CN105311300A - Pharmaceutical composition, herba houttuyniae suppository and preparation method and application - Google Patents
Pharmaceutical composition, herba houttuyniae suppository and preparation method and application Download PDFInfo
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Abstract
The invention relates to a pharmaceutical composition used for treating a prostate disease, a suppository prepared from the pharmaceutical composition and a preparation method of the suppository. The suppository is prepared from, by weight, 90-110 parts of herba houttuyniae extract, 5-15 parts of saw palmetto oil, 2-7 parts of an antioxidant, 2-7 parts of transdermal enhancer, 120-180 parts of a suppository substrate and 20-50 parts of water. The suppository mainly treats the symptoms such as frequent micturition, urgent urination, odynuria, endless urine, frequent urination at night, uroschesis, white secreta dropping from a urethral orifice, urethral discomfort, testicular pain, lower abdominal pain and perineum pain which are caused by chronic prostatitis and hyperplasia of prostate or prostatic hyperplasia. The suppository has the advantages of intraectal administration and external targeted therapy, the effective components can directly reach the prostate affected part, the drug therapy concentration of a prostate local lesion is increased, the curative effect is definite, and drug use is convenient.
Description
Technical field
The present invention relates to technical field of Chinese medicines, particularly relate to a kind of pharmaceutical composition and Herba Houttuyniae suppository and preparation method and application.
Background technology
Prostatosis is the commonly encountered diseases of male reproductive system.Wherein chronic prostatitis is blue or green, middle-aged male commonly encountered diseases; Prostatic hyperplasia is then the commonly encountered diseases of middle-aged and elderly people.General youth is ill is main mainly with inflammation, and the pathological change of hypertrophy occurred afterwards at 40 years old, occurs even leading to complications the related symptoms such as dysuria, urine retention, frequent micturition, urgent micturition after 50 years old, as: urinary tract infection, cystitis, uremia etc.So-called hypertrophy refer to cause due to parenchyma increasing number tissue, cell volume increase, be the result that cell mitogen activity that a variety of causes causes strengthens.Treatment prostatosis, current western medical treatment means are oral antibiotic quinolone antibiotic, methoxy card pyridine (TMP) and Sulfamethoxazole (SMZ) etc. mainly, but all cannot directly arrive at prostate diseases position, and also easily cause adverse effect due to long-term prescription.Chinese traditional treatment is then by " stranguria " prescribe medicine, and point dominance of heat in the interior and damp-heat accumulation amphitypy Coryza Treated by Syndrome Differentiation, wherein the safest method had no side effect is topical administration therapy, as: " herbal enema ", " plug anus therapy ", " partial hot compressing ", " hot water hip-bath " etc., but its treatment and operation are all inconvenient.
Summary of the invention
Based on defect and the deficiency of prior art, first object of the present invention is to provide a kind of pharmaceutical composition, and by weight, described pharmaceutical composition comprises following component: 90-110 part Herba Houttuyniae extract, 5-15 part Serenoa repens oil.
Herba Houttuyniae is the dry aerial parts of saururaceae plant houttuynia cordata HouttuyniacordataThunb., and principal agent Herba Houttuyniae extract contains plurality of active ingredients, and as volatile oil, its main component is methylnonanone and houttuynine sodium bisulfite etc.; Flavonoids effective constituent is Quercetin; Aminoacid ingredient has glutamic acid etc.Wherein with methylnonanone and houttuynine sodium bisulfite content the highest.Houttuynine sodium bisulfite has antibacterial, antiviral, antiinflammatory, antiallergic, antitumor, the effect of diuresis, also can enhancing human body immunity power etc., has Comprehensive Treatment effect to Patients of Prostatic Diseases.
Serenoa repens oil can suppress the generation of two hydrogen testosterone in prostate, reduce the risk factor of two hydrogen testosterone hypertrophy in prostate, have effect that is female in two-ways regulation body, androgen balance, thus reach alleviation and treatment prostatic hyperplasia symptom, Serenoa repens oil also has suppository lubrication in addition.Herba Houttuyniae extract and the composite use of Serenoa repens oil, have good curative effect to prostatosis.
In the present invention, Herba Houttuyniae extract prepares by the following method: get Herba Houttuyniae, adds Herba Houttuyniae weight 6-10 ethanol doubly, reflux, extract, 0.5-2h, filtered while hot, and removing ethanol, to obtain final product.
Invention further provides a kind of preparation method of preferably Herba Houttuyniae extract, be specially: get Herba Houttuyniae, add 90% ethanol of Herba Houttuyniae weight 8 times, reflux, extract, 1h, filtered while hot, removing ethanol, to obtain final product.
In the present invention, the weight ratio of Herba Houttuyniae extract and Serenoa repens oil is preferably 10:1.
In order to improve curative effect of medication further, described pharmaceutical composition also comprises 2-7 part antioxidant, and further preferably, described antioxidant is lycopene, astaxanthin, beta-carotene, the combination of one or more in anthocyanidin; Antioxidant of the present invention most preferably is lycopene.
The unique concatemeric structure of lycopene, has strong elimination free radical ability and oxidation resistance, also has simultaneously and strengthens the biochemical action such as cell-tocell transmission and cell generation regulation and control.Lycopene and Herba Houttuyniae extract and the composite use of Serenoa repens oil, have good synergism, can strengthen the curative effect of medicine further.
The invention provides one preferably pharmaceutical composition, comprise following component: 100 parts of Herba Houttuyniae extracts, 9-12 part Serenoa repens oil, 4-6 part lycopene.
Further, the invention provides a kind of pharmaceutical composition of the best, comprise following component: 100 parts of Herba Houttuyniae extracts, 10 parts of Serenoa repens oil, 5 parts of lycopenes.These three kinds of components with the use of, best therapeutic effect can be reached.
