CN103083286A - Toad venom lipophilic extract dry powder inhaler, as well as preparation method and application thereof - Google Patents
Toad venom lipophilic extract dry powder inhaler, as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a dry powder inhaler, and in particular relates to a dry powder inhaler prepared from toad venom lipophilic extract, a preparation method of the dry powder inhaler and an application of the dry powder inhaler in preparing a medicament for treating lung tumors. The toad venom lipophilic extract dry powder inhaler is characterized by consisting of toad venom lipophilic extract and pharmaceutically acceptable auxiliary materials in a mass ratio of 1:0-1:100. According to the dry powder inhaler, the dry powder inhaler prepared from the toad venom lipophilic extract can be used for directly acting on the focus of the lung, so that the occurrence of toxic or side effect can be reduced, and the bioavailability of the medicament can be improved. The dry powder inhaler can be used for overcoming the defects that an oral preparation is slow in response, has first-pass effect of liver and systemic toxic or side effect, low in preparation bioavailability, and can be used for solving the problems of using inconvenience, poor patient compliance and the like.
Description
The application is dividing an application of an application for a patent for invention.The applying date of original application is on 06 02nd, 2011, and application number is 201110147767.3, and invention and created name is " a kind of Senso fat-soluble extract dry powder inhalation and preparation method thereof, application ".
Technical field
The present invention relates to Foradil Aerolizer formoterol fumarate, specifically the preparation method of the Foradil Aerolizer formoterol fumarate made of Venenum Bufonis liposoluble extract, described Foradil Aerolizer formoterol fumarate and the application in preparation treatment lung tumors medicine.
Background technology
Venenum Bufonis is the secretions of the epidermis body of gland of Bufonidae (Bufonidae) animal Bufo siccus Bufobufo gargarizans Cantor, have detoxifcation, ease pain, have one's ideas straightened out, the multiple efficacies such as antitumor, be used for, the disease such as late tumor, chronic hepatitis B.What have antitumor action in Venenum Bufonis is mainly bufotoxin class (bufotoxins) and hydrolyzate bufotalin class (bufageins), bufotenine class (bufoteinines) etc.Oral liquid, the tablet that contains at present Venenum Bufonis extract has been applied to clinical, hepatocarcinoma, pulmonary carcinoma, gastric cancer etc. had curative effect preferably, and chemotherapy and radiation is had synergism.Although the antitumous effect of Venenum Bufonis liposoluble extract is better, toxicity is larger, may cause larger general toxicity after oral.After the Venenum Bufonis liposoluble extract is made inhalant, medicine will directly act on patient part, can greatly reduce the general toxic and side effects that produces because of oral.
Lung has great surface area, and drug molecule very easily enters blood, the plurality of advantages such as that the lung inhalation has is rapid-action, local drug concentration is high and untoward reaction is little.(the drypowder inhalers of Foradil Aerolizer formoterol fumarate in the lung inhalation, DPIs) do not use propellant and solvent, the air-flow that produces by patient's autonomous respiration makes the drug powder atomizing, and then make drug powder be delivered to pulmonary, having targeting, efficient, quick-acting, toxic and side effects is little and use the characteristics such as convenient, is a kind of novel drug-supplying system.
Adopt site-specific delivery of drugs antitumor drug to be transported to the tumor patient part of human body, can improve medicine in the concentration of patient part, to the toxic and side effects that reduces medicine, the therapeutic effect that improves medicine, have great clinical value.Employing can directly be passed to the Venenum Bufonis liposoluble extract focus of pulmonary carcinoma through the inhalant of lung administering mode, is conducive to improve the Venenum Bufonis liposoluble extract to the curative effect of pulmonary carcinoma and reduces the toxic and side effects of its normal tissue.The sickness rate of pulmonary carcinoma rises rapidly in worldwide, has become first of the cancer cause of the death.Urgent need can directly be sent to medicine the treatment that is used for pulmonary carcinoma to the dosage form of pulmonary carcinoma focus with Foradil Aerolizer formoterol fumarate is this.The research that has at present the Senso fat-soluble extract dry powder inhalation of resisting tumor of lung effect has no report.
Summary of the invention
Goal of the invention: an object of the present invention is to provide pulmonary's dry powder inhaler formulations of Venenum Bufonis liposoluble extract and preparation method thereof.Another object of the present invention is to provide the application of Foradil Aerolizer formoterol fumarate of the present invention in preparation treatment lung tumors medicine.
