CN105456947A - Pharmaceutical composition for treating avascular necrosis of femoral head and application thereof - Google Patents

Pharmaceutical composition for treating avascular necrosis of femoral head and application thereof Download PDF

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CN105456947A
CN105456947A CN201610009875.7A CN201610009875A CN105456947A CN 105456947 A CN105456947 A CN 105456947A CN 201610009875 A CN201610009875 A CN 201610009875A CN 105456947 A CN105456947 A CN 105456947A
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weight portion
radix
rhizoma
pharmaceutical composition
herba
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张云峰
刘卫华
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Qingdao Municipal Hospital
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Qingdao Municipal Hospital
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Abstract

The invention discloses a pharmaceutical composition for treating avascular necrosis of femoral head and the application thereof. The pharmaceutical composition is prepared from prepared rehmannia root, radix angelicae sinensis, radix paeoniae alba, ligusticum wallichii, red-rooted salvia root, rhizoma sparganii, curcuma zedoary, garden balsam stem, lumbricus, centipede, leech, roasted carapax trionycis, stir-baked rhizoma dioscoreae, fructus corni, raw eucommia ulmoides, raw rhizoma atractylodis macrocephalae, raw radix astragali, poria cocos, cassia twig, honey-fried licorice root, cassia bark, rhizoma alismatis, achyranthes root, hairyvein agrimony, oldenlandia diffusa and scutellariae barbatae. The pharmaceutical composition is remarkable in clinical effect, short in treatment course, capable of becoming effective quickly, free of toxic or side effect, and worth clinical application and popularization.

Description

A kind of pharmaceutical composition and application thereof for the treatment of ischemic necrosis of femoral head
Technical field
The present invention relates to technical field of Chinese medicine, particularly relate to a kind of medicine for the treatment of hormonal ischemic necrosis of femoral head.
Background technology
Femur head necrosis (Osteonecrosisofthefemoralhead, ONFH), also known as ischemic necrosis of femoral head (Avascularnecrosisofthefemoralhead, AVNFH), because of blood supply of the femoral head interruption or impaired, cause the dead and reparation subsequently of osteocyte and marrow components, then femoral head structural change is caused, collapse of the femoral head, cause the disease of patient articular's pain, joint function disturbance, being a kind of commonly encountered diseases in Orthopedic Clinical work, is also refractory disease in field of orthopaedics.ONFH can be divided into the traumatic and large class of atraumatic two, and the former causes primarily of the hip trauma such as fracture of femoral neck and dislocation of hip joint, and the factor such as application, excessive drinking, decompression sickness, smoking, anemia that the latter is mainly glucocorticoid is relevant.Since Pietrogrand reports steroid-induced femoral head necrosis, occur that similar cases is reported all over the world successively.In recent years, along with glucocorticoid extensive use clinically, the sickness rate of corticosteroid femur head necrosis (steroid-inducedosteonecrosisoffemoralhead, SONFH) presents ascendant trend year by year.The Patients with Aseptic Necrosis of Femoral that bibliographical information China need treat is 5,000,000-750 ten thousand, and annual new cases are 150,000-20 ten thousand, and this wherein, is one of topmost factor again, accounts for 50% of atraumatic restorative technique with the application of glucocorticoid.
Record without the name of disease of corticosteroid femur head necrosis in Chinese medicine, but according to its characteristics of incidence, the disease category such as " osteomyelitis " in Chinese medicine, " atrophic debility of bones ", " rheumatism involving the bone " can be belonged to.In recent years, grinding makes internal disorder or usurp shows that the pathogenesis of SONFH is relevant to factors such as intravascular coagulation, osteoporosis, fat metabolic disturbance, bone inner high voltages, but its definite pathogenesis is completely unclear yet.Therefore, numerous scholar is devoted to the pathogeny illustrating SONFH.Chinese medicine scholar also inquires into the etiology and pathogenesis of SONFH and Chinese medicine to its mechanism of action from all angles, provides experimental basis and theories integration for using Chinese medicine prevention SONFH clinically.Therefore, the experiment of TCM about SONFH grinds to make internal disorder or usurp becomes one of current focus studied, and also achieves greater advance.
Literature research finds, the Chinese medicine about SONFH grinds that making internal disorder or usurp focuses mostly on to dehumidify three kinds of method for the treatment of in liver and kidney tonifying, blood circulation promoting and blood stasis dispelling, spleen invigorating.Find that liver and kidney tonifying class Chinese medicine can increase SONFH model femur head necrosis and organize Bone Gla protein and bone density if any scholar, can break up by inducing bone mesenchymal stem cell to osteoblast, be reduced to the differentiation of fat direction, reach the effect for the treatment of SONFH.Also there is the indexs such as hemorheology in SONFH patient changes to have scholar to find, femur head necrosis tissue local VEGF (Vascularendothelialgrowthfactor, and endothelial progenitor cells number and active to reduce VEGF), vessel patency is become to decline, and blood-activating stasis-removing kind Chinese medicine can improve SONFH hemorheology index, improve femoral head microcirculation, promote slough reparation.In addition, some experimental results show that glucocorticoid causes patient's fat metabolic disturbance, reduce Osteoblast Differentiation, inducing bone mesenchymal stem cell etc. are to the differentiation of one-tenth fat direction, cause blood lipid to raise, form fatty acid molecules tiny blood vessels, microcirculation disturbance, discuss the generation of SONFH from the traditional Chinese medical science " phlegm-damp " cause of disease, therefore clinical treatment should be taken into account spleen invigorating and eliminates the phlegm.But about the experimentation to different tcm treatment method treatment SONFH, then report less.
Pharmaceutical composition of the present invention, grinds according to current relevant SONFH the progress that makes internal disorder or usurp, and long-term treatment SONFH experience clinically, thinks existence " stasis of blood, void, expectorant " pathogenic characteristic in corticosteroid femur head necrosis.Because pathogen (i.e. hormone) causes the stasis of blood, causes void, gives birth to expectorant, the stasis of blood, void, expectorant three tight association, and influence each other, be jointly present in the generation of SONFH disease, evolution.Therefore, propose the kidney invigorating, invigorate blood circulation, the Therapeutic Principle of eliminating the phlegm, prescription combination drug, observe it to rabbit SONFH model different time points hemorheology, the index such as blood fat and bone metabolism, and femur head necrosis organizes ultra micro organizational structure, RT-qPCR detects the downright bad ancient sacrificial utensil of femoral head in rabbits and knits osteoprotegerin (osteoprotegerin, 0PG), bone morphogenetic protein 2 (bonemorphogeneticprotein-2, BMP-2), VEGF (vascularendothelialgrowthfactor, VEGF) mRNA, the kidney invigorating is inquired into curative effect timeliness, invigorate blood circulation, to eliminate the phlegm the mechanism of action of three kinds of different tcm treatment methods in SONFH, for using the kidney invigorating clinically, invigorate blood circulation, timid expectorant class treatment by Chinese herbs SONFH provides experimental basis and theory support, develop advantage and the characteristic of motherland therapeutic treatment SONFH.Meanwhile, with this experimental result for the strong point, " stasis of blood, void, the expectorant " that enriches SONFH is further theoretical, for later stage research lays the foundation.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of pharmaceutical composition being used for the treatment of hormonal ischemic necrosis of femoral head, and its clinical effectiveness is remarkable, short treating period, instant effect, and has no side effect, and clinic is applied.
Based on this, the invention provides a kind of pharmaceutical composition being used for the treatment of hormonal ischemic necrosis of femoral head, its crude drug comprises Radix Rehmanniae Preparata, Radix Angelicae Sinensis, the Radix Paeoniae Alba, Rhizoma Chuanxiong, Radix Salviae Miltiorrhizae, Rhizoma Sparganii, Rhizoma Curcumae, Herba speranskiae tuberculatae, Pheretima, Scolopendra, Hirudo, Carapax Trionycis (processed), Rhizoma dioscoreae (parched), Fructus Corni, Cortex Eucommiae, Rhizoma Atractylodis Macrocephalae, Radix Astragali, Poria, Ramulus Cinnamomi, Radix Glycyrrhizae Preparata, Cortex Cinnamomi, Rhizoma Alismatis, Radix Achyranthis Bidentatae, Herba Agrimoniae, Herba Hedyotidis Diffusae and Herba Scutellariae Barbatae.
Wherein, in described pharmaceutical composition, the weight portion of each crude drug is respectively Radix Rehmanniae Preparata 20 weight portion ~ 30 weight portion, Radix Angelicae Sinensis 15 weight portion ~ 25 weight portion, the Radix Paeoniae Alba 20 weight portion ~ 30 weight portion, Rhizoma Chuanxiong 15 weight portion ~ 25 weight portion, Radix Salviae Miltiorrhizae 15 weight portion ~ 25 weight portion, Rhizoma Sparganii 25 weight portion ~ 40 weight portion, Rhizoma Curcumae 30 weight portion ~ 40 weight portion, Herba speranskiae tuberculatae 10 weight portion ~ 20 weight portion, Pheretima 10 weight portion ~ 15 weight portion, Scolopendra 10 weight portion ~ 15 weight portion, Hirudo 15 weight portion ~ 20 weight portion, Carapax Trionycis (processed) 10 weight portion ~ 20 weight portion, Rhizoma dioscoreae (parched) 15 weight portion ~ 25 weight portion, Fructus Corni 20 weight portion ~ 35 weight portion, Cortex Eucommiae 10 weight portion ~ 15 weight portion, Rhizoma Atractylodis Macrocephalae 20 weight portion ~ 30 weight portion, Radix Astragali 20 weight portion ~ 30 weight portion, Poria 15 weight portion ~ 25 weight portion, Ramulus Cinnamomi 15 weight portion ~ 20 weight portion, Radix Glycyrrhizae Preparata 20 weight portion ~ 30 weight portion, Cortex Cinnamomi 10 weight portion ~ 20 weight portion, Rhizoma Alismatis 15 weight portion ~ 20 weight portion, Radix Achyranthis Bidentatae 25 weight portion ~ 30 weight portion, Herba Agrimoniae 10 weight portion ~ 15 weight portion, Herba Hedyotidis Diffusae 10 weight portion ~ 20 weight portion and Herba Scutellariae Barbatae 10 weight portion ~ 20 weight portion.
Wherein, in described pharmaceutical composition, the weight portion of each crude drug is respectively Radix Rehmanniae Preparata 25 weight portion ~ 30 weight portion, Radix Angelicae Sinensis 20 weight portion ~ 25 weight portion, the Radix Paeoniae Alba 25 weight portion ~ 30 weight portion, Rhizoma Chuanxiong 15 weight portion ~ 20 weight portion, Radix Salviae Miltiorrhizae 20 weight portion ~ 25 weight portion, Rhizoma Sparganii 30 weight portion ~ 35 weight portion, Rhizoma Curcumae 35 weight portion ~ 40 weight portion, Herba speranskiae tuberculatae 10 weight portion ~ 15 weight portion, Pheretima 10 weight portion ~ 15 weight portion, Scolopendra 10 weight portion ~ 15 weight portion, Hirudo 15 weight portion ~ 20 weight portion, Carapax Trionycis (processed) 15 weight portion ~ 20 weight portion, Rhizoma dioscoreae (parched) 20 weight portion ~ 25 weight portion, Fructus Corni 25 weight portion ~ 30 weight portion, Cortex Eucommiae 10 weight portion ~ 15 weight portion, Rhizoma Atractylodis Macrocephalae 25 weight portion ~ 30 weight portion, Radix Astragali 25 weight portion ~ 30 weight portion, Poria 15 weight portion ~ 20 weight portion, Ramulus Cinnamomi 15 weight portion ~ 20 weight portion, Radix Glycyrrhizae Preparata 25 weight portion ~ 30 weight portion, Cortex Cinnamomi 10 weight portion ~ 15 weight portion, Rhizoma Alismatis 15 weight portion ~ 20 weight portion, Radix Achyranthis Bidentatae 25 weight portion ~ 30 weight portion, Herba Agrimoniae 10 weight portion ~ 15 weight portion, Herba Hedyotidis Diffusae 10 weight portion ~ 15 weight portion and Herba Scutellariae Barbatae 10 weight portion ~ 15 weight portion.