Any one pharmaceutical composition above-mentioned, can be prepared into any dosage form as required, as peroral dosage form, and injection type etc.
In order to avoid oral or that when injecting, medicine produces toxic and side effects, second object of the present invention is to provide a kind of Herba Houttuyniae suppository, the application method of this suppository is rectal application, the feature of rectal application and the mode of outer targeted therapy, its effective ingredient can be made to go directly prostate affected part, not only greatly improve the drug concentration levels of prostate local lesion, and avoid the generation of toxicity, medication is convenient, and curative effect is more definite.
A kind of Herba Houttuyniae suppository, described Herba Houttuyniae suppository is prepared by the component comprising following weight portion: 90-110 part Herba Houttuyniae extract, 5-15 part Serenoa repens oil, 2-7 part antioxidant, 2-7 part transdermal enhancer, 120-180 part suppository base, 20-50 part water.
The optimum weight ratio of described Herba Houttuyniae extract and described Serenoa repens oil is 10:1.
Further, described antioxidant is lycopene, astaxanthin, beta-carotene, the combination of one or more in anthocyanidin, more preferably lycopene.
Further, described transdermal enhancer is that this area routine is selected, more preferably Borneolum Syntheticum, menthol, Oleum Caryophylli, and eucalyptus oil, one or more the combination in Rhizoma Chuanxiong oil, is further preferably Borneolum Syntheticum.
Further, described suppository base is Polyethylene Glycol, cocoa butter, glycerin gelatine, Polysorbate-61, one or more combination in pluronic copolymer, the more preferably combination of PEG400 and Macrogol 4000, be further preferably PEG400 and Macrogol 4000 feeds intake according to weight ratio 7:8.
Preferred further, the transdermal enhancer that the present invention adopts is Borneolum Syntheticum, and suppository base is PEG400 and Macrogol 4000, and the two feeds intake according to weight ratio 7:8.Under the comprehensive function of this kind of adjuvant, effective ingredient can fully discharge, and reaches best therapeutic effect.
As the present invention's preferably technical scheme, a kind of Herba Houttuyniae suppository is provided, described Herba Houttuyniae suppository is prepared by following component: 100 parts of Herba Houttuyniae extracts, 9-12 part Serenoa repens oil, 4-6 part lycopene, 4-6 part Borneolum Syntheticum, 65-75 part PEG400,75-85 part Macrogol 4000,25-35 part water.
As the technical scheme of the best of the present invention, provide a kind of Herba Houttuyniae suppository, described Herba Houttuyniae suppository is prepared by following component: 100 parts of Herba Houttuyniae extracts, 10 parts of Serenoa repens oil, 5 parts of lycopenes, 5 parts of Borneolum Syntheticums, 70 parts of PEG400s, 80 parts of Macrogol 4000s, 30 parts of water.
Invention also provides the preparation method of above-mentioned Herba Houttuyniae suppository, comprise the steps:
(1) prepare Herba Houttuyniae extract: get Herba Houttuyniae, add Herba Houttuyniae weight 6-10 ethanol doubly, heating and refluxing extraction 0.5-2h, filtered while hot in described Herba Houttuyniae, removing ethanol, to obtain final product;
(2) prepare Herba Houttuyniae suppository: by formula ratio, the Herba Houttuyniae extract obtained by step (1), Serenoa repens oil, antioxidant, transdermal enhancer, water mixes, and is heated to be uniformly dispersed, obtains medicinal liquid A at 60-70 DEG C; Suppository base is melted, obtains matrix liquid B; After medicinal liquid A and matrix liquid B mix homogeneously, pour into suppository mold, cooling, molding, to obtain final product.
Preferred further, being operating as of step (1): get Herba Houttuyniae extract, adds 90% ethanol of Herba Houttuyniae extract weight 8 times, reflux, extract, 1h, filtered while hot, and removing ethanol, to obtain final product.
In a kind of concrete embodiment, get 100g Herba Houttuyniae extract, 10g Serenoa repens oil, 5g lycopene, 5g Borneolum Syntheticum, 70g PEG400,80g Macrogol 4000,30g water, according to above-mentioned preparation method, prepare 150 Herba Houttuyniae bolts, every heavy 2g, in this suppository, Herba Houttuyniae extract is principal agent, with Herba Houttuyniae extract weighing scale, every containing 0.67g principal agent.
3rd object of the present invention is to provide any one pharmaceutical composition above-mentioned or the application of Herba Houttuyniae suppository in preparation treatment prostatosis medicine.
Concrete, the indication of this Herba Houttuyniae suppository and function cure mainly into: clearing away heat-damp and promoting diuresis is treating stranguria, changes turbid clearance pain relieving.Cure mainly chronic prostatitis and the frequent micturition caused by hyperplasia of prostate (prostate hyperplasia), urgent micturition, dysurea, urinate endless, the card such as frequent urination at night, urine retention, whitish discharge from urinary meatus, urethra discomfort, testicular pain, lower abdominal pain, perineal pain.
The usage and dosage of this suppository is: emptying stool, clean anus, and bring fingerstall, bolt of getting it filled inserts anus about 3 ~ 5 centimeters, lies on one's side 6 ~ 8 minutes.One time 1,1 time on the one one month is a course for the treatment of or follow the doctor's advice.
Accompanying drawing explanation
The structure chart of Fig. 1 modeling first day and second day prostata tissue.
The meaning of the lower right corner letter representative of Fig. 1 structure chart photo is respectively: A: blank group; B: negative control group; C: positive controls; D: low dose group; E: middle dosage group; F: high dose group; G: pole high dose group.
Detailed description of the invention
Following examples for illustration of the present invention, but are not used for limiting the scope of the invention.
Embodiment 1
A kind of Herba Houttuyniae suppository, is prepared by following component: 100g Herba Houttuyniae extract, 10g Serenoa repens oil, 5g lycopene, 5g Borneolum Syntheticum, 70g PEG400,80g Macrogol 4000,30g water.
