treatment development. Chronic pelvic inflammatory disease is efficient reaches 93.33% for this product treatment,

85%. (2) during 45 for the treatment of examples are observed, chronic pelvic inflammatory disease treatment (8 a days) total effective rate course for the treatment of is 82%, obvious effective rate is 54%, symptom take a favorable turn, curative effect is general, but significantly be better than alone antibiotic group, during medication, have a few patients to be found that times of defecation increases and the phenomenon such as vomiting.

The applicant has also studied the technique of extract dry repeatedly: take dry extract moisture content＜5% as index

Drying means	Process conditions	The result		Remarks
		The result			Moisture content (%)	Proterties
		Constant pressure and dry	80～85 ℃, dry 6 hours		Moisture content (%)	Proterties	4.2	The part coking is arranged	Ointment sample after the heating
60～65 ℃, dry 12 hours	4.5		80～85 ℃, dry 6 hours	The small part coking is arranged			4.2	The part coking is arranged
60～65 ℃, dry 12 hours	4.5		50～55 ℃, dry 48 hours	The small part coking is arranged		The ointment shape	The mud paste is difficult to drying
Vacuum drying	Vacuum 0.07～0.08Mpa, 40～45 ℃, 48 hours		50～55 ℃, dry 48 hours	4.2		The ointment shape	The mud paste is difficult to drying	Dried cream is more loose	When dry, medicinal extract rises cellular, and it is dry to be the film sample
	Vacuum 0.07～0.08Mpa, 40～45 ℃, 48 hours	Vacuum 0.07～0.08Mpa, 50～55 ℃, 48 hours	3.8	4.2
	Vacuum 0.07～0.08Mpa, 60～65 ℃, 24 hours	Vacuum 0.07～0.08Mpa, 50～55 ℃, 48 hours	3.8	3.2
	Vacuum 0.07～0.08Mpa, 60～65 ℃, 24 hours	Vacuum 0.07～0.08Mpa, 70～75 ℃, 24 hours	3.1	3.2	Dried cream is more loose, and the smell of burning is arranged
	Spray-drying	Vacuum 0.07～0.08Mpa, 70～75 ℃, 24 hours	3.1	1.10,120～150 ℃ of hot blasts of sample rate		3.3	Lumps is more	Sticking wall, caking are seriously
1.15,120～150 ℃ of hot blasts of sample rate		4.5		1.10,120～150 ℃ of hot blasts of sample rate		3.3

According to above result, more satisfactory with the reduced vacuum drying, its condition is: vacuum 0.07～0.08Mpa, 70～75 ℃, 24 hours.

Description of drawings: accompanying drawing 1 is medicinal powder hydroscopicity schematic diagram of the present invention, and accompanying drawing 2 is particle moisture absorption schematic diagrames of the present invention.

Claims

1, a kind of capsule preparations for the treatment of gynecological disease is characterized in that: calculate according to components by weight percent, it is mainly by 1500～2000 parts of caulis loniceraes, 1500～2000 parts of reticulate millettias, 1500～2000 parts of rhizoma cibotii; 500～750 parts of dandelions, 500～750 parts of motherworts, 500～750 parts of Asiatic plantains, 300～500 parts of the radix paeoniae rubrathe, 300～500 parts of Ligusticum wallichiis are prepared from.

2, according to the capsule preparations for the treatment of gynecological disease claimed in claim 1, it is characterized in that: it makes 1000 capsules with caulis lonicerae 1667g reticulate millettia 1667g rhizoma cibotii 1667g dandelion 666.7g motherwort 666.7g, Asiatic plantain 666.7g radix paeoniae rubrathe 400g Ligusticum wallichii 400g.

3, treat as claimed in claim 1 or 2 the preparation technology of the capsule preparations of gynecological disease, it is characterized in that: be cut into suitable size after medicinal material is taken by weighing, boiling is extracted 2～4 times, adds the water yield of 6～12 times of medicinal materials at every turn, the each decoction 1.5～3 hours, filter, filtrate is concentrated in right amount, spray-drying or drying under reduced pressure, get dry extract, be ground into fine powder, mixing, filled capsules.

4, according to the preparation technology of the capsule preparations of the described treatment gynecological disease of claim 3, it is characterized in that: it is 1.05～1.30 (90 ℃) that the filtrate that obtains behind the poach is concentrated into relative density, adding ethanol is 45～75% to containing the alcohol amount, stir evenly, left standstill the leaching supernatant 12～48 hours, be concentrated into thick paste behind the Recycled ethanol, spray-drying or drying under reduced pressure are ground into fine powder, are filled to capsule.

5, according to the preparation technology of the capsule preparations of the described treatment gynecological disease of claim 3, it is characterized in that: medicinal material is cut into suitable size or is ground into meal, with 45～75% ethanol percolations, collect percolate, be concentrated into thick paste behind the Recycled ethanol, spray-drying or drying under reduced pressure are ground into fine powder, are filled to capsule.

6, according to the preparation technology of the capsule preparations of claim 3 or 5 described treatment gynecological diseases, it is characterized in that: medicinal material is cut into suitable size, adding 45～75% alcohol refluxs extracts 2～4 times, each 1～2 hour, filter, be concentrated into thick paste behind the filtrate recycling ethanol, spray-drying or drying under reduced pressure, be ground into fine powder, be filled to capsule.

7, according to the preparation technology of the capsule preparations of claim 3,4 or 5 described treatment gynecological diseases, it is characterized in that: adopt reduced vacuum dry, its technical conditions are: vacuum 0.07～0.08Mpa, 70～75 ℃, 24 hours.