Wherein, in described pharmaceutical composition, the weight portion of each crude drug is respectively Radix Rehmanniae Preparata 25 weight portion, Radix Angelicae Sinensis 20 weight portion, the Radix Paeoniae Alba 25 weight portion, Rhizoma Chuanxiong 20 weight portion, Radix Salviae Miltiorrhizae 20 weight portion, Rhizoma Sparganii 30 weight portion, Rhizoma Curcumae 35 weight portion, Herba speranskiae tuberculatae 15 weight portion, Pheretima 10 weight portion, Scolopendra 10 weight portion, Hirudo 15 weight portion, Carapax Trionycis (processed) 15 weight portion, Rhizoma dioscoreae (parched) 20 weight portion, Fructus Corni 30 weight portion, Cortex Eucommiae 10 weight portion, Rhizoma Atractylodis Macrocephalae 25 weight portion, Radix Astragali 25 weight portion, Poria 20 weight portion, Ramulus Cinnamomi 20 weight portion, Radix Glycyrrhizae Preparata 25 weight portion, Cortex Cinnamomi 15 weight portion, Rhizoma Alismatis 20 weight portion, Radix Achyranthis Bidentatae 30 weight portion, Herba Agrimoniae 10 weight portion, Herba Hedyotidis Diffusae 15 weight portion and Herba Scutellariae Barbatae 15 weight portion.
Wherein, described pharmaceutical composition is granule, tablet, pill, capsule, electuary, oral liquid, soft extract, syrup or mixture.
Wherein, described pharmaceutical composition is oral liquid.
Present invention also offers the preparation method of described pharmaceutical composition, it comprises:
The first step, takes each crude drug component by above-mentioned weight portion, pulverizes respectively, mix, and adopts ethanol percolate extraction, with purification with macroreticular resin, recycling design, dry, pulverize, and crosses 200 mesh sieves;
Second step, gets the product that the 200g first step obtains, and under constantly stirring, add the purified water of 8 times amount, medicinal liquid was in 0 DEG C of cold preservation more than 90 hours, use plate-and-frame filtration again, adjust ph to 7.0, it is 1000ml that filtrate is concentrated into volume, adds 15g sucrose, regulate pH to 7.5, embedding, sterilizing, to obtain final product.
The described first step is specially further and takes each crude drug component by above-mentioned weight portion, pulverize respectively, mix, with determining alcohol be 50% ~ 70% alcoholic solution seepage pressure effects is carried out to crude drug, collect percolate, alcoholic solution is 10 ~ 18L/kg with the volume mass ratio of mixed material medicine, the percolation time is 12 ~ 18 hours, use DA-201 purification by macroporous resin, first being washed till pH with deionized water is 5, be the ethanol elution of 80% with determining alcohol again, eluent concentrating under reduced pressure is reclaimed ethanol, the macroporous resin column of every 5g crude drug amount 100g resin dress DA-201 macroporous resin, ethanol elution consumption is 6 ~ 8 times of resin volume, recycling design, dry, pulverize, cross 200 mesh sieves.
Useful technique effect
The invention provides a kind of pharmaceutical composition being used for the treatment of hormonal ischemic necrosis of femoral head, its clinical effectiveness is remarkable, short treating period, instant effect, and has no side effect, and clinic is applied.
Detailed description of the invention
The invention provides a kind of pharmaceutical composition being used for the treatment of hormonal ischemic necrosis of femoral head, its crude drug comprises Radix Rehmanniae Preparata, Radix Angelicae Sinensis, the Radix Paeoniae Alba, Rhizoma Chuanxiong, Radix Salviae Miltiorrhizae, Rhizoma Sparganii, Rhizoma Curcumae, Herba speranskiae tuberculatae, Pheretima, Scolopendra, Hirudo, Carapax Trionycis (processed), Rhizoma dioscoreae (parched), Fructus Corni, Cortex Eucommiae, Rhizoma Atractylodis Macrocephalae, Radix Astragali, Poria, Ramulus Cinnamomi, Radix Glycyrrhizae Preparata, Cortex Cinnamomi, Rhizoma Alismatis, Radix Achyranthis Bidentatae, Herba Agrimoniae, Herba Hedyotidis Diffusae and Herba Scutellariae Barbatae.
Pharmaceutical composition of the present invention adopts the theoretical result of current experimentation and a large amount of clinical researches in legislation, thinks to there is " stasis of blood, void, expectorant " pathogenic characteristic in corticosteroid femur head necrosis.Because pathogen (i.e. hormone) causes the stasis of blood, causes void, gives birth to expectorant, the stasis of blood, void, expectorant three tight association, and influence each other, be jointly present in the generation of SONFH disease, evolution.Therefore, propose the kidney invigorating, invigorate blood circulation, the Therapeutic Principle of eliminating the phlegm, prescription combination drug, Rhizoma Sparganii is used in side's medicine, Rhizoma Curcumae removing blood stasis Xiao Disorder, blood circulation promoting and blood stasis dispelling, for monarch drug, use Radix Rehmanniae Preparata, Radix Angelicae Sinensis, the Radix Paeoniae Alba, Rhizoma Chuanxiong, Radix Salviae Miltiorrhizae coordinates monarch drug with effect of row blood circulation promoting and blood stasis dispelling, Radix Angelicae Sinensis, the Radix Paeoniae Alba, Radix Rehmanniae Preparata also has the effect nourished blood, the stasis of blood goes new life, femoral head is very responsive to blood supply, therefore nourshing blood and promoting blood circulation, recover femoral head and Peripheral blood confession, for the disease progression controlling femur head necrosis, in addition, pharmaceutical composition of the present invention adds Herba speranskiae tuberculatae, Pheretima, Scolopendra, Hirudo, insect medicine physical property is walked to alter, medicine letter power is special, medicine carrying enters meridians, muscles and bones, muscle, promote that femoral head recovers to have a very important role, because the stasis of blood causes another the important pathogenesis that void is primary disease, therefore pharmaceutical composition of the present invention adds Rhizoma dioscoreae (parched), Fructus Corni, Cortex Eucommiae, Rhizoma Atractylodis Macrocephalae, Radix Astragali, Poria, Ramulus Cinnamomi, Radix Glycyrrhizae Preparata, Cortex Cinnamomi, Radix Achyranthis Bidentatae, liver spleen kidney is with mending, with Fructus Corni, Radix Achyranthis Bidentatae tonifying liver, with Rhizoma dioscoreae (parched), Rhizoma Atractylodis Macrocephalae, Radix Astragali, Poria, Ramulus Cinnamomi, Radix Glycyrrhizae Preparata invigorating the spleen and replenishing QI, congenital to support to mend the day after tomorrow, QI and blood biochemistry is active, body recovery is rapid, add the medicine that bone is filled in the kidney invigorating simultaneously, Radix Rehmanniae Preparata, Carapax Trionycis (processed), Cortex Eucommiae, Cortex Cinnamomi, Radix Achyranthis Bidentatae, Rhizoma dioscoreae (parched), assist the same invigorating the liver and kidney of tonifying liver medicine, Psoralen nourishing muscle and tendon, promote the recovery of femur head necrosis, be combined into ministerial drug, because the stasis of blood causes void, because of the raw expectorant of void, expectorant is pathological product is pathogenic factor again, and therefore eliminating the phlegm is also important method for the treatment of, and therefore use Poria, Rhizoma Atractylodis Macrocephalae, Pheretima, Scolopendra, Radix Glycyrrhizae Preparata, Rhizoma Alismatis invigorating the spleen and benefiting QI to reduce phlegm, entering meridians extorts expectorant heresy, is adjuvant drug, in addition according to the application characteristic of hormone, be that poison is evil, pathogenic heat, therefore add Rhizoma Alismatis, Herba Agrimoniae, Herba Hedyotidis Diffusae, Herba Scutellariae Barbatae heat-clearing and toxic substances removing, Herba Agrimoniae again can be wet in sharp blood, and it is turbid that Rhizoma Alismatis lets out kidney, for making medicine.All medicines share, and play effect of liver and kidney tonifying, blood circulation promoting and blood stasis dispelling, spleen invigorating dehumidifying altogether.In addition, confirm its mechanism of action through experimentation, experimental basis and theory support are provided, develop advantage and the characteristic of motherland's therapeutic treatment hormonal ischemic necrosis of femoral head.For the clinical practice applying medicine composite for curing hormonal ischemic necrosis of femoral head of the present invention lays the foundation.
Further preferably, described pharmaceutical composition is only prepared from by above-mentioned raw materials medicine.
In described pharmaceutical composition, the weight portion of each crude drug is respectively Radix Rehmanniae Preparata 20 weight portion ~ 30 weight portion, Radix Angelicae Sinensis 15 weight portion ~ 25 weight portion, the Radix Paeoniae Alba 20 weight portion ~ 30 weight portion, Rhizoma Chuanxiong 15 weight portion ~ 25 weight portion, Radix Salviae Miltiorrhizae 15 weight portion ~ 25 weight portion, Rhizoma Sparganii 25 weight portion ~ 40 weight portion, Rhizoma Curcumae 30 weight portion ~ 40 weight portion, Herba speranskiae tuberculatae 10 weight portion ~ 20 weight portion, Pheretima 10 weight portion ~ 15 weight portion, Scolopendra 10 weight portion ~ 15 weight portion, Hirudo 15 weight portion ~ 20 weight portion, Carapax Trionycis (processed) 10 weight portion ~ 20 weight portion, Rhizoma dioscoreae (parched) 15 weight portion ~ 25 weight portion, Fructus Corni 20 weight portion ~ 35 weight portion, Cortex Eucommiae 10 weight portion ~ 15 weight portion, Rhizoma Atractylodis Macrocephalae 20 weight portion ~ 30 weight portion, Radix Astragali 20 weight portion ~ 30 weight portion, Poria 15 weight portion ~ 25 weight portion, Ramulus Cinnamomi 15 weight portion ~ 20 weight portion, Radix Glycyrrhizae Preparata 20 weight portion ~ 30 weight portion, Cortex Cinnamomi 10 weight portion ~ 20 weight portion, Rhizoma Alismatis 15 weight portion ~ 20 weight portion, Radix Achyranthis Bidentatae 25 weight portion ~ 30 weight portion, Herba Agrimoniae 10 weight portion ~ 15 weight portion, Herba Hedyotidis Diffusae 10 weight portion ~ 20 weight portion and Herba Scutellariae Barbatae 10 weight portion ~ 20 weight portion.