Embodiment 2
A kind of Herba Houttuyniae suppository, is prepared by following component: 110g Herba Houttuyniae extract, 12g Serenoa repens oil, 7g lycopene, 7g Borneolum Syntheticum, 80g PEG400,100g Macrogol 4000,50g water.
Embodiment 3
A kind of Herba Houttuyniae suppository, is prepared by following component: 90g Herba Houttuyniae extract, 9g Serenoa repens oil, 4g lycopene, 4g Borneolum Syntheticum, 50g PEG400,70g Macrogol 4000,20g water.
Embodiment 4
A kind of Herba Houttuyniae suppository, is prepared by following component: 666.7g Herba Houttuyniae extract, 66.7g Serenoa repens oil, 33.4g lycopene, 33.4g Borneolum Syntheticum, 466.9g PEG400,533.6g Macrogol 4000,200.1g water.
Embodiment 5
A kind of Herba Houttuyniae suppository, is prepared by following component: 100g Herba Houttuyniae extract, 10g Serenoa repens oil, 5g anthocyanidin, 5g Borneolum Syntheticum, 70g PEG400,80g Macrogol 4000,30g water.
Embodiment 6
A kind of Herba Houttuyniae suppository, is prepared by following component: 100g Herba Houttuyniae extract, 10g Serenoa repens oil, 5g lycopene, 5g menthol, 70g PEG400,80g Macrogol 4000,30g water.
Embodiment 7
The present embodiment provides the preparation method of Herba Houttuyniae extract in embodiment 1-6: get Herba Houttuyniae 10kg, adds content 90% alcoholic solution 80kg reflux, extract, 1h in water-bath, filtered while hot, then vacuum decompression reclaims ethanol, i.e. obtained Herba Houttuyniae extract.
Embodiment 8
The present embodiment provides the preparation method of the Herba Houttuyniae suppository described in embodiment 1: by the Herba Houttuyniae extract of recipe quantity, Borneolum Syntheticum, in the water that lycopene adds recipe quantity and Serenoa repens oil, in 60-70 DEG C of heating, stirs, to being dispersed into even medicinal liquid A; In another container, add PEG400 and the Macrogol 4000 of recipe quantity, heating in water bath melts, and obtains residuite liquid B, 40 DEG C ± 2 DEG C guarantors; Under agitation imported in matrix liquid B by medicinal liquid A, stir evenly the homogenizing system forming rufous, pour in suppository mold, cooling, molding, obtains 150, Herba Houttuyniae bolt.
Embodiment 9
The present embodiment provides the preparation method of the Herba Houttuyniae suppository of embodiment 4, and its preparation method is with embodiment 5, and difference is only to make 1000, in actual fabrication process, and its yield rate is 98.7%, i.e. obtained finished product 987.
Embodiment 10
The present embodiment provides the preparation method of the Herba Houttuyniae suppository of embodiment 4, and its preparation method is with embodiment 5, and difference is only to make 1000, in actual fabrication process, and its yield rate is 98.2%, i.e. obtained finished product 982.
Embodiment 11
The present embodiment provides the preparation method of the Herba Houttuyniae suppository of embodiment 4, and its preparation method is with embodiment 5, and difference is only to make 1000, in actual fabrication process, and its yield rate is 99.1%, i.e. obtained finished product 991.
In order to verify the drug effect of Herba Houttuyniae bolt of the present invention further, be described below by way of testing.
The dosage below related in test is all the Weight computation with Herba Houttuyniae extract.
One, pharmacodynamic experiment
The main agents below related in experiment: Herba Houttuyniae suppository (prepares according to the method for embodiment 8, every containing 0.67g Herba Houttuyniae extract, i.e. plan clinical dosage), Prostant (Livzon Pharmaceutical Factory, Livzon Group), carrageenin (Bei Lian bio tech ltd, Shanghai); Chloral hydrate (Wuhan City and prosperous Chemical Co., Ltd.); Acetic acid (Chinasun Specialty Products Co., Ltd, analytical pure, acetic acid content > 99.5%).Other reagent related to, the means by this area routine prepare, or commercially available acquisition.
The animal below related in test: SD rat (male, body weight 200 ~ 250g, Wuhan University's Experimental Animal Center provides, the laboratory animal quality certification number: 42000600001376, use certificate number: 00120333); (body weight 18 ~ 22g, male, Wuhan University's Experimental Animal Center provides Kunming mouse, the laboratory animal quality certification number: 42000600001376, use certificate number: 00120332).
1, Herba Houttuyniae suppository on Carrageenan causes the pharmacodynamic evaluation of rat nonbacterial prostatitis
1.1 experimental technique
Get SD rat 80, be divided into 7 groups at random, often organize 10, be respectively blank group, negative control group, positive controls (Prostant group) and basic, normal, high, the high dosage of Herba Houttuyniae prostate suppository four administration groups (being equivalent to 0.5 times of plan clinical dosage, 1 times, 2 times and 5 times respectively).Positive controls and four administration groups give relative medicine respectively, and negative control group and blank group give bare substrate, and administering mode is rectally.Before administration, Rat Fast can't help water 12h, the abundant defecation of stimulation in rats.After pre-for suppository thermal softening, with irrigation stomach device learn from else's experience conversion after each dose drug push Rat-rectum 1.5cm place.The equivalent dosage (with Herba Houttuyniae extract gauge) calculating rat according to surface area method is respectively 5mg/Kg (low dosage), 10mg/Kg (middle dosage), 20mg/Kg (high dose), 50mg/Kg (high dosage), is scaled suppository dosing volume and is only 0.2ml/.At once fill in anus with sponge after administration, take off after 2h, each group daily once.Pre-administration carried out modeling after 7 days, by 300mg/kg lumbar injection chloral hydrate (10%, g/ml), anaesthetize successfully, ventral seta is cut off with Shearing shears, iodophor disinfection liquid disinfectant, at median incision of lower abdomen about 2 ~ 3cm under aseptic condition, through abdominal cavity, bladder and both sides seminal vesicle are proposed, expose the prostate notopodium invested inside seminal vesicle, blank group is in injecting 0.05ml normal saline herein, negative control group, positive controls, four administration groups inject the Carrageenan solution that 0.05ml concentration is 1% (g/ml) respectively, suturing them muscle skin, povidone iodine sterilization wound, put back to Mus cage, free diet.