For the foregoing invention purpose, the invention provides following technical scheme:
A kind of Senso fat-soluble extract dry powder inhalation, it is characterized in that it is comprised of Venenum Bufonis liposoluble extract and medically acceptable adjuvant, Venenum Bufonis liposoluble extract (according to gained solids quality after drying) is 1:0-1:100 with the mass ratio of described adjuvant.
Described a kind of Senso fat-soluble extract dry powder inhalation is the powder that adds adjuvant to make by the Venenum Bufonis liposoluble extract, and powder agglomeration forms re-dispersable particles; Or the Venenum Bufonis liposoluble extract loads on granules of accessories surface formation granule; The particle diameter of above-mentioned two kinds of granules is with D
50Meter is between the 0.5-1000 micron.
Described Venenum Bufonis liposoluble extract, the extract that makes through extracting purification for the Venenum Bufoniss of Bufonidae animal Bufo siccus or Bufo melanostictus etc.The preparation method of Venenum Bufonis liposoluble extract is:
Get 1 part of Venenum Bufonis, add 2-100 and doubly measure ethanol (60%-100%, W/W), reflux or ultrasonic or microwave or lixiviate or percolation extract 1-10 time, 0.1-48 hour at every turn, merge extractive liquid,, filter, reclaim ethanol, concentrating under reduced pressure obtains the Venenum Bufonis liposoluble extract after spray-dried, lyophilization or vacuum drying.
Described adjuvant is selected one or more mixture in sugar, alcohol, aminoacid, phospholipid, surfactant, cyclodextrin, polymer substance, magnesium stearate, stearic acid, hard ester fumaric acid sodium, micropowder silica gel, Pulvis Talci.
Described sugar can be selected one or more mixture in galactose, lactose, glucose, fructose, sucrose, trehalose, Raffinose; Described alcohol can be selected one or more mixture in mannitol, xylitol, maltose alcohol, sorbitol; Described aminoacid can be selected one or more in glycine, Aspartic Acid, alanine, tryptophan, isoleucine, threonine, glutamic acid, phenylalanine, leucine, cystine, lysine, proline, arginine; Described phospholipid can be selected one or more in soybean phospholipid, lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, synthetic phospholipid; Described surfactant can be selected one or more mixture in pulmonary surfactant such as dipalmitoyl phosphatidyl choline, DLPC, cholesterol; Described polymer substance, can select the macromolecule that meets safety requirements, preferred biodegradable polymer substance is one or more mixture in albumin, starch, polylactic acid, poly lactic-co-glycolic acid, Polyethylene Glycol, poloxamer, hyaluronic acid, hyaluronate sodium, sodium alginate for example.
Preferred mode is that described adjuvant is the 50-225 micron for sucking with the lactose granule mean diameter, and micronization lactose mean diameter is 1-10 micron or its mixture, and wherein the mass ratio of lactose granule and micronization lactose is 1100:1-1:1.Most preferred mode is that the mass ratio of lactose granule and micronization lactose is 105:1-10:1.
A kind of method for preparing Senso fat-soluble extract dry powder inhalation, its preparation process is as follows:
The Venenum Bufonis liposoluble extract is made powder by pulverizing or spray drying, be packaged in capsule or bubble-cap or Diskus; The Venenum Bufonis liposoluble extract is made powder by pulverizing or spray drying, and powder and adjuvant mix homogeneously are made to suck and are used powder, are packaged in capsule or bubble-cap or Diskus; Perhaps with Venenum Bufonis liposoluble extract and adjuvant mix homogeneously, make to suck by pulverizing or spray drying and use powder, be packaged in capsule or bubble-cap or Diskus; Perhaps with partial supplementary material mix homogeneously in Venenum Bufonis liposoluble extract and prescription, make powder by pulverizing or spray drying, in powder and prescription, residue adjuvant mix homogeneously is made to suck and is used powder, is packaged in capsule or bubble-cap or Diskus.
A kind of method for preparing Senso fat-soluble extract dry powder inhalation, its preparation process is as follows:
The Venenum Bufonis liposoluble extract is made powder by pulverizing or spray drying, powder and adjuvant mix homogeneously, reuniting forms re-dispersable particles, is packaged in capsule or bubble-cap or Diskus; Perhaps with Venenum Bufonis liposoluble extract and adjuvant mix homogeneously, make powder by pulverizing or spray drying, reuniting forms re-dispersable particles, is packaged in capsule or bubble-cap or Diskus; Perhaps with partial supplementary material mix homogeneously in Venenum Bufonis liposoluble extract and prescription, make powder by pulverizing or spray drying, residue adjuvant mix homogeneously in powder and prescription, the formation re-dispersable particles of reuniting is packaged in capsule or bubble-cap or Diskus; Perhaps the Venenum Bufonis liposoluble extract is made powder by pulverizing or spray drying, powder load is packaged in capsule or bubble-cap or Diskus at granules of accessories surface formation granule.