Further preferably, in described pharmaceutical composition, the weight portion of each crude drug is respectively Radix Rehmanniae Preparata 25 weight portion ~ 30 weight portion, Radix Angelicae Sinensis 20 weight portion ~ 25 weight portion, the Radix Paeoniae Alba 25 weight portion ~ 30 weight portion, Rhizoma Chuanxiong 15 weight portion ~ 20 weight portion, Radix Salviae Miltiorrhizae 20 weight portion ~ 25 weight portion, Rhizoma Sparganii 30 weight portion ~ 35 weight portion, Rhizoma Curcumae 35 weight portion ~ 40 weight portion, Herba speranskiae tuberculatae 10 weight portion ~ 15 weight portion, Pheretima 10 weight portion ~ 15 weight portion, Scolopendra 10 weight portion ~ 15 weight portion, Hirudo 15 weight portion ~ 20 weight portion, Carapax Trionycis (processed) 15 weight portion ~ 20 weight portion, Rhizoma dioscoreae (parched) 20 weight portion ~ 25 weight portion, Fructus Corni 25 weight portion ~ 30 weight portion, Cortex Eucommiae 10 weight portion ~ 15 weight portion, Rhizoma Atractylodis Macrocephalae 25 weight portion ~ 30 weight portion, Radix Astragali 25 weight portion ~ 30 weight portion, Poria 15 weight portion ~ 20 weight portion, Ramulus Cinnamomi 15 weight portion ~ 20 weight portion, Radix Glycyrrhizae Preparata 25 weight portion ~ 30 weight portion, Cortex Cinnamomi 10 weight portion ~ 15 weight portion, Rhizoma Alismatis 15 weight portion ~ 20 weight portion, Radix Achyranthis Bidentatae 25 weight portion ~ 30 weight portion, Herba Agrimoniae 10 weight portion ~ 15 weight portion, Herba Hedyotidis Diffusae 10 weight portion ~ 15 weight portion and Herba Scutellariae Barbatae 10 weight portion ~ 15 weight portion.
Most preferably, in described pharmaceutical composition, the weight portion of each crude drug is respectively Radix Rehmanniae Preparata 25 weight portion, Radix Angelicae Sinensis 20 weight portion, the Radix Paeoniae Alba 25 weight portion, Rhizoma Chuanxiong 20 weight portion, Radix Salviae Miltiorrhizae 20 weight portion, Rhizoma Sparganii 30 weight portion, Rhizoma Curcumae 35 weight portion, Herba speranskiae tuberculatae 15 weight portion, Pheretima 10 weight portion, Scolopendra 10 weight portion, Hirudo 15 weight portion, Carapax Trionycis (processed) 15 weight portion, Rhizoma dioscoreae (parched) 20 weight portion, Fructus Corni 30 weight portion, Cortex Eucommiae 10 weight portion, Rhizoma Atractylodis Macrocephalae 25 weight portion, Radix Astragali 25 weight portion, Poria 20 weight portion, Ramulus Cinnamomi 20 weight portion, Radix Glycyrrhizae Preparata 25 weight portion, Cortex Cinnamomi 15 weight portion, Rhizoma Alismatis 20 weight portion, Radix Achyranthis Bidentatae 30 weight portion, Herba Agrimoniae 10 weight portion, Herba Hedyotidis Diffusae 15 weight portion and Herba Scutellariae Barbatae 15 weight portion.
Described pharmaceutical composition is granule, tablet, pill, capsule, electuary, oral liquid, soft extract, syrup, mixture or injection, be preferably oral liquid and injection, above-mentioned raw materials medicine is made granule, tablet, pill, capsule, electuary, oral liquid, soft extract, syrup, mixture or injection through extraction acquisition active ingredient and pharmaceutically acceptable carrier.
Present invention also offers the preparation method of described pharmaceutical composition as oral liquid formulation, it comprises:
The first step, takes each crude drug component by above-mentioned weight portion, pulverizes respectively, mix, and adopts ethanol percolate extraction, with purification with macroreticular resin, recycling design, dry, pulverize, and crosses 200 mesh sieves;
Second step, gets the product that the 200g first step obtains, and under constantly stirring, add the purified water of 8 times amount, medicinal liquid was in 0 DEG C of cold preservation more than 90 hours, use plate-and-frame filtration again, adjust ph to 7.0, it is 1000ml that filtrate is concentrated into volume, adds 15g sucrose, regulate pH to 7.5, embedding, sterilizing, to obtain final product.
The described first step is specially further and takes each crude drug component by above-mentioned weight portion, pulverize respectively, mix, with determining alcohol be 50% ~ 70% alcoholic solution seepage pressure effects is carried out to crude drug, collect percolate, alcoholic solution is 10 ~ 18L/kg with the volume mass ratio of mixed material medicine, the percolation time is 12 ~ 18 hours, use DA-201 purification by macroporous resin, first being washed till pH with deionized water is 5, be the ethanol elution of 80% with determining alcohol again, eluent concentrating under reduced pressure is reclaimed ethanol, the macroporous resin column of every 5g crude drug amount 100g resin dress DA-201 macroporous resin, ethanol elution consumption is 6 ~ 8 times of resin volume, recycling design, dry, pulverize, cross 200 mesh sieves.
Present invention also offers the preparation method of described pharmaceutical composition as oral liquid formulation, it comprises:
The first step, takes each crude drug component by above-mentioned weight portion, pulverizes respectively, mix, and adopts ethanol percolate extraction, with purification with macroreticular resin, recycling design, dry, pulverize, and crosses 200 mesh sieves;
Second step, gets powder 50g prepared by the first step, injects with water appropriate, regulates medicinal liquid pH7.3-7.7, inject water to 1000ml with 10% sodium hydroxide, stirs, and medicinal liquid fine straining is extremely clear and bright, embedding, 115 DEG C, 45min sterilizing and get final product.
The described first step is specially further and takes each crude drug component by above-mentioned weight portion, pulverize respectively, mix, with determining alcohol be 50% ~ 70% alcoholic solution seepage pressure effects is carried out to crude drug, collect percolate, alcoholic solution is 10 ~ 18L/kg with the volume mass ratio of mixed material medicine, the percolation time is 12 ~ 18 hours, use DA-201 purification by macroporous resin, first being washed till pH with deionized water is 5, be the ethanol elution of 80% with determining alcohol again, eluent concentrating under reduced pressure is reclaimed ethanol, the macroporous resin column of every 5g crude drug amount 100g resin dress DA-201 macroporous resin, ethanol elution consumption is 6 ~ 8 times of resin volume, recycling design, dry, pulverize, cross 200 mesh sieves.
Each crude drug pharmacology is as follows:
Radix Rehmanniae Preparata: have another name called Radix Rehmanniae Preparata, sweet in the mouth, slightly warm in nature, enters liver, kidney channel, has YIN nourishing of enriching blood, and beneficial essence fills out the effect of marrow, for blood deficiency and yellow complexion; Dizzy, cardiopalmus, insomnia, menoxenia, collapses more than; Hepatic and renal YIN deficiency, night sweat, sufficient knee joint pain, soreness of the waist and knees, Hiccough and deaf, the head is dim-sighted; Seminal emission sexual impotence; Infertility; Menoxenia; Metrostaxis; Early whitening of beard and hair; Quench one's thirst; Constipation; To suffer from a deficiency of the kidney the cards such as dyspnea with rapid and short breath.
Radix Angelicae Sinensis: latin name AngelicaeSinensisRadix, sweet in the mouth, pungent, warm in nature, enter liver, the heart, spleen channel, having enriches blood invigorates blood circulation, menstruction regulating and pain relieving, effect of loosening bowel to relieve constipation, cures mainly having a dizzy spell of deficiency of heart-blood, fatigue and weakness, shortness of breath and palpitation, the sea of blood is hollow, the menoxenia of the cold and deficiency of CHONG and REN meridians or congestion retardance, dysmenorrhoea, produces or stomachache, and other blood stasis are had a pain and the card such as the constipation of deficiency of YIN insufficiency of blood dryness of the intestine, its can improve uterus blood circulation, alleviate pelvic congestion, relieving dysmenorrhea.
The Radix Paeoniae Alba: latin name PaeoniaeRadixAlba, bitter in the mouth, acid, cool in nature, enter liver, spleen channel, there is nourishing blood to suppress the hyperactive liver, pain relieving in slow, yin fluid astringing receives effect of antiperspirant, cures mainly the breast abdomen pain over the hypochondriac region, and dysentery is suffered from abdominal pain, spontaneous sweating, fever due to yin deficiency, menoxenia, metrorrhagia, is with inferior card.
Rhizoma Chuanxiong: acrid in the mouth, warm in nature, return liver, gallbladder, pericardium channel, have blood-activating and qi-promoting, effect of wind-expelling pain-stopping, cures mainly menoxenia; Amenorrhea dysmenorrhea; The stagnant raw meat pain of the stasis of blood in puerperal; Lump in the abdomen lump; Pain in chest and hypochondrium; Have a headache dizzy; Anemofrigid-damp arthralgia; Traumatic injury; The cards such as ulcer sores.
Radix Salviae Miltiorrhizae: latin name SalviaeMiltiorrhizaeRadixetRhizoma, bitter in the mouth, cold nature, enter the heart, Liver Channel, there is promoting blood flow to regulate menstruation, stasis-dispelling and pain-killing, removing heat from blood eliminating carbuncle, clear away heart-fire relieving restlessness, effect of nourishing blood to tranquillize the mind, for menoxenia, amenorrhea dysmenorrhea, lump in the abdomen, breast ventral spine pain, pyretic arthralgia pain, skin infection swells and ache, dysphoria and insomnia; Hepatosplenomegaly, the cards such as angina pectoris.
Rhizoma Sparganii: bitter in the mouth, pungent, property is put down, and enters liver, spleen channel, has removing blood stasis circulation of qi promoting, effect of removing food stagnancy pain relieving, for blood stasis amenorrhea, dysmenorrhea, the stagnant stomachache of the stasis of blood in puerperal, lump in the abdomen mass in the abdomen in abdomen, stagnation of QI due to dyspepsia, the cards such as abdominal distention.
Rhizoma Curcumae: acrid in the mouth, hardship, warm in nature, enter liver, spleen channel, have removing blood stasis circulation of qi promoting, effect of removing food stagnancy pain relieving, for the lump in the abdomen mass in the abdomen of caused by energy stagnation and blood stasis, breast abdomen stasis of blood pain, amenorrhea, dysmenorrhea, abdominal distention, traumatic injury, blood stasis such as to swell and ache at the card.
Herba speranskiae tuberculatae: sweet in the mouth, pungent, warm in nature, enters lung, liver two warp, has relaxing muscles and tendons and activating QI and blood in the collateral, expelling wind and dampness, promoting blood circulation and stopping pain, and softening the hard mass disappears effect of painful abdominal mass, cures mainly rheumatic arthralgia; Muscles and bones contracture; The disturbance of lower legs due to pathogenic cold and dampness; Lumbar strain; Paralysis; Amenorrhea; Eczema scrotum; The cards such as furuncle toxic swelling.
Pheretima: salty in the mouth, cold in nature, return liver, spleen, urinary bladder channel, have heat clearing away arresting convulsion, dredging collateral is relievingd asthma, effect of diuresis, cures mainly unconsciousness due to high fever, arthralgia, numb limbs and tense tendons, hemiplegia, lung-heat cough with asthma, effect of edema oliguria.
Scolopendra: warm in nature, acrid in the mouth, has and dispels the wind, arresting convulsion, counteracting toxic substances, effect of eliminating stagnation.Cure mainly apoplexy, infantile convulsion, tetanus, pertussis, scrofula, tuberculosis ， mass in the abdomen tumor block, sore swollen toxin, tinea corporis, bald in vain, anal fistula, the cards such as scald.
Hirudo: salty in the mouth, hardship, property is put down, and enters Liver Channel, has effect of removing blood stasis, for blood stasis amenorrhea, lump in the abdomen stomachache, blood-retention, traumatic blood stasis are had a pain, the disease such as carbuncle erysipelas.