1.2 observation index
1.2.1 prostate anatomy is observed
Postoperative 1 day, often group put to death half rat, and residue rat is normally administered once again, puts to death next day.Cut open the belly, fully expose Ventral Prostates body, the prostatic volume of perusal, quality, glossiness, color, organize apparent with the adhesion degree, gland tissue surface canescence point-like tuberosity etc. of surrounding tissue.Careful stripping prostate, takes weight in wet base, calculates prostate index (%)=prostate weight in wet base (mg)/body weight (g).
1.2.2 numeration of leukocyte in prostate
Get the left side prostate of test Mus, add normal saline 4 μ l by every 1mg prostata tissue, shred, fully mix.Get 1, test tube, add leukocyte diluent 0.38ml, accurately draw the above-mentioned prostata tissue specimen fluids 20 μ l prepared with pipettor and release gently in being equipped with bottom diluent test tube, mixing.In the above-mentioned diluent shaken up, drawing a small amount of liquid with little dropper adds in blood countng chamber, fill pond, static 1 ~ 2 minute, treat that leukocyte sinks, with the total white blood cells in the block plaid of low power lens counting 4, corner, leukocyte count × 50 × 10 in leukocyte count/L=4 block plaid
6.
1.2.3 histopathological examination
Take out prostate siphonal lobe, put 10% formalin internal fixtion specimen, conventional dehydration, specimens paraffin embedding slices, slice thickness 5 μm, HE dyes, and the application XYTX-2000 full-automatic Quantitative Pathologic Image Analysis system of medicine nonphosphorylated neurofilament H 20 × 10 visuals field under light microscopic, semiquantitative method judges prostatic lesion degree.Formulate grade scoring standard as follows: (1) prostata tissue, without obvious struvite change, is designated as "-", 0 point; (2) prostate interstitial Mild edema, visible a small amount of inflammatory cell infiltration, is designated as "+", 1 point; (3) the obvious edema of prostate interstitial, visible a large amount of cell infiltration, glandular epithelial local necrosis comes off, and fibroplasia is obvious, is designated as " ++ ", 2 points; (4) prostate is treating serious edema caused, dispersivity inflammatory cell infiltration, and body of gland sheet comes off necrosis, and fibroplasia is obvious, is designated as " +++ ", 3 points.
1.2.4 statistical procedures
Adopt SPSS18.0 statistical software analytical data, tissue pathologic change degree data represent with scoring value and meansigma methods, and measurement data data are used
represent, analyze with t inspection between two groups, nonparametric rank test ranked data, test level α=0.05.
1.3 result
1.3.1 Herba Houttuyniae suppository is on the impact of rat prostate mode of appearance
Blank group rat prostate tissue is soft, ruddy glossy, with surrounding tissue without adhesion.Modeling first day, negative control group and the more blank group of obvious enlargement of basic, normal, high dosage group rat prostate, in vain light, be dispersed in inflammation pus point, quality hardening and in body of gland leukocyte count significantly increase; In positive controls and pole high dose group rat prostate volume size, color, form, quality and body of gland, leukocyte count and blank group are without significant difference.Modeling second day, respectively organizes rat prostate form compared with first day without significant change.
1.3.2 Herba Houttuyniae suppository is on the impact of rat prostate exponential sum leukocyte count
From table 1, blank group, positive controls and pole high dose group compare with negative control group, its prostate exponential sum leukocyte count reduces and all significantly reduces (* * * P < 0.01), basic, normal, high dosage group prostate exponential sum leukocyte count compares without significant difference (P > 0.05) with negative control group, result no significant difference between modeling two days.
Table 1 Herba Houttuyniae suppository is on the impact (n=70) of rat nonbacterial prostatitis model prostate exponential sum leukocyte count
Compare with negative control group, * P < 0.05, * * 0.01 < P < 0.05, * * * P < 0.01
1.3.3 Herba Houttuyniae suppository is on the impact of rat prostate tissue pathological change
Please refer to Fig. 1 and table 2, modeling 1st ~ 2 days, blank group, high dosage and positive controls rat prostate tissue structural integrity, glandular epithelial has no downright bad, comes off, and interstitial has a small amount of inflammatory cell to invade profit; Negative control group and the visible massive inflammatory cells infiltrated of basic, normal, high dosage group prostata tissue interstitial, even occur that the necrosis of body of gland large area comes off, point out the effect that Herba Houttuyniae suppository pole high dose group tool has clear improvement nonbacterial prostatitis rat prostate tissue pathological changes.