The application of a kind of Senso fat-soluble extract dry powder inhalation in preparation lung tumors medicine.
Beneficial effect:
1, lung has great surface area and abundant blood vessel, makes drug molecule very easily enter blood, so the lung inhalation has the plurality of advantages such as rapid-action, that local drug concentration is high and untoward reaction is little.(the drypowder inhalers of Foradil Aerolizer formoterol fumarate in the lung inhalation, DPIs) do not use propellant and solvent, the air-flow that produces by patient's autonomous respiration makes the drug powder atomizing, and then make drug powder be delivered to pulmonary, having targeting, efficient, quick-acting, toxic and side effects is little and use the characteristics such as convenient, is a kind of novel drug-supplying system.At present multiplex in the infection for the treatment of respiratory tract and pulmonary relevant for Foradil Aerolizer formoterol fumarate, but have no treatment for lung tumors.Simultaneously, the research that has a similar preparation of resisting tumor of lung effect also has no report.Oral liquid, the tablet that contains at present Venenum Bufonis extract has been applied to clinical, hepatocarcinoma, pulmonary carcinoma, gastric cancer etc. had curative effect preferably, and chemotherapy and radiation is had synergism.Although the antitumous effect of Venenum Bufonis liposoluble extract is better, toxicity is larger, may cause larger toxicity after oral.Using the Foradil Aerolizer formoterol fumarate of Venenum Bufonis liposoluble extract is mainly for lung tumors, directly act on pulmonary lesions, improve the drug level of lesions position, do not have liver first-pass effect, and can reduce the toxic and side effects of medicine, new drug development is had great prospect.
2, the Venenum Bufonis liposoluble extract is mixture, in order to make its granularity requirements that reaches Foradil Aerolizer formoterol fumarate, need to pulverize.Find in practical operation, the reunion that the electrostatic interaction that adds the specific adjuvant of certain proportioning can overcome extract to produce when being crushed to certain particle size, cohesiveness etc. cause reduces hygroscopicity.The applicant passes through great many of experiments to be known, particularly adjuvant is selected the mixture of lactose granule and micronization lactose or adopted the powder agglomeration technology can make the good Foradil Aerolizer formoterol fumarate of intake performance.
The specific embodiment
Below in conjunction with example, the present invention is described in further detail, but scope of the present invention is not subjected to any restriction of these examples.
Embodiment 1
1, the preparation of Venenum Bufonis liposoluble extract: get Venenum Bufonis and clean, add 10 times of amount 95%(W/W) ethanol, reflux 2 times, and each 1.5 hours, merging filtrate after filtering reclaimed ethanol, is concentrated into thick paste, and 60 ℃ of dryings obtain the Venenum Bufonis liposoluble extract.
2, the preparation of inhalant: adopt comminution by gas stream to D the Venenum Bufonis liposoluble extract
50Below 6 microns, with the lactose of particle diameter 50-80 micron in mass ratio 1:12 mix, drug powder is packaged in capsule or bubble-cap or Diskus, obtain inhalant.
Embodiment 2
1, the preparation of Venenum Bufonis liposoluble extract: get Venenum Bufonis and clean, add 12 times of amount 95%(W/W) ethanol, reflux 2 times, and each 2 hours, merge extractive liquid, also filtered, and carries out spray drying after concentrated filtrate, obtains Venenum Bufonis liposoluble extract powder, powder D
50Below 5 microns.
2, the preparation of inhalant: with Venenum Bufonis liposoluble extract powder, particle diameter the lactose of 80-125 micron, particle diameter the leucine of 30-50 micron in mass ratio the ratio of 9:100:1 mix, be packaged in capsule or bubble-cap or Diskus, obtain inhalant.
Embodiment 3
1, the preparation of Venenum Bufonis liposoluble extract: get Venenum Bufonis and clean, add 30 times of amount 70%(W/W) ethanol, microwave-assisted extracts 3 times, and each 1 hour, merge extractive liquid, also filtered, and carries out spray drying after concentrated filtrate, obtains Venenum Bufonis liposoluble extract powder, powder D
50Below 5 microns.