Carapax Trionycis (processed): salty in the mouth, cold in nature, have nourishing kidney YANG hyperactivity suppressing, effect of hard masses softening and resolving, cures mainly fever due to yin deficiency, consumptive fever hectic fever due to YIN-deficiency, consumption of YIN caused by febrile disease, stirring-up of pathogenic wind in the interior resulting from deficiency, pediatric epilepsy scared, malaria with splenomegaly, amenorrhea, ulcer, the cards such as burn due to hot liquid or fire.
Rhizoma dioscoreae (parched): latin name dioscoreaerhizoma, sweet in the mouth, property is put down, enter lung, spleen, kidney channel, there is strengthening the spleen and tonifying the lung, stomach reinforcing the kidney invigorating, benefit of reinforcing the kidney essence, hearing-improing and eyesight improving, help the five internal organs, bone and muscle strengthening, long will are calmed the nerves, effect of life lengthening, cure mainly that weakness of the spleen and stomach, lassitude, inappetence, chronic diarrhea and dysentery, insufficiency of lung-QI are dry, phlegm dyspnea cough, kidney qi loss, soreness of the waist and knees, lower limb flaccidity be weak, the red disease such as swollen, fat of frequent micturition of quenching one's thirst, premature ejaculation of passing out semen, leukorrhagia nebulousurine, skin.
Fructus Corni: latin name cornifructus, sour in the mouth, puckery, slightly warm in nature, returns liver, kidney channel, has liver and kidney tonifying, effect of essence astringing and desertion stemming.Cure mainly vertigo and tinnitus, soreness of waist and knee joint, impotence and seminal emission, enuresis frequent micturition, bleeding not during menses, profuse sweating is collapsed.Interior-heat such as to be quenched one's thirst at the card.
Cortex Eucommiae: sweet in the mouth, micro-pungent, warm in nature, enters liver, kidney channel, has blood pressure lowering, invigorating the liver and kidney, bone and muscle strengthening, the effect of antiabortive gas, for caused by liver and kidney deficiency, card see dizzy, soreness of waist and knee joint, muscles and bones flaccidity are weak; Instability of kidney QI, frequent micturition or dripping urination, uncontrolled urination are itched, sexual impotence, anemia of pregnant woman are weak, frequent fetal movement or waist pendant pain; The cards such as chronic joint diseases, bone tuberculosis, dysmenorrhea, dysfunctional uterine bleeding, chronic pelvic inflammatory disease.
Rhizoma Atractylodis Macrocephalae: latin name atractylodismacrocephalaerhizoma, bitter in the mouth, sweet, warm in nature, enter spleen, stomach warp, there is invigorating the spleen and benefiting QI, dampness diuretic, strengthening superficial resistance to stop perspiration, antiabortive effect, for weakness of the spleen and stomach, lack of appetite distension, fatigue and weakness, have loose bowels, water-damp retention, phlegm retention, edema, the cards such as exterior deficiency spontaneous perspiration.
Radix Astragali: latin name astragaliradix, sweet in the mouth, warm in nature, enter spleen, lung meridian, there is benefit strengthening spleen and lung, elevate a turnable ladder yang-energy, strengthening superficial resistance to stop perspiration, the effects such as holder skin ulcer granulation promoting, are mainly used in the weak anorexia and loose stool that deficiency of both the splenic and pulmonary QI is caused, shortness of breath and palpitation, the visceroptosis of sinking of QI of middle-JIAO, the metrorrhagia of QI failing to control blood is had blood in stool, chronic diarrhea proctoptosis; The spontaneous sweating of exterior deficiency, the cards such as insufficiency of vital energy and blood.
Poria: sweet in the mouth, light, property is put down, and enters spleen, lung, bladder, heart channel, has the effect of eliminating dampness and diuresis, spleen invigorating mind calming, be mainly used in the edema of retention of water-damp, dysuria; The pyretic stranguria of damp-heat accumulation, the card such as anorexia and loose stool, phlegm retention stagnation, epilepsy of stagnation of dampness due to deficiency of the spleen.
Ramulus Cinnamomi: latin name cinnamomiramulus is the dry twig of canella Cortex Cinnamomi, acrid in the mouth, sweet, warm in nature, GUIXIN, lung, urinary bladder channel, have diaphoresis expelling pathogenic factors from muscles, warming the meridian and promoting blood circulation, supporing yang activating QI, effect of dispersing cold for relieving pain, Ramulus Cinnamomi warming the meridian and promoting blood circulation, horizontal logical podomere, for affection of exogenous wind-cold exterior syndrome, no matter have antiperspirant, losslessly all can to apply, also for rheumatic arthralgia, cold syndrome of the stomach stomachache, amenorrhea, dysmenorrhea, rheumatic arthralgia, the cards such as shoulder arm podomere cold type of pain, phlegm retention syndrome and bladder water-retention, heart deficiency of spleen-YANG, retention of water-damp in the body, fullness and distention in the chest and hypochondrium, cough with dyspnea dizziness waits phlegm retention syndrome.
Radix Glycyrrhizae Preparata: sweet in the mouth, property put down, enter 12 warps, be in harmonious proportion the property of medicine, the effect of expelling phlegm for arresting cough, and can spleen invigorating and in, relieving spasm to stop pain, is mainly used in invigorating the spleen and replenishing QI, heat-clearing and toxic substances removing, expelling phlegm for arresting cough, relieving spasm to stop pain, coordinating the actions of various ingredients in a prescription.
Cortex Cinnamomi: extremely hot in nature, acrid in the mouth, sweet, return kidney, spleen, the heart, Liver Channel, have that to mend fire supporing yang, let the fire back to its origin, dispersing cold for relieving pain, effect of promoting blood circulation to restore menstrual flow, for warming the spleen and stomach, removing accumulated cold, promoting blood circulation.Control decline of the fire from the gate of life, cold extremities faint pulse, YANG-depletion is collapsed, and stomachache is had loose bowels, colic of cold type renal mass, chills and pain of the waist and kness, amenorrhea lump in the abdomen, carbuncle of yin nature, multiple abscess, and empty sun is more floating, the cards such as heat in the upper and cold in the lower.
Rhizoma Alismatis: sweet in the mouth, light, cold in nature, enters kidney, urinary bladder channel, has promoting diuresis to eliminate damp pathogen, purging heat and treating stranguria, the lung that clears away heart-fire, rushes down the effect of kidney fire, is mainly used in insufficiency of the spleen retention of water-damp, the wet hydrosarca of spreading unchecked of water; The tired resistance of the heresy of diseases caused by retention of fluid phlegm-damp, what cause that clear YANG failing to ascend voiced sound do not fall is dizzy; The dysuria of damp invasion of lower energizer, red short puckery pain, and the card such as jaundice due to damp-heat.
Radix Achyranthis Bidentatae: bitter in the mouth, acid, property is put down, and enters the heart, liver, large intestine three warp, has promoting blood circulation to remove blood stasis, damp eliminating diuresis, effect of heat-clearing and toxic substances removing.Cure mainly gonorrhea, hematuria, women's amenorrhea, lump in the abdomen, rheumatic arthritis, beriberi, edema, dysentery, malaria, diphtheria, carbuncle, the cards such as traumatic injury.
Herba Agrimoniae: latin name AgrimoniaeHerba, bitter in the mouth, puckery, property is put down, GUIXIN, Liver Channel, there is astringing to arrest bleeding, effect of dysentery relieving parasite killing, cure mainly various hemorrhage card, such as: haematemesis, hematuria, have blood in stool, metrorrhagia, spitting of blood, epistaxis, dysentery, impairment caused by overstrain takes off power, carbuncle, traumatic injury, the cards such as wound hemorrhage.
Herba Hedyotidis Diffusae: bitter in the mouth, sweet, cold in nature, enters the heart, liver, spleen, large intestine channel, has heat-clearing and toxic substances removing, the effect of promoting diuresis to eliminate damp pathogen, for dyspnea and cough due to lung-heat, laryngopharynx swelling and pain, acute appendicitis, furuncle and phyma skin infection, venom, the puckery pain of pyretic stranguria, edema, dysentery, enteritis, jaundice due to damp-heat, the cards such as cancerous protuberance.
Herba Scutellariae Barbatae: acrid in the mouth, hardship, cold in nature, enter lung meridian, Liver Channel, kidney channel, there is the effect of heat-clearing and toxic substances removing, dissipating blood stasis hemostasis, inducing diuresis to remove edema, cure mainly: pyretic toxicity carbuncle; Have sore throat; Lung abscess; Intestinal carbuncle; Scrofula; Venom; Traumatic injury; Spit blood; Epistaxis; Stranguria with blood; Edema; Ascites and cancer.
Below adopt embodiment to describe embodiments of the present invention in detail, to the present invention, how application technology means solve technical problem whereby, and the implementation procedure reaching technique effect can fully understand and implement according to this.
Embodiment 1 oral liquid 1
Take Radix Rehmanniae Preparata 25g, Radix Angelicae Sinensis 20g, Radix Paeoniae Alba 25g, Rhizoma Chuanxiong 20g, Radix Salviae Miltiorrhizae 20g, Rhizoma Sparganii 30g, Rhizoma Curcumae 35g, Herba speranskiae tuberculatae 15g, Pheretima 10g, Scolopendra 10g, Hirudo 15g, Carapax Trionycis (processed) 15g, Rhizoma dioscoreae (parched) 20g, Fructus Corni 30g, Cortex Eucommiae 10g, Rhizoma Atractylodis Macrocephalae 25g, Radix Astragali 25g, Poria 20g, Ramulus Cinnamomi 20g, Radix Glycyrrhizae Preparata 25g, Cortex Cinnamomi 15g, Rhizoma Alismatis 20g, Radix Achyranthis Bidentatae 30g, Herba Agrimoniae 10g, Herba Hedyotidis Diffusae 15g and Herba Scutellariae Barbatae 15g pulverizes respectively, mix, with determining alcohol be 60% alcoholic solution seepage pressure effects is carried out to crude drug, collect percolate, alcoholic solution is 16L/kg with the volume mass ratio of mixed material medicine, the percolation time is 16 hours, use DA-201 purification by macroporous resin, first being washed till pH with deionized water is 5, be the ethanol elution of 80% with determining alcohol again, eluent concentrating under reduced pressure is reclaimed ethanol, the macroporous resin column of every 5g crude drug amount 100g resin dress DA-201 macroporous resin, ethanol elution consumption is 8 times of resin volume, recycling design, dry, pulverize, cross 200 mesh sieves, get this product of 200g, the purified water of 8 times amount is added under constantly stirring, medicinal liquid was in 0 DEG C of cold preservation more than 90 hours, use plate-and-frame filtration again, adjust ph to 7.0, it is 1000ml that filtrate is concentrated into volume, add 15g sucrose, regulate pH to 7.5, embedding, sterilizing, obtain.