Table 2 Herba Houttuyniae suppository is on the impact (n=70) of rat nonbacterial prostatitis model lesion tissue
Compare with negative control group (rank test), * P < 0.05, * * 0.01 < P < 0.05, * * * P < 0.01
2, Herba Houttuyniae suppository is to the pharmacodynamic evaluation of mouse experiment prostatic hyperplasia
2.1 experimental technique
Get male mice in kunming 70, body weight 18 ~ 22g, be divided into that blank group, negative control group (model group), Herba Houttuyniae prostate suppository are basic, normal, high, pole high dose group, positive controls (Prostant group) at random, often organize 10.The sterile saline 0.2ml of blank group subcutaneous injection equivalent, all the other are group subcutaneous injection every day 1 testosterone propionate 0.2ml (5mg/Kg) respectively, difference rectally 1 time after 1h, each dosage group equivalence dosage (with Herba Houttuyniae extract gauge) calculating mice according to surface area method is respectively 13.5mg/Kg, 27mg/Kg, 54mg/Kg, 135mg/Kg, be scaled suppository dosing volume and be only 0.05ml/, negative control group and blank group give bare substrate, administering mode is rectally, at once anus is filled in sponge after administration, take off after 2h.Successive administration is after 30 days, and within the 31st day, put to death mice, carefully peel off each Mus prostate, weigh (mg) respectively, and (weight of prostate (mg/10g body weight), the results are shown in Table 3 to calculate prostate index.
Table 3 Herba Houttuyniae suppository is on the impact (X ± S) of Experimental Mice prostatic hyperplasia
Compare with negative control group, * * 0.01 < P < 0.05, * * * P < 0.01
From table 3, middle and high dosage Herba Houttuyniae suppository all obviously suppresses mouse experiment prostatic hyperplasia; High dosage Herba Houttuyniae suppository can extremely significantly suppress mouse experiment prostatic hyperplasia, and with the pharmacodynamics there was no significant difference of commercially available Prostant.
3, the pharmacodynamic evaluation of Herba Houttuyniae suppository antiinflammatory action
3.1 xylol cause the swollen impact of mouse ear
Get male mice in kunming 60, body weight 18 ~ 22g, be divided into negative control group (model group) at random, Herba Houttuyniae prostate suppository be basic, normal, high for positive controls (Prostant group), pole high dose group (being equivalent to 0.5 times of plan clinical dosage, 1 times, 2 times and 5 times respectively), often organize 10.Each dosage group and positive controls respectively rectum only give medicine 0.05ml/, and blank group and negative control group respectively rectum give medicine equal-volume bare substrate, every day 1 time, continuous 7 days.30min after last administration, animal etherization, is coated with dimethylbenzene 0.05ml in each group of mouse right ear front and rear sides and causes inflammation, after 4h, cervical dislocation puts to death mice, lays auricle, weigh with diameter 8mm card punch in left and right ear same area, record left and right auricle weight, with left and right auricle weight for swelling.The results are shown in Table 4.
The impact (X ± S) of table 4 Herba Houttuyniae suppository xylol induced mice ear swelling
Compare with blank group, * * 0.01 < P < 0.05, * * * P < 0.01
From table 4, the Herba Houttuyniae suppository of each dosage and Prostant all significantly can suppress the mice auricle swelling caused by dimethylbenzene, and the effect of pole high dose group Herba Houttuyniae suppository is suitable with Prostant.
3.2 impacts on mice granuloma induced by implantation of cotton pellets
Get male mice in kunming 60, body weight 18 ~ 22g, be divided into negative control group (model group) at random, Herba Houttuyniae prostate suppository be basic, normal, high for positive controls (Prostant group), pole high dose group (being equivalent to 0.5 times of plan clinical dosage, 1 times, 2 times and 5 times respectively), often organize 10.In each Mus side armpit skin degerming under waking state, to be subcutaneously worth into 10mg sterilizing dry cotton ball each one, complete administration immediately of performing the operation.Each dosage group and positive controls respectively rectum only give medicine 0.05ml/, and blank group and negative control group respectively rectum give medicine equal-volume bare substrate, every day 1 time, continuous 7 days.Each dosage group and negative and positive matched group respectively rectum give medicine or equal-volume substrate, every day 1 time, continuous 10 days, put to death mice in the 11st day, carefully peel off armpit cotton balls granulation tissue, removing fatty tissue, after putting 60 DEG C of baking ovens placement 12h, weigh respectively, deduct raw cotton ball weight, obtain granulation net weight, respectively organize granulation weight and calculate suppression ratio.The results are shown in Table 5.
Table 5 Herba Houttuyniae suppository is on the impact (X ± S) of Experimental Mice granuloma induced by implantation of cotton pellets
Compare with blank group, * * 0.01 < P < 0.05, * * * P < 0.01
From table 5, middle and high, high dosage Herba Houttuyniae suppository all has the effect obviously suppressing mice granuloma induced by implantation of cotton pellets hamartoplasia, and the effect of height, pole dosage group and commercially available Prostant there was no significant difference.
4, the pharmacodynamic evaluation (acetic acid writhing test) of Herba Houttuyniae suppository analgesic activity
Get male mice in kunming 70, body weight 18 ~ 22g, grouping and administering mode are with under " 1 " item.Each dosage group equivalence dosage (with Herba Houttuyniae extract gauge) calculating mice according to surface area method is respectively 13.5mg/Kg, 27mg/Kg, 54mg/Kg, 135mg/Kg, is scaled suppository dosing volume and is only 0.05ml/.In last administration 2h pneumoretroperitoneum injection acetic acid normal saline solution (1%, ml/ml) 0.2ml, the writhing number of times of mice in observed and recorded 30min.Difference between more each group, the results are shown in Table 5.
Table 5 Herba Houttuyniae suppository Dichlorodiphenyl Acetate causes the impact (n=70) of mouse writhing reaction
Compare with blank group, * * 0.01 < P < 0.05, * * * P < 0.01
The each dosage group of Herba Houttuyniae suppository and positive controls all significantly can reduce acetic acid induced mice writhing number of times, wherein with pole high dose group most pronounced effects (P < 0.01), prompting Herba Houttuyniae suppository Dichlorodiphenyl Acetate induced mice pain has obvious analgesic activity.