Embodiment 2 oral liquid 2
Take Radix Rehmanniae Preparata 25g, Radix Angelicae Sinensis 20g, Radix Paeoniae Alba 25g, Rhizoma Chuanxiong 15g, Radix Salviae Miltiorrhizae 20g, Rhizoma Sparganii 30g, Rhizoma Curcumae 35g, Herba speranskiae tuberculatae 10g, Pheretima 10g, Scolopendra 10g, Hirudo 15g, Carapax Trionycis (processed) 15g, Rhizoma dioscoreae (parched) 20g, Fructus Corni 25g, Cortex Eucommiae 10g, Rhizoma Atractylodis Macrocephalae 25g, Radix Astragali 25g, Poria 15g, Ramulus Cinnamomi 15g, Radix Glycyrrhizae Preparata 25g, Cortex Cinnamomi 10g, Rhizoma Alismatis 15g, Radix Achyranthis Bidentatae 25g, Herba Agrimoniae 10g, Herba Hedyotidis Diffusae 10g and Herba Scutellariae Barbatae 10g pulverizes respectively, mix, with determining alcohol be 60% alcoholic solution seepage pressure effects is carried out to crude drug, collect percolate, alcoholic solution is 16L/kg with the volume mass ratio of mixed material medicine, the percolation time is 16 hours, use DA-201 purification by macroporous resin, first being washed till pH with deionized water is 5, be the ethanol elution of 80% with determining alcohol again, eluent concentrating under reduced pressure is reclaimed ethanol, the macroporous resin column of every 5g crude drug amount 100g resin dress DA-201 macroporous resin, ethanol elution consumption is 8 times of resin volume, recycling design, dry, pulverize, cross 200 mesh sieves, get this product of 200g, the purified water of 8 times amount is added under constantly stirring, medicinal liquid was in 0 DEG C of cold preservation more than 90 hours, use plate-and-frame filtration again, adjust ph to 7.0, it is 1000ml that filtrate is concentrated into volume, add 15g sucrose, regulate pH to 7.5, embedding, sterilizing, obtain.
Embodiment 3 oral liquid 3
Take Radix Rehmanniae Preparata 30g, Radix Angelicae Sinensis 25g, Radix Paeoniae Alba 30g, Rhizoma Chuanxiong 20g, Radix Salviae Miltiorrhizae 25g, Rhizoma Sparganii 35g, Rhizoma Curcumae 40g, Herba speranskiae tuberculatae 15g, Pheretima 15g, Scolopendra 15g, Hirudo 20g, Carapax Trionycis (processed) 20g, Rhizoma dioscoreae (parched) 25g, Fructus Corni 30g, Cortex Eucommiae 15g, Rhizoma Atractylodis Macrocephalae 30g, Radix Astragali 30g, Poria 20g, Ramulus Cinnamomi 20g, Radix Glycyrrhizae Preparata 30g, Cortex Cinnamomi 15g, Rhizoma Alismatis 20g, Radix Achyranthis Bidentatae 30g, Herba Agrimoniae 15g, Herba Hedyotidis Diffusae 15g and Herba Scutellariae Barbatae 15g pulverizes respectively, mix, with determining alcohol be 60% alcoholic solution seepage pressure effects is carried out to crude drug, collect percolate, alcoholic solution is 16L/kg with the volume mass ratio of mixed material medicine, the percolation time is 16 hours, use DA-201 purification by macroporous resin, first being washed till pH with deionized water is 5, be the ethanol elution of 80% with determining alcohol again, eluent concentrating under reduced pressure is reclaimed ethanol, the macroporous resin column of every 5g crude drug amount 100g resin dress DA-201 macroporous resin, ethanol elution consumption is 8 times of resin volume, recycling design, dry, pulverize, cross 200 mesh sieves, get this product of 200g, the purified water of 8 times amount is added under constantly stirring, medicinal liquid was in 0 DEG C of cold preservation more than 90 hours, use plate-and-frame filtration again, adjust ph to 7.0, it is 1000ml that filtrate is concentrated into volume, add 15g sucrose, regulate pH to 7.5, embedding, sterilizing, obtain.
Embodiment 4 acute toxicity test of science
Laboratory animal
SPF level, kunming mice, 40,20 ± 2g, male and female half and half.
Test medicine
Experimental group: oral liquid 1 prepared by the embodiment of the present invention 1, be made into the solution of crude drug content 2.0g/ml, 4 DEG C save backup.
Matched group: gavage normal saline, all the other conditions are with medicine group of the present invention.
Experimental technique
Grouping
Get SPF level, kunming mice 40, male and female half and half, adaptability is raised one week.By table of random numbers method, mice being divided into 2 groups, is matched group 20 respectively, experimental group 20, male and female half and half, sub-cage rearing.
Medication
Before experiment, the fasting of each group mice can't help water 12h, matched group gavage distilled water 0.2ml/20g body weight, 3 times/day, experimental group, oral liquid 1,0.2ml/20g body weight prepared by the gavage embodiment of the present invention 1,3 times/day, dosing interval 4h.Successive administration 7 days, drug withdrawal observes 3 days.
Observation index
Ordinary circumstance
Observe during administration and drug withdrawal viewing duration, the ordinary circumstance of each group mice, as developmental state (body temperature, body weight, heart rate), coat condition, the mental status, each natural hole situation, autonomic activities situation.
Internal organs check and Physico-chemical tests
, there is animal dead during administration in experimentally requirement, dissects immediately, observes each internal organs situation, peel off each internal organs, weigh, and calculate organ index, heart extracting blood Physico-chemical tests; As nothing is dead, then experimentally requirement, after the observation period, gives 10% chloral hydrate anesthesia, opens abdominal cavity, observes each internal organs situation, and abdominal aortic blood is put to death, and does Physico-chemical tests, peels off each internal organs, weigh, and calculate organ index.
Result
Experimental session, without dead mouse, experimentally arranges to carry out coherent detection.
Ordinary circumstance
During administration and drug withdrawal viewing duration, each group mice at the baseline signs such as body weight, body temperature, Non Apparent Abnormality, two groups are compared, no difference of science of statistics, outward appearance is normal, without deformity, fur color and luster is normal, the mental status is good, and each natural hole is clean, secretions without exception, autonomic activities is normal, behavior without exception.
Internal organs check and Physico-chemical tests
Experimentally requirement, after the observation period, gives 10% chloral hydrate anesthesia, and abdominal aortic blood is put to death, open abdominal cavity, observe each internal organs situation, the arrangement of each group mice organs is normal, without adhesion, without hemorrhage, blood of getting does Physico-chemical tests, each group of Mouse Blood routine is without exception, and liver function, kidney merit check without exception, peel off each internal organs, weigh, calculate organ index, through statistical analysis, no difference of science of statistics, two groups of same periods compare, statistics zero difference.
Conclusion
Pass through acute toxicity test in mice, mice dosage is 60g/kg/d, be converted into adult normal dosage 600g/kg/d (mice and 60kg health adult conversion coefficient are 10.0), for 150 times (normal 60kg adult Chinese medicine intake is 4g/kg/d) that adult normal daily measures, it is generally acknowledged, in zoopery, administration behaves more than 100 times, and without obvious toxic-side effects, can think that medicine is safe.Can be confirmed by this experiment, Chinese medicine of the present invention, in acute toxicity test, without acute toxic reaction, without delayed toxicity, substantially can think safe, therefore Clinical practice is safe.
Mice long term toxicity test of the present invention
Experiment material
Laboratory animal
SPF level, kunming mice, 40,20 ± 2g, male and female half and half.
Test medicine
Experimental group: oral liquid 1 prepared by the embodiment of the present invention 1, water dissolution is made into the solution of crude drug content 1.0g/ml, 0.75g/ml, 0.5g/ml, and 4 DEG C save backup.
Matched group: gavage normal saline, all the other conditions are with medicine group of the present invention.
Experimental technique
Grouping
Get SPF level, kunming mice 40, male and female half and half, adaptability is raised one week.By table of random numbers method, mice being divided into 2 groups, is matched group 10, high dose group 10, middle dosage group 10, low dose group 10 respectively, male and female half and half, sub-cage rearing.
Medication
Before experiment, the fasting of each group mice can't help water 12h, matched group gavage distilled water 0.2ml/20g body weight, 2 times/day, high, medium and low dosage group, oral liquid 1.0g/ml, 0.75g/ml, 0.5g/ml of the gavage embodiment of the present invention 1 preparation respectively, 0.2ml/20g body weight, 2 times/day, dosing interval 6h.Successive administration 14 days, drug withdrawal observes 7 days.
Observation index
Ordinary circumstance
Observe during administration and drug withdrawal viewing duration, the ordinary circumstance of each group mice, as developmental state (body temperature, body weight, heart rate), coat condition, the mental status, each natural hole situation, autonomic activities situation.
Internal organs check and Physico-chemical tests
, there is animal dead during administration in experimentally requirement, dissects immediately, observes each internal organs situation, peel off each internal organs, weigh, and calculate organ index, heart extracting blood Physico-chemical tests; As nothing is dead, then experimentally requirement, after the observation period, gives 10% chloral hydrate anesthesia, opens abdominal cavity, observes each internal organs situation, and abdominal aortic blood is put to death, and does Physico-chemical tests, peels off each internal organs, weigh, and calculate organ index.
Result
Experimental session, without dead mouse, experimentally arranges to carry out coherent detection.
Ordinary circumstance
During administration and drug withdrawal viewing duration, each group mice at the baseline signs such as body weight, body temperature, Non Apparent Abnormality, two groups are compared, no difference of science of statistics, outward appearance is normal, without deformity, fur color and luster is normal, the mental status is good, and each natural hole is clean, secretions without exception, autonomic activities is normal, behavior without exception.
Internal organs check and Physico-chemical tests
Experimentally requirement, after the observation period, gives 10% chloral hydrate anesthesia, and abdominal aortic blood is put to death, open abdominal cavity, observe each internal organs situation, the arrangement of each group mice organs is normal, without adhesion, without hemorrhage, blood of getting does Physico-chemical tests, each group of Mouse Blood routine is without exception, and liver function, kidney merit check without exception, peel off each internal organs, weigh, calculate organ index, through statistical analysis, no difference of science of statistics, two groups of same periods compare, statistics zero difference.
Conclusion
By mice long term toxicity test, mice dosage is 20g/kg/d, 15g/kg/d, 10g/kg/d, be converted into adult normal dosage 200g/kg/d, 150g/kg/d, 100g/kg/d, 50 times, 37.5 times, 25 times that daily measure for adult normal, can be confirmed by this experiment, Chinese medicine of the present invention is in long term toxicity test, without cumulative toxicity, without delayed toxicity, substantially can think safe, therefore Clinical practice is safe.
Embodiment 5 injection 1
Take Radix Rehmanniae Preparata 25g, Radix Angelicae Sinensis 20g, Radix Paeoniae Alba 25g, Rhizoma Chuanxiong 20g, Radix Salviae Miltiorrhizae 20g, Rhizoma Sparganii 30g, Rhizoma Curcumae 35g, Herba speranskiae tuberculatae 15g, Pheretima 10g, Scolopendra 10g, Hirudo 15g, Carapax Trionycis (processed) 15g, Rhizoma dioscoreae (parched) 20g, Fructus Corni 30g, Cortex Eucommiae 10g, Rhizoma Atractylodis Macrocephalae 25g, Radix Astragali 25g, Poria 20g, Ramulus Cinnamomi 20g, Radix Glycyrrhizae Preparata 25g, Cortex Cinnamomi 15g, Rhizoma Alismatis 20g, Radix Achyranthis Bidentatae 30g, Herba Agrimoniae 10g, Herba Hedyotidis Diffusae 15g and Herba Scutellariae Barbatae 15g pulverizes respectively, mix, with determining alcohol be 60% alcoholic solution seepage pressure effects is carried out to crude drug, collect percolate, alcoholic solution is 16L/kg with the volume mass ratio of mixed material medicine, the percolation time is 16 hours, use DA-201 purification by macroporous resin, first being washed till pH with deionized water is 5, be the ethanol elution of 80% with determining alcohol again, eluent concentrating under reduced pressure is reclaimed ethanol, the macroporous resin column of every 5g crude drug amount 100g resin dress DA-201 macroporous resin, ethanol elution consumption is 8 times of resin volume, recycling design, dry, pulverize, cross 200 mesh sieves, get the powder 50g of preparation, inject with water appropriate, medicinal liquid pH7.3-7.7 is regulated with 10% sodium hydroxide, inject water to 1000ml, stir, medicinal liquid fine straining is to clear and bright, embedding, 115 DEG C, 45min sterilizing and get final product.
Embodiment 6 injection toxicology detects
Anxious toxicity test research
Experimental technique
Active general anaphylaxis, passive cutaneous anaphylaxis test is adopted to investigate the safety of Chinese medicine injection prepared by the embodiment of the present invention 5.
Laboratory animal
Cavia porcellus, male and female half and half, body weight 300 ~ 400g (regular grade), SD rat, male and female half and half, body weight 250 ~ 300g (SPF level); Animal sub-cage rearing, is numbered every animal and weighs, and quarantine is tested after observing 3d.Carry out outward appearance sign, behavioral activity, food ration and body weight to laboratory animal to observe.Feeding environment, room temperature 19 ~ 26 DEG C, temperature difference per day≤4 DEG C, relative humidity 40% ~ 70%, round the clock light and shade alt time 12h/12h.
Experimental drug
Ovalbumin, Hua Ying Bioisystech Co., Ltd
Injection 1 prepared by the embodiment of the present invention 5, being configured to crude drug concentration is 0.75g/ml, and 4 DEG C save backup, return to room temperature during use.
Method and result
Active general anaphylaxis
Get Cavia porcellus 36, be divided into 3 groups at random, often organize 12: the injection 6ml/kg of positive controls (ovalbumin 3mg/ only), the preparation of negative control group (0.9% sodium chloride injection), the embodiment of the present invention 1.Each group of guinea pig intraperitoneal injection administration sensitization, the next day 1 time, totally 5 times.After last sensitization, the 14th day Cavia porcellus hind leg small saphenous vein drug administration by injection excites, and booster dose is 2 times of priming dose.During sensitization, every day observes animal symptom, first, last sensitization and excited measured the weight of animals the same day.Excite the reaction of every animal in rear detailed observation 30min, symptom appearance and extinction time, if symptoms of allergic appears in administration treated animal, need to extend observing time to 3h.Observe, record anaphylaxis occurrence degree and calculate anaphylaxis incidence rate.Comprehensive descision is carried out according to anaphylaxis incidence rate and occurrence degree.If anaphylaxis appears in medicine group, get the non-sensitized guinea pig of health 2, the medicine of intravenous injection priming dose, observes with or without anaphylactoid reaction symptom.
Result: the general status such as the activity of administration treated animal and feed show no obvious abnormalities, and the body weight change of each group Cavia porcellus has no notable difference.After intravenously administrable excites, all 6 Cavia porcellus majorities of positive controls occur scratching nose, cough, urinate, spasm, dead at 1 ~ 5min after horizontal turn, anaphylaxis incidence rate 100%; All the other treated animals do not find symptoms of allergic, and anaphylaxis incidence rate is 0%, show that invention formulation injection does not cause Cavia porcellus initiatively systemic anaphylaxis under this experiment condition.
Passive cutaneous anaphylaxis test
Get rat 6, be divided into 3 groups at random: the injection 50ml/kg group of positive controls (ovalbumin 3mg/ only), the preparation of negative control group (0.9% sodium chloride injection), the embodiment of the present invention 5, often organize 2.Lumbar injection relative medicine sensitization, the next day 1 time, totally 5 times.Blood sampling in 12nd day after last sensitizing injection, the centrifugal 10min of 2000r/min, separation of serum ,-20 DEG C of preservations, for subsequent use in 2 weeks.Separately get rat 18 to be divided at random 3 groups (method is the same), often organize 6.Back, rat both sides depilation 3cm × 4cm 2, above-mentioned each group of antiserum normal saline dilution becomes 1: 2 and 1: 8, respectively gets 0.1ml difference intradermal injection in the respective sets rat back left and right sides.The common 1ml of 0.5% azovan blue dyestuff that the challenging antigen that after 24h, the intravenous injection of each group is identical with priming dose adds equivalent excites.Each treated animal ventral aorta blood sampling after exciting 20min, centrifuging and taking determination of serum SERUM IgE content, puts to death animal after blood sampling at once, measures the blue spot size of skin inner layer, and diameter > 5mm person is positive.The general status such as the activity of administration treated animal and feed show no obvious abnormalities.
Result: after exciting, all there is locus coeruleus in all 6 rat left and right sides of positive controls, diameter > 5mm, left side locus coeruleus diameter (13.2 ± 2.98) mm, right side locus coeruleus diameter (4.31 ± 2.03) mm, there is not diameter > 5mm locus coeruleus in all the other Group Animals.Compared with negative control group, positive controls SERUM IgE content obviously increases (P < 0.01), and all the other are respectively organized SERUM IgE content and have no obvious change.Above result to show that under this experiment condition invention formulation penetrates liquid and does not cause allotransplantation in rats passive cutaneous anaphylaxis, PCA.
Injection long_term toxcity is tested
Experimental technique
Adopt the safety of vascular stimulation tests and hemolysis in vitro experiment investigation Chinese medicine injection.
Laboratory animal
New Zealand's white big ear rabbit, body weight 2.0 ~ 3.0kg (regular grade); Animal sub-cage rearing, is numbered every animal and weighs, and quarantine is tested after observing 3d.Carry out outward appearance sign, behavioral activity, food ration and body weight to laboratory animal to observe.Feeding environment, room temperature 19 ~ 26 DEG C, temperature difference per day≤4 DEG C, relative humidity 40% ~ 70%, round the clock light and shade alt time 12h/12h.
Vascular stimulation tests
Get normal healthy rabbits 18, be divided into 3 groups at random, be i.e. high, medium and low dosage group (invention formulation injection 0.85g/ml, 0.6g/ml, 0.45g/ml).By 0.5ml/kg body weight, rabbit auricular vein left ear instillation said medicine, dosage 0.9% sodium chloride injections such as auris dextra instillation, administration every day 1 time, continuous 5d, 48h carries out perusal to animal and injection site before administration every day and after last administration, and observed and recorded injection site is with or without the stimulation phenomenon such as red and swollen, congested.After last administration, 48h often organizes and puts to death half animal, with auricular vein injection point to centripetal direction (avoiding injection site) 2cm, get 3 sections of blood vessels continuously together with surrounding tissue, every section of 1cm, fix by 10% formalin, do histopathologic examination, observe venous vascular tissue with or without inflammatory reaction, the even significance such as degeneration, necrosis irritant reaction.Residue animal carries out histopathological examination, again to understand the reversibility of irritative response after continuing to observe 14d.
Result
Experimental session, left ear and the auris dextra administration local vascular of laboratory animal are showed no any irritant reaction symptom, and irritant reaction scoring is 0 point.Pathological examination result display administration terminated and at the end of convalescent period, and laboratory animal 0.9% sodium chloride injection control sides and high, medium and low dosage group blood vessel and surrounding tissue are showed no obvious abnormalities.Under this experimental condition, rabbit vein injection gives invention formulation injection high, medium and low dosage, to injection site nonirritant.
Embodiment 7 clinical research
Physical data
240 examples are the ischemic necrosis of femoral head patient of 2013-2015 years hospitalization, all follow up a case by regular visits to more than 1 year after treatment, all make a definite diagnosis through x-ray, CT or MRI, and meet State Administration of Traditional Chinese Medicine's " Chinese medical disease Standardization of diagnosis and curative effect ".Wherein male 180 example, women 60 example; Minimum 17 years old of age, maximum 73 years old, average 46.18 years old; Site of pathological change: one-sided 145 examples, bilateral 95 example; Totally 335 hips.Pathogenic factor: hormonal 197 example, 43 examples of remaininging can be looked into without cause specific; Disease time 1 month ~ 2.5 years, average 10.5 months.All patients all show as hip pain in various degree, and pain is radiated to buttocks or knee, function limitation, limping.By ARCO allotment method, I phase 24 hip, II phase 177 hip, III phase 105 hip, IV phase 29 hip.Syndrome Differentiation of Traditional Chinese Medicine qi stagnation and blood stasis type 53 example, deficiency of the liver and kidney 79 example, retention of damp-heat 108 example.
Western medicine diagnose standard
With reference to " expert advice of femur head necrosis Clinics and Practices " of orthopaedics and tranmstology branch of Chinese Medical Association joint surgery group proposition in 2006.
Syndrome Differentiation of Traditional Chinese Medicine standard
With reference to " new Chinese medicine guideline of clinical investigations ".Ischemic necrosis of femoral head is divided into 3 types in conjunction with patients with clinical manifestations and tongue, pulse condition by my section:
1. qi stagnation and blood stasis type: hip pain, twinge does not move, joint joint stuffiness.Purplish tongue is dark or have petechia, stringy pulse or heavy.
2. retention of damp-heat: the heavy pain of hip, limbs are tired heavy, pain in fixed position, joint stuffiness.Accompany dysphoria with smothery sensation uncomfortable in chest, indigestion and loss of appetite, constipation with dry stool, oliguria with yellow urine, red tongue with yellowish and greasy fur, slippery and rapid pulse.
3. deficiency of the liver and kidney: hip pain is indistinctly, endlessly continuous, pain relieved by pressing happiness is rubbed, and ankylosis, amyotrophy, accompanies vexed insomnia, thirsty and dry pharynx, flushed face.Red tongue, tongue is few, thready and rapid pulse; Or the hot fear of cold of companion's happiness, pain is met weather and is changed aggravation, weak, and Mian Se Koushi is white, the fat white and thin fur of light red tongue, thready and weak pulse.
Inclusive criteria
Meet Western medicine diagnose standard and Syndrome Differentiation of Traditional Chinese Medicine standard person; Age > 16 years old.
Exclusion standard
Do not meet inclusive criteria; Trimester of pregnancy or women breast-feeding their children; Continue application hormone; Merge cerebrovascular, cardiovascular, liver, kidney and hemopoietic system serious disease; Merge psychosis; Suffers from rheumatoid arthritis; Suffers from ankylosing spondylitis; Acetabular dysplasia; Have not by regulation medication or data not congruent affect the treatment and safety judge situation.
Method
Chinese medical discrimination medication
The oral liquid of Chinese medicine embodiment 1 preparation of the present invention 150ml/ time, 2 times/day, oral.
Dailyly to nurse
Hold up crutches, avoid the too much walking with load of suffering limb.Pain severe patient is lain up, and coordinates traction therapeutic.Quadriceps femoris, gluteus medius, gluteus maximus static(al) contractile function is instructed to take exercise.Instruct the functional exercise of hip joint mobility.
The standard of curative effect evaluation
1. cure: hip arthralgia transference cure, travel distance is unrestricted.Positive sign disappears, and various function recovers normal completely.X-ray image display femur head necrosis osteocyte absorbs, and bone density is recovered, and normally, bearing capacity is normal for load-bearing bone girder and the bone trabecular geometric shape of tension force.Various regions bone density numerical value is normal.
2. effective: the hip arthralgia transference cure when rest and short walk.Hip joint positive sign major part disappears, and range of activity and limping are clearly better.X-ray femur head necrosis osteocyte and hardening sclerotin basic absorption, the basic filling of cryptomere transparent area, bone trabecula is formed, and load-bearing bone girder and the bone trabecular geometric shape of tension force are bordering on normally.Femoral head low-density numerical value rises.
3. take a turn for the better: symptom and positive sign part alleviate or disappear, osteocyte necrosis stops, and hardening bone parts absorbs, and minority bone trabecula is formed.Femoral head low density area and trigonum bone density numerical value rise, and high density area bone density numerical value is unchanged.