5, the pharmacodynamic evaluation of Herba Houttuyniae suppository In Vitro Bacteriostasis
By the Pseudomonas aeruginosa (10211) after activation, large intestine Erichsen bacterium (44102), staphylococcus aureus (26003), Bacillus proteus (49027) four kinds of vaccines dilute 1000 times with sterile saline respectively, bacterium liquid after dilution inoculates 0.1ml respectively in being followed successively by 108 containing drug level, 54, 27, 13, 5, 6, 25, 3.12, 1.56, in the small test tube of the M-H fluid medium 1ml of 0.75mg/ml, negative control is not inoculated, after postvaccinal small test tube being placed in 37 DEG C of constant-temperature shaking culture 24h, observed result also measures the minimum inhibitory concentration (MIC) of Herba Houttuyniae suppository.The results are shown in Table 6.
The In Vitro Bacteriostasis of table 6 Herba Houttuyniae suppository
From table 6, Herba Houttuyniae suppository has obvious bacteriostasis when 27mg/ml and above concentration thereof to Pseudomonas aeruginosa; To colon bacillus, there is obvious bacteriostasis when 54mg/ml and above concentration thereof, to staphylococcus aureus and Bacillus proteus, there is obvious bacteriostasis when 13.5mg/ml and above concentration thereof.
Shown by above-mentioned experiment: Herba Houttuyniae suppository of the present invention significantly can reduce the prostate exponential sum leukocyte count of nonbacterial prostatitis rat model, repair prostata tissue inflammatory lesions, lapse to prostate normal morphology; Prostatic hyperplasia mice is caused to lumbar injection testosterone propionate there is obvious inhibitory action.
Herba Houttuyniae suppository also significantly can suppress the swelling of mice caused by dimethylbenzene xylene auricle acute inflammation, granuloma induced by implantation of cotton pellets hamartoplasia is caused to subcutaneous implantation sterilizing dry cotton ball and also has obvious inhibitory action, mice " writhing " reaction times caused by obvious reduction lumbar injection acetic acid, prompting this product has significant antiinflammatory, analgesic activity, and its effect presents dose dependent.
Extracorporeal bacteria inhibitor test shows, Herba Houttuyniae suppository all has obvious bacteriostasis to Pseudomonas aeruginosa, escherichia coli, staphylococcus aureus and Bacillus proteus.
Two, anxious poison test
Grouping: 50 SD rats are divided into 5 groups at random, often organizes 10, is respectively low dose group, middle dosage group, high dose group, pole high dose group, blank group.Calculate each dosage group equivalence dosage of mice according to surface area method, low dose group is 25mg/Kg, and middle dosage group is 50mg/Kg, and high dose group is 75mg/Kg, and pole high dose group is 100mg/Kg.
Administration: four administration groups give relative medicine respectively, and blank group gives bare substrate, and administering mode is rectally.Before administration, Rat Fast can't help water 12h, the abundant defecation of stimulation in rats, manually presses rectum place if necessary before administration and helps rat defecation, medicine irrigation stomach device is injected Rat-rectum 1.5cm place, at once fills in anus with sponge, take off after 4h after administration.
Toxic reaction: the performance of observation rat body and situation of being poisoned to death, comprises the change of the body weight of animal, medicine-feeding part red and swollen degree, hair color, eyes and mucosa, the changes such as breathing, circulation, extremity activity and central nervous system's behavior expression.If chance animal dead, accurate recording of time.
The postmortem of animal and if desired histopathological examination: give tested material forward and backward, when animal dead and off-test, take the body weight of animal.The animal that all animals comprise death or execution performs an autopsy on sb..
Observation period: raise tested rat according to a conventional method, observe and record time of various toxic reaction appearing and subsiding, from 1h after taking percutaneous drug delivery patch off be the 1st observing time point, afterwards after taking percutaneous drug delivery patch off 7h, 24h, 48h, 72h by the 7th day, Continuous Observation record 1 week.Toxic reaction as animal still existed by the 7th day, then continue observation 7 days.
Result of the test: the test of each group shows, after basic, normal, high, the high dosed administration of Herba Houttuyniae suppository, animal activity is normal, and every physical signs and sign, without significant change, have no overt toxicity reaction and occur, the results are shown in Table 7.
Table 7 Herba Houttuyniae suppository acute toxicity test observed result
Three, long term toxication
Grouping: 40 male SD rats are divided into 4 groups at random, be respectively blank group (not the bare substrate bolt of drug containing), high dose group (2 times of plan dosage, containing Herba Houttuyniae extract 1.34g/ grain), middle dosage group (1.5 times of plan dosage, containing Herba Houttuyniae extract 1.00g/ grain), low dose group (plan dosage, containing Herba Houttuyniae extract 0.67g/ grain).
Administration: three administration groups give relative medicine respectively, and blank group gives bare substrate, and administering mode is rectally.Before administration, Rat Fast can't help water 6h, the abundant defecation of stimulation in rats, manually presses rectum place if necessary before administration and helps rat defecation, medicine irrigation stomach device is injected Rat-rectum 1.5cm place, at once fills in anus with sponge, take off after 2h after administration.Each group daily once, successive administration 3 months, Per-Hop behavior 6d.
After drug withdrawal, often group leaves 4, then raises 14d and carry out convalescent period observation, the degree of reversibility determining tested material toxic reaction and the retardance toxic reaction that may occur.Carry out comprehensive gross anatomy to other tested rats, main organs is weighed and is calculated organ coefficient.
Observation index: administration phase and convalescent period, every day carries out gross examination of skeletal muscle to rat, comprises the observation of outward appearance sign, behavioral activity, food ration, body weight, feces character, administration local response, hematological indices, blood biochemical analysis index, urinalysis, histopathological examination etc.
Result of the test: study by above-mentioned long term toxicity test method, result shows: Herba Houttuyniae suppository uses 3 months continuously under basic, normal, high 3 dosage, have no obvious long term toxicity reaction, can support clinical drug the course for the treatment of≤1 month time the clinical research of III phase.