4. invalid: hip arthralgia symptom and nothing of walking lamely are alleviated, each sign and the iconography display state of an illness even increase the weight of without improvement.
Result
This group patient 240 example, 335 hips, treat after 6 ~ 18 months, follow up time 6 ~ 60 months.Efficacy evaluation is carried out with reference to " Chinese disease Standardization of diagnosis and curative effect ".Result cures 57 hips, effective 152 hips, and take a turn for the better 98 hips, invalid 28 hips.Expectant treatment is always cured improvement rate and is reached 88.33%.13 examples total hip arthroplasty in refractory patient.Concrete condition (see table 1).
A table 1 liang group therapeutic effect compares
Discuss
Ischemic necrosis of femoral head is belonged to the category such as " osteomyelitis ", " atrophic debility of bones ", " rheumatism involving the bone " by Chinese medicine.Oral medicinal herb and reconditioning comparatively fast can alleviate clinical symptoms, improve function of joint, play promoting the flow of QI in the collateral by warming the meridian effect, make local vascular dilation, improve blood supply and nutrition, promote osteanagenesis process, can very fast alleviating pain.Reconditioning comprises muscular strength and range of motion is taken exercise, and is taken exercise, can retain function of joint to greatest extent, improve gait, reduce disability rate by active and passive muscular strength and mobility.Employing integrated approach is treated, and improves clinical efficacy to greatest extent.
The routine patient of clinical observation 240, healing, effective person mostly are ARCO I phase, ARCO II phase patient, and femur head necrosis is Coronary intervention before bone subsides, and can reach good clinical efficacy.Subside once there is bone, treated by integrated approach, still can reach mill and make joint, increase articular surface matching degree, improve the effect of clinical symptoms and range of motion.ARCO IV phase patient, its curative effect is not fully up to expectations, and therefore ischemic necrosis of femoral head emphasizes early discovery, early treatment, adopts Chinese medicine associating reconditioning as early as possible, contributes to reducing disability rate.
Embodiment 8 animal experiment study
Femur head necrosis can be caused by many reasons, and along with the extensive application of hormone, especially during SARS, a large amount of pooled applications in the hormone short time, corticosteroid femur head necrosis is uprushed at the sickness rate of China in recent years.The sickness rate of femur head necrosis in report SARS patient is had to reach 53.50%.The morbidity of corticosteroid femur head necrosis is a complicated pathological process, and many Chinese scholars have carried out large quantifier elimination in recent years, prove from many aspects.Hormone causes bone marrow fatty tissue's hypertrophy, makes that pulp cavity is intrinsic pressure to be increased, and the intrinsic pressure rising of pulp cavity can cause ischemia, anoxia, metabolism disorder and edema, produce Secondary cases pulp cavity inner high voltage, make microcirculation disturbance in bone, increase the weight of ischemia, anoxia further, so repeatedly, vicious cycle is formed; Be that hormone is directly suppressed to bone cell growth on the other hand, cause into bone disorders, finally cause osteocyte downright bad.For pathogenesis, research about femoral head necrosis therapeutic is also varied, Chinese medicine preparation of the present invention plays the advantage of Chinese medicine, adopt Chinese medicine preparation of the present invention, coordinate lignocaine and sodium bicarbonate, use the method for nerve block, observe the pathological manifestations of corticosteroid femur head necrosis from tectology aspect, check the curative effect of Chinese medicine preparation of the present invention.
Material and method
Main agents and instrument
Hematoxylin: Q/HDLBDO01, the large chemical reagent factory of power nation;
Prednisolone acetate: often prop up sml (125mg), lot number NDO465, produced by BelgiumNA/SA company;
Endotoxin: lot number 0111:B4, is produced by Sigma Co., USA;
2% lidocaine injection: often prop up 10ml, lot number: H31021073, is produced by Beijing Yi Min medicinal liquid company limited;
5% sodium bicarbonate injection: often prop up 10ml, lot number: 0312041, reaches medicinal liquid Co., Ltd by Datong District's curry favour and produces;
Chinese medicine preparation injection 1 prepared by the embodiment of the present invention 5, often props up 10ml;
Paraffin slicing machine (rotary microtome): ReiChert-JungHIStoeut820-11 type, German;
U.S. MIS-2000SP type 3Y microscopy image analysis instrument;
Japan's NikonHS-202AN microscope and Polaroid digital micrograph video camera;
Nikon stereomicroscope;
Decalcifying Fluid is composed as follows, concentrated hydrochloric acid 5ml, dense formic acid 5ml, 75% ethanol 90ml, and simultaneously feature is fixed and decalcification, and decalcification is rapid, and little to histologic lesion, tissue bulking is few, little on the impact of dyeing.
The preparation of animal model and grouping
30 male adult albefaction rats of Wistar (two grades), body weight 300 ± 20g, is divided into 3 groups at random.
(1) blank group:
Random selecting 6 is blank group (hereinafter referred to as blank group), conventional raising.
(2) endotoxin+heavy dose of hormone group:
Random selecting 24 rats, tail vein injection endotoxin (10pg/kg) 1 time.Endotoxin injection is after 24 hours, the every 20mg/kg/d of lumbar injection predniso lone acetate, for three days on end, and every minor tick 24 hours.Subsequently modeling animal is divided into 2 groups at random: treatment group and model group.
1. treatment group: 12, started from obturator nerve surrounding injection complex liquid (Chinese medicine preparation injection of the present invention: lignocaine: sodium bicarbonate ratio is 1:1:l), 2ml/kg from the 4th day, 3 times/week, totally 8 weeks.
2. model group: 12, conventional raising.Treatment group, model group and blank group and after modeling the first day of the 9th week put to death.
Put to death, draw materials with fixing
All rats first day of the 9th week after modeling, puts to death after intraperitoneal anesthesia, draws materials.Concrete operations are as follows: with 0.3% pentobarbital sodium intraperitoneal injection of anesthesia (lml/100g), put to death rat, take off femoral head on the right side of rat, fixing, to be checked with 4% paraformaldehyde (0.0lMPBS liquid is prepared, pH value 7.2-7.4).
Prepare paraffin section
According to the requirement of pathological tissue dyeing, after room temperature fixes 4 days, carry out decalcification, dehydration, waxdip and embedding.
HE colouring method
According to HE colouring method, preparation HE stained preparation.(1) dewax (2) de-benzene (3) washing (4) haematoxylin dyeing (5) fully washing (6) hydrochloride alcohol differentiation (7) fully washing (9) fully washing (11) dehydration (12) resin glue mounting.
Result: ripe bone trabecula is light red, area of new bone girder is peony, and cartilage is light blue, and replacement bone is dark red and pale red alternate, and sequestrum is pale pink; Nucleus is bluish violet, collagen fiber and loose connective tissue pinkiness.
Graphical analysis
Gather program and the condition of image
Program: DireetforDMC.
Object lens enlargement ratio: empty bone lacuna rate, bone lacuna area: x40;
Average bone trabecula area: X10;
Microscope condenser aperture grating: 0.23;
Filament voltage: 10v;
Time of exposure: 13ms-16ms;
Colour temperature: 5500.
Get figure position according to " Z " font, every bar line is got a point as getting figure point, each observation index gets 3 visuals field same section, averaged.
Statistical method
Use SPSSll.5 software statistics, one factor analysis of variance is carried out to the data obtained.
Result
Om observation
Blank group
1. bone trabecula neatly clear, queueing discipline, fine and close full.
2. in cortical bone and bone trabecula, osteocyte is high-visible, and core is comparatively large, is positioned at central authorities, and even visible bone lacuna is hollow.
3. damp line is complete, and calcification zone is connected intact with subchondral bone girder.
4. in pulp cavity, hematopoietic cell enriches, and form is normal.Under cartilage, blood vessel is abundanter, and the wall structures that caliber is larger is clear.
5. bone trabecula edge osteoclast number is more, and in pulp cavity, amount of osteoclast is less.
Model group
1. bone trabecula is sparse, tall and thin, even has phenomenon of rupture, structure disturbance.
2. in bone trabecula, visible part osteocyte is downright bad, and empty bone lacuna compared with normal increases.
3. fat vacuole apparition in pulp cavity, hematopoietic cells number reduces.
4. bone trabecula gap has obvious fibrous tissue to extend into hypertrophy sign in pulp cavity.
5. osteoclast number reduces, and bone trabecula distribution has no obviously new bone apposition growth.
6. multinucleated osteoclast increasing number in pulp cavity.
7. under cartilage, thin vessels quantity obviously reduces, and blood sinus owes abundant.
8. damp line (tidemark) is interrupted or disappear, and calcification zone and subchondral bone girder rupture or discontinuous.
Treatment group
1. bone trabecula is thicker compared with model group, and quantity increases, and structure is substantially clear.
2. visible many genus normal bone cells in bone trabecula, a small amount of necrotic bone cell, empty bone lacuna comparatively model group obviously reduces.
3. fat vacuole comparatively model group minimizing in pulp cavity, hematopoietic cells number comparatively model group increases.4. osteoclast number comparatively model group increase.
5. in pulp cavity multinucleated osteoclast quantity comparatively model group obviously reduce.
6. thin vessels quantity comparatively model group showed increased under cartilage, blood sinus is enriched.
Compare between empty bone lacuna rate, bone lacuna area, bone trabecula area group
Compare between observation group under table 2 light microscopic
Grouping Number of slices Empty bone lacuna rate % Bone lacuna area/μm 2 Bone trabecula area/μm 2
Model group 12 64.8±9.4 * 57.5±11.3 * 15674±2476 *
Treatment group 12 27.3±6.7 * 47.0±7.3 20123±2013 *
Normal group 6 19.3±5.8 36.8±8.4 25981±2105
Note: *p<0.05, has significant difference.
To blank group, the indices of model group and treatment group carries out statistical analysis.
Result:
1. empty bone lacuna rate: the empty bone lacuna rate of model group obviously raises, and compares with treatment group and blank group, and group difference significantly (P<0.05); The empty bone lacuna rate for the treatment of group obviously reduces, but compared with blank group, group difference still significantly (P<0.05).
2. bone lacuna area: model group bone lacuna area obviously raises, and compares with blank group, group difference is significantly (P<0.05); Treatment group bone lacuna area obviously reduces, compared with blank group, and there was no significant difference (P>0.05) between group.
3. bone trabecula area: model group bone trabecula area obviously reduces, and compares with blank group, group difference is significantly (P<0.05); Treatment group bone trabecula area obviously raises, but compared with blank group, group difference still significantly (P<0.05); Treatment group bone trabecula area numerically higher than model group, but compares there was no significant difference (P>0.05) between the two group.
3 discuss
The Therapeutic Method of femur head necrosis mainly comprises conservative and operation two kinds.Wherein conservative treatment be traditional Chinese medical herbal treatment, interventional therapy, oral improve systemic microcirculation state treatment.
This experimentation illustrates the effect by Chinese medicine preparation complex liquid blood circulation promoting and blood stasis dispelling of the present invention, nourishing YIN and benefiting blood, heat-clearing and toxic substances removing, anti-inflammatory analgesic, has good early prevention and treatment effect to the femur head necrosis that hormone causes.Illustrate that Chinese medicine preparation complex liquid of the present invention has the effect of protection osteocyte; this may be relevant with the effect of Chinese medicine preparation nourishing YIN and benefiting blood of the present invention; because Chinese medicine preparation of the present invention improves the toleration of femur head necrosis district osteocyte for ischemia, anoxia; the pathology damage of part osteocyte is alleviated, avoids by degeneration, develop into downright bad process.At present, since the application of hormone is inevitable, it is perhaps a good method that the Chinese medicine preparation being representative in order to Chinese medicine preparation complex liquid of the present invention carrys out anti-treating caput femoris necrosis.The research that this experiment is just preliminary, although in experiment in empty bone lacuna rate and bone trabecula area two indices, Chinese medicine preparation complex liquid treatment group of the present invention and blank group still have difference, but be obviously better than hormone group, this may be relevant with our treatment time length, dosage and administering mode.
This description of test of brief summary: the administration of (l) endotoxin escalated dose Glucocorticoid impact can cause rat femur head downright bad.(2) by using Chinese medicine preparation complex liquid of the present invention to carry out rat Obturator nerve block, the early stage corticosteroid femur head necrosis for the treatment of rat, bone trabecula quantity can be increased, increase osteoblast and hematopoietic cells number, reduce necrotic bone cell, empty bone lacuna and multinucleated osteoclast quantity, obviously alleviate the degree of osteonecrosis.
All above-mentioned this intellectual properties of primary enforcement, not setting restriction this new product of other forms of enforcement and/or new method.Those skilled in the art will utilize this important information, and foregoing is revised, to realize similar implementation status.But all modifications or transformation belong to the right of reservation based on new product of the present invention.
The above is only preferred embodiment of the present invention, and be not restriction the present invention being made to other form, any those skilled in the art may utilize the technology contents of above-mentioned announcement to be changed or be modified as the Equivalent embodiments of equivalent variations.But everyly do not depart from technical solution of the present invention content, any simple modification, equivalent variations and the remodeling done above embodiment according to technical spirit of the present invention, still belong to the protection domain of technical solution of the present invention.

Claims (9)

1. be used for the treatment of a pharmaceutical composition for hormonal ischemic necrosis of femoral head, it is characterized in that: crude drug comprises Radix Rehmanniae Preparata, Radix Angelicae Sinensis, the Radix Paeoniae Alba, Rhizoma Chuanxiong, Radix Salviae Miltiorrhizae, Rhizoma Sparganii, Rhizoma Curcumae, Herba speranskiae tuberculatae, Pheretima, Scolopendra, Hirudo, Carapax Trionycis (processed), Rhizoma dioscoreae (parched), Fructus Corni, Cortex Eucommiae, Rhizoma Atractylodis Macrocephalae, Radix Astragali, Poria, Ramulus Cinnamomi, Radix Glycyrrhizae Preparata, Cortex Cinnamomi, Rhizoma Alismatis, Radix Achyranthis Bidentatae, Herba Agrimoniae, Herba Hedyotidis Diffusae and Herba Scutellariae Barbatae.
2. be used for the treatment of the pharmaceutical composition of hormonal ischemic necrosis of femoral head as claimed in claim 1, it is characterized in that: the weight portion of each crude drug is respectively Radix Rehmanniae Preparata 20 weight portion ~ 30 weight portion, Radix Angelicae Sinensis 15 weight portion ~ 25 weight portion, the Radix Paeoniae Alba 20 weight portion ~ 30 weight portion, Rhizoma Chuanxiong 15 weight portion ~ 25 weight portion, Radix Salviae Miltiorrhizae 15 weight portion ~ 25 weight portion, Rhizoma Sparganii 25 weight portion ~ 40 weight portion, Rhizoma Curcumae 30 weight portion ~ 40 weight portion, Herba speranskiae tuberculatae 10 weight portion ~ 20 weight portion, Pheretima 10 weight portion ~ 15 weight portion, Scolopendra 10 weight portion ~ 15 weight portion, Hirudo 15 weight portion ~ 20 weight portion, Carapax Trionycis (processed) 10 weight portion ~ 20 weight portion, Rhizoma dioscoreae (parched) 15 weight portion ~ 25 weight portion, Fructus Corni 20 weight portion ~ 35 weight portion, Cortex Eucommiae 10 weight portion ~ 15 weight portion, Rhizoma Atractylodis Macrocephalae 20 weight portion ~ 30 weight portion, Radix Astragali 20 weight portion ~ 30 weight portion, Poria 15 weight portion ~ 25 weight portion, Ramulus Cinnamomi 15 weight portion ~ 20 weight portion, Radix Glycyrrhizae Preparata 20 weight portion ~ 30 weight portion, Cortex Cinnamomi 10 weight portion ~ 20 weight portion, Rhizoma Alismatis 15 weight portion ~ 20 weight portion, Radix Achyranthis Bidentatae 25 weight portion ~ 30 weight portion, Herba Agrimoniae 10 weight portion ~ 15 weight portion, Herba Hedyotidis Diffusae 10 weight portion ~ 20 weight portion and Herba Scutellariae Barbatae 10 weight portion ~ 20 weight portion.
3. be used for the treatment of the pharmaceutical composition of hormonal ischemic necrosis of femoral head as claimed in claim 1 or 2, it is characterized in that: the weight portion of each crude drug is respectively Radix Rehmanniae Preparata 25 weight portion ~ 30 weight portion, Radix Angelicae Sinensis 20 weight portion ~ 25 weight portion, the Radix Paeoniae Alba 25 weight portion ~ 30 weight portion, Rhizoma Chuanxiong 15 weight portion ~ 20 weight portion, Radix Salviae Miltiorrhizae 20 weight portion ~ 25 weight portion, Rhizoma Sparganii 30 weight portion ~ 35 weight portion, Rhizoma Curcumae 35 weight portion ~ 40 weight portion, Herba speranskiae tuberculatae 10 weight portion ~ 15 weight portion, Pheretima 10 weight portion ~ 15 weight portion, Scolopendra 10 weight portion ~ 15 weight portion, Hirudo 15 weight portion ~ 20 weight portion, Carapax Trionycis (processed) 15 weight portion ~ 20 weight portion, Rhizoma dioscoreae (parched) 20 weight portion ~ 25 weight portion, Fructus Corni 25 weight portion ~ 30 weight portion, Cortex Eucommiae 10 weight portion ~ 15 weight portion, Rhizoma Atractylodis Macrocephalae 25 weight portion ~ 30 weight portion, Radix Astragali 25 weight portion ~ 30 weight portion, Poria 15 weight portion ~ 20 weight portion, Ramulus Cinnamomi 15 weight portion ~ 20 weight portion, Radix Glycyrrhizae Preparata 25 weight portion ~ 30 weight portion, Cortex Cinnamomi 10 weight portion ~ 15 weight portion, Rhizoma Alismatis 15 weight portion ~ 20 weight portion, Radix Achyranthis Bidentatae 25 weight portion ~ 30 weight portion, Herba Agrimoniae 10 weight portion ~ 15 weight portion, Herba Hedyotidis Diffusae 10 weight portion ~ 15 weight portion and Herba Scutellariae Barbatae 10 weight portion ~ 15 weight portion.
4. the pharmaceutical composition being used for the treatment of hormonal ischemic necrosis of femoral head as described in claims 1 to 3, it is characterized in that: the weight portion of each crude drug is respectively Radix Rehmanniae Preparata 25 weight portion, Radix Angelicae Sinensis 20 weight portion, the Radix Paeoniae Alba 25 weight portion, Rhizoma Chuanxiong 20 weight portion, Radix Salviae Miltiorrhizae 20 weight portion, Rhizoma Sparganii 30 weight portion, Rhizoma Curcumae 35 weight portion, Herba speranskiae tuberculatae 15 weight portion, Pheretima 10 weight portion, Scolopendra 10 weight portion, Hirudo 15 weight portion, Carapax Trionycis (processed) 15 weight portion, Rhizoma dioscoreae (parched) 20 weight portion, Fructus Corni 30 weight portion, Cortex Eucommiae 10 weight portion, Rhizoma Atractylodis Macrocephalae 25 weight portion, Radix Astragali 25 weight portion, Poria 20 weight portion, Ramulus Cinnamomi 20 weight portion, Radix Glycyrrhizae Preparata 25 weight portion, Cortex Cinnamomi 15 weight portion, Rhizoma Alismatis 20 weight portion, Radix Achyranthis Bidentatae 30 weight portion, Herba Agrimoniae 10 weight portion, Herba Hedyotidis Diffusae 15 weight portion and Herba Scutellariae Barbatae 15 weight portion.
5. the pharmaceutical composition being used for the treatment of hormonal ischemic necrosis of femoral head as described in Claims 1-4, is characterized in that: described pharmaceutical composition is granule, tablet, pill, capsule, electuary, oral liquid, soft extract, syrup or mixture.
6. the pharmaceutical composition being used for the treatment of hormonal ischemic necrosis of femoral head as described in claim 1 to 5, is characterized in that: described pharmaceutical composition is oral liquid.
7. the preparation method of pharmaceutical composition described in claim 1 to 6, is characterized in that, comprising:
The first step, takes each crude drug component by above-mentioned weight portion, pulverizes respectively, mix, and adopts ethanol percolate extraction, with purification with macroreticular resin, recycling design, dry, pulverize, and crosses 200 mesh sieves;
Second step, gets the product that the 200g first step obtains, and under constantly stirring, add the purified water of 8 times amount, medicinal liquid was in 0 DEG C of cold preservation more than 90 hours, use plate-and-frame filtration again, adjust ph to 7.0, it is 1000ml that filtrate is concentrated into volume, adds 15g sucrose, regulate pH to 7.5, embedding, sterilizing, to obtain final product.
8. the preparation method of pharmaceutical composition described in claim 1 to 6, is characterized in that, comprising:
The first step, takes each crude drug component by above-mentioned weight portion, pulverizes respectively, mix, and adopts ethanol percolate extraction, with purification with macroreticular resin, recycling design, dry, pulverize, and crosses 200 mesh sieves;
Second step, gets powder 50g prepared by the first step, injects with water appropriate, regulates medicinal liquid pH7.3-7.7, inject water to 1000ml with 10% sodium hydroxide, stirs, and medicinal liquid fine straining is extremely clear and bright, embedding, 115 DEG C, 45min sterilizing and get final product.
9. the preparation method of pharmaceutical composition as described in claim 7 or 8, it is characterized in that: the described first step is specially further and takes each crude drug component by above-mentioned weight portion, pulverize respectively, mix, with determining alcohol be 50% ~ 70% alcoholic solution seepage pressure effects is carried out to crude drug, collect percolate, alcoholic solution is 10 ~ 18L/kg with the volume mass ratio of mixed material medicine, the percolation time is 12 ~ 18 hours, use DA-201 purification by macroporous resin, first being washed till pH with deionized water is 5, be the ethanol elution of 80% with determining alcohol again, eluent concentrating under reduced pressure is reclaimed ethanol, the macroporous resin column of every 5g crude drug amount 100g resin dress DA-201 macroporous resin, ethanol elution consumption is 6 ~ 8 times of resin volume, recycling design, dry, pulverize, cross 200 mesh sieves.
CN201610009875.7A 2016-01-08 2016-01-08 Pharmaceutical composition for treating avascular necrosis of femoral head and application thereof Pending CN105456947A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110237171A (en) * 2019-06-24 2019-09-17 陈楚翁 A kind of pharmaceutical composition for caput femoris necrosis and preparation method thereof and purposes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
吴绪平: "《股骨头缺血性坏死针刀治疗与康复》", 31 May 2010, 中国医药科技出版社 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110237171A (en) * 2019-06-24 2019-09-17 陈楚翁 A kind of pharmaceutical composition for caput femoris necrosis and preparation method thereof and purposes
CN110237171B (en) * 2019-06-24 2022-02-11 陈楚翁 Medicine composition for femoral head necrosis and preparation method and application thereof

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