Four, rectal distention stimulation test method
Grouping: be malely divided into 3 groups at random by 15, often organizes 5, is respectively plan dosage group (containing Herba Houttuyniae extract 0.67g/ grain), 1.5 times of plan dosage groups (containing Herba Houttuyniae extract 1.00g/ grain), blank groups.
Medication: two administration groups give relative medicine respectively, and blank group gives bare substrate, and administering mode is rectally.Before administration, water 6h is can't help in animal fasting, the abundant defecation of stimulation in rats, manually presses rectum place if necessary before administration and helps rat defecation, medicine is filled in rabbit rectum 2cm place, at once fill in sponge after administration, close anus, take off after 4h.Each group daily once, plan dosage group administration 1 time 1, successive administration 14d.After last is to test medicine, 24h puts to death animal, observes by following index.
Observation index: observe every day such as the general state of animal, behavior, sign etc., observe local response and the general reaction of animal rectum in detail simultaneously, comprise anal regions and anal sphincter, clinical manifestation after administration (as pain symptom) and feces (as blood, mucus), the death of animal and postmortem situation after administration, local organization, with or without phenomenon, degree and scopes such as hyperemia, erythema, edema, need carry out the histopathologic examination of crissum mucosa if change.If there is irritative response, the convalescent period after drug withdrawal should be carried out and observe, with the recovery situation of clear and definite toxic reaction.
Result of the test: study by above-mentioned rectal distention stimulation test method, result shows: Herba Houttuyniae suppository has no obvious irritation reaction.
Conclusion: when Herba Houttuyniae suppository plan presses clinical treatment use by dosage group and 1.5 times of plan dosage groups, without mucous membrane of rectum zest.
Four, the stability test of Herba Houttuyniae suppository
1, accelerated test
By embodiment 9,10, the 11 Herba Houttuyniae bolt simulation listing packagings prepared, be packaged in polyethylene tube, 30 DEG C ± 2 DEG C, place 6 months, respectively at the 0th, 1 under the condition of relative humidity 65% ± 5%, 2, sampling in 3,6 months, carries out every inspection and measures, and compared with the 0th day, result of the test is as table 8.
Table 8 Herba Houttuyniae suppository accelerated test result
Accelerated test result shows: 30 DEG C, under the condition of relative humidity 65%, three batch samples of simulation listing packaging are carried out to the accelerated test of 6 months by a definite date, every inspection target has no significant change, shows that this product has good stability under commercially available back condition.
2, long term test
By embodiment 9,10, the 11 Herba Houttuyniae bolt simulation listing packagings prepared, be packaged in polyethylene tube, 25 DEG C ± 2 DEG C, place, respectively at the 0th under relative humidity 60% ± 10% condition, 3,6,9,12, sampling in 18,24 months, carries out every inspection and measures, and compared with the 0th day, result of the test is as table 9.
Table 9 Herba Houttuyniae suppository long-term test results
Long-term test results shows: 25 DEG C, under the condition of relative humidity 60%, three batch samples of simulation listing packaging are carried out to the long term test of 24 months by a definite date, every inspection target has no significant change, shows that this product has good stability.
3, strong illumination test
Place 10 days under the test sample of embodiment 9 being placed in illumination 4500Lx illuminance.Respectively at sampling in the the 0th, 5,10 day, carry out inspection according to every test method and measure, and compared with the 0th day, result of the test was as table 10.
Table 10 Herba Houttuyniae prostate suppository intense light irradiation irradiates (4500lx) result of the test
| Time | Character | Differentiate | Melt and become the time limit |
| 0 day | Rufous torpedo solid | Conform with the regulations | Conform with the regulations |
| 5 days | Rufous torpedo solid | Conform with the regulations | Conform with the regulations |
| 10 days | Rufous torpedo solid | Conform with the regulations | Conform with the regulations |
Above-mentioned " character " standard related to is: rufous torpedo solid.
The assay method of above-mentioned " discriminating " that relate to is: get this product 2, put in round-bottomed flask, according to determination of volatile oil method (" Chinese Pharmacopoeia " 2010 editions one annex Ⅹ D) 40ml that adds water, ethyl acetate 1ml, slowly be heated to boil, and keep micro-and boil 4 hours, leave standstill half an hour, divide and get acetic acid ethyl fluid as need testing solution.Separately get methylnonanone reference substance 0.1ml, put in 10ml volumetric flask, add acetic acid ethyl dissolution to scale (making the solution of every 1ml containing 10 μ l), product solution in contrast.Test according to thin layer chromatography (" Chinese Pharmacopoeia " 2010 editions one annex VI B), draw above-mentioned need testing solution 5 μ l, reference substance solution 2 μ l, put respectively in same with sodium carboxymethyl cellulose be adhesive silica gel g thin-layer plate on, with n-hexane-ethyl acetate (9:1) for developing solvent, launch, take out, dry, spray with dinitrophenylhydrazine test solution.In test sample chromatograph, on the position corresponding to reference substance chromatograph, aobvious identical yellow spotting.
The assay method of above-mentioned " melt become time limit " of relating to into: get this product 3, after room temperature places 1 hour, be placed on respectively on lower floor's plectane of 3 metal rack, load in respective sleeve, and fix with hook.Unless otherwise specified, be dipped vertically into by said apparatus in the container filling the 37.0 DEG C ± 0.5 DEG C of water being no less than 4L respectively, its upper end position should at 90mm place, underwater.Fill a rot in container, overturn this device in the solution once every 10 minutes.Melt in " Chinese Pharmacopoeia " version in 2010 annex Ⅻ B and become overtime check method, regulation: " unless otherwise specified, the suppository 3 of fatty substrate all should melt in 30 minutes, softening or press time without hard-core; The suppository 3 of water-soluble base should dissolve in 60 minutes.Against regulation if any 1, separately should get 3 retrials, all should conform with the regulations.”
Although above with general explanation, detailed description of the invention and test, the present invention is described in detail, and on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (10)
1. a pharmaceutical composition, is characterized in that: by weight, and described pharmaceutical composition comprises following component: 90-110 part Herba Houttuyniae extract, 5-15 part Serenoa repens oil.
2. pharmaceutical composition according to claim 1, is characterized in that: described pharmaceutical composition also comprises 2-7 part antioxidant; Preferably, described antioxidant is lycopene, astaxanthin, beta-carotene, the combination of one or more in anthocyanidin; More preferably, described antioxidant is lycopene.
3. pharmaceutical composition according to claim 1 and 2, is characterized in that: by weight, and described pharmaceutical composition comprises following component: 100 parts of Herba Houttuyniae extracts, 9-12 part Serenoa repens oil, 4-6 part lycopene.
4. according to the arbitrary described pharmaceutical composition of claim 1-3, it is characterized in that: described Herba Houttuyniae extract prepares by the following method: get Herba Houttuyniae, add Herba Houttuyniae weight 6-10 ethanol doubly, reflux, extract, 0.5-2h, filtered while hot, removing ethanol, to obtain final product.
5. a Herba Houttuyniae suppository, is characterized in that, described Herba Houttuyniae suppository is prepared by the component comprising following weight portion: 90-110 part Herba Houttuyniae extract, 5-15 part Serenoa repens oil, 2-7 part antioxidant, 2-7 part transdermal enhancer, 120-180 part suppository base, 20-50 part water.
6. Herba Houttuyniae suppository according to claim 5, is characterized in that: described antioxidant is lycopene, astaxanthin, beta-carotene, the combination of one or more in anthocyanidin, is preferably lycopene;
Described transdermal enhancer is Borneolum Syntheticum, menthol, Oleum Caryophylli, eucalyptus oil, one or more the combination in Rhizoma Chuanxiong oil, is preferably Borneolum Syntheticum;
Described suppository base is Polyethylene Glycol, cocoa butter, glycerin gelatine, Polysorbate-61, one or more the combination in pluronic copolymer, is preferably the combination of PEG400 and Macrogol 4000.
7. the Herba Houttuyniae suppository according to claim 5 or 6, it is characterized in that: described Herba Houttuyniae suppository is prepared by following component: 100 parts of Herba Houttuyniae extracts, 9-12 part Serenoa repens oil, 4-6 part lycopene, 4-6 part Borneolum Syntheticum, 65-75 part PEG400,75-85 part Macrogol 4000,25-35 part water.
8. the preparation method of the arbitrary described Herba Houttuyniae suppository of claim 5-7, is characterized in that, comprise the steps:
(1) prepare Herba Houttuyniae extract: get Herba Houttuyniae, add Herba Houttuyniae weight 6-10 ethanol doubly, heating and refluxing extraction 0.5-2h, filtered while hot in described Herba Houttuyniae, removing ethanol, to obtain final product;
(2) prepare Herba Houttuyniae suppository: by formula ratio, the Herba Houttuyniae extract obtained by step (1), Serenoa repens oil, antioxidant, transdermal enhancer, water mixes, and is heated to be uniformly dispersed, obtains medicinal liquid A at 60-70 DEG C; Suppository base is melted, obtains matrix liquid B; After medicinal liquid A and matrix liquid B mix homogeneously, pour into suppository mold, cooling, molding, to obtain final product.
9. the arbitrary described pharmaceutical composition of claim 1-4 or the application of the arbitrary described Herba Houttuyniae bolt of claim 5-8 in preparation treatment prostatosis medicine.
10. application according to claim 9, is characterized in that: described prostatosis comprises following disease: chronic prostatitis and the frequent micturition caused by hyperplasia of prostate (prostate hyperplasia), urgent micturition, dysurea, urinate endless, frequent urination at night, urine retention, whitish discharge from urinary meatus, urethra discomfort, testicular pain, lower abdominal pain, perineal pain.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106074821A (en) * | 2016-07-27 | 2016-11-09 | 南京正宽医药科技有限公司 | The process of preparing Chinese medicine extracting method of a kind of Herba Houttuyniae decoction pieces and Herba Houttuyniae compositions |
| CN107961288A (en) * | 2017-12-14 | 2018-04-27 | 西安交通大学 | Application of the cordate houttuynia water extract in the medicine for improving aortic endothelial cell function is prepared |
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| JPH10127249A (en) * | 1996-10-29 | 1998-05-19 | Bizen Kasei Kk | Composition containing extract from saw palmetto fruit |
| JP2001342142A (en) * | 2000-06-01 | 2001-12-11 | Nissui Pharm Co Ltd | Composition for preventing and curing urologic disease |
| JP2007230983A (en) * | 2006-02-27 | 2007-09-13 | Shonan Institute For Medical & Preventive Science | Prostatic hypertrophy inhibitor |
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| JPH10127249A (en) * | 1996-10-29 | 1998-05-19 | Bizen Kasei Kk | Composition containing extract from saw palmetto fruit |
| JP2001342142A (en) * | 2000-06-01 | 2001-12-11 | Nissui Pharm Co Ltd | Composition for preventing and curing urologic disease |
| JP2007230983A (en) * | 2006-02-27 | 2007-09-13 | Shonan Institute For Medical & Preventive Science | Prostatic hypertrophy inhibitor |
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Cited By (2)
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| CN106074821A (en) * | 2016-07-27 | 2016-11-09 | 南京正宽医药科技有限公司 | The process of preparing Chinese medicine extracting method of a kind of Herba Houttuyniae decoction pieces and Herba Houttuyniae compositions |
| CN107961288A (en) * | 2017-12-14 | 2018-04-27 | 西安交通大学 | Application of the cordate houttuynia water extract in the medicine for improving aortic endothelial cell function is prepared |
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Application publication date: 20160210 |