2, the preparation of inhalant: Venenum Bufonis liposoluble extract powder packets is packed in capsule or bubble-cap or Diskus, obtain inhalant.
Embodiment 4
1, the ethanol preparation of Venenum Bufonis liposoluble extract: get Venenum Bufonis and clean, add 12 times of amount 85%(W/W), reflux, extract, 2 times, each 2 hours, merge extractive liquid,, deepfreeze 48 hours, filter, carry out spray drying after concentrated filtrate, obtain Venenum Bufonis liposoluble extract powder.
2, the preparation of inhalant: with Venenum Bufonis liposoluble extract powder, lactose, mannitol, glycine, DLPC, lecithin, magnesium stearate in mass ratio the ratio of 1:5:4:2:0.5:0.5:0.1 mix, comminution by gas stream is to powder D
50Below 8 microns, drug powder is packaged in capsule or bubble-cap or Diskus, obtain inhalant.
Embodiment 5
1, the ethanol preparation of Venenum Bufonis liposoluble extract: get Venenum Bufonis and clean, add 20 times of amount 60%(W/W), reflux, extract, 2 times, each 1 hour, merge extractive liquid, filtered, and filtrate recycling ethanol is concentrated into thick paste, and lyophilization obtains the Venenum Bufonis liposoluble extract.
2, the preparation of inhalant: Venenum Bufonis liposoluble extract, lactose, cholesterol are mixed in the ratio of 1:7:1, and comminution by gas stream is to powder D
50Below 5 microns, drug powder is packaged in capsule or bubble-cap or Diskus, obtain inhalant.
Embodiment 6
1, the preparation of Venenum Bufonis liposoluble extract: get Venenum Bufonis and clean, add the dehydrated alcohol of 10 times of amounts, reflux, extract, 3 times, each 1 hour, merge extractive liquid, also filtered, and reclaims ethanol, reclaims liquid and carries out spray drying, obtains the Venenum Bufonis liposoluble extract.
2, the preparation of inhalant: lactose, polyethylene glycol 6000, the albumin with 5 times, 1 times, 2 times of contained solid qualities in above-mentioned Venenum Bufonis liposoluble extract adds in the Venenum Bufonis liposoluble extract respectively, spray drying, powder D
50Below 6 microns, drug powder is packaged in capsule or bubble-cap or Diskus, obtain inhalant.
Embodiment 7
1, the ethanol preparation of Venenum Bufonis liposoluble extract: get Venenum Bufonis and clean, add the 95%(W/W of 15 times of amounts), percolation extracts 2 times, and each 10 hours, merge extractive liquid, reclaimed ethanol, and spray drying obtains the Venenum Bufonis liposoluble extract, powder D
50Below 6 microns.
2, the preparation of inhalant: with Venenum Bufonis liposoluble extract drug powder, particle diameter the mannitol of 30-95 micron, micronization silica gel in mass ratio the ratio of 10:88:2 mix, be packaged into after mix homogeneously in capsule or bubble-cap or Diskus, obtain inhalant.
Embodiment 8
1, the ethanol preparation of Venenum Bufonis liposoluble extract: get Venenum Bufonis and clean, add the 95%(W/W of 8 times of amounts), supersound extraction 2 times, each 1 hour, merge extractive liquid, reclaimed ethanol to nothing alcohol flavor, and lyophilization obtains Venenum Bufonis liposoluble extract powder.
2, the preparation of inhalant: with Venenum Bufonis liposoluble extract drug powder, mannitol, leucine in mass ratio the ratio of 10:100:4 mix, add water after mixing appropriate, spray drying obtains D
50Be the powder of 4.9 microns, mix with the rotary blender that polymer inner liner is arranged, make loose aggregate, the D of aggregate
50Be 312 microns, be packaged in capsule or bubble-cap or Diskus, obtain inhalant.
Embodiment 9
1, the ethanol preparation of Venenum Bufonis liposoluble extract: get Venenum Bufonis and clean, add the 85%(W/W of 10 times of amounts), reflux, extract, 3 times, each 0.5 hour, merge extractive liquid, filtered and concentrates, and concentrated solution carries out spray drying, powder D
50Below 5 microns.
2, the preparation of inhalant: with Venenum Bufonis liposoluble extract powder, mannitol, leucine in mass ratio the ratio of 9:80:2 mix, mix with the rotary blender that polymer inner liner is arranged, make loose aggregate, the D of aggregate
50Be 122 microns, be packaged in capsule or bubble-cap or Diskus, obtain inhalant.
Embodiment 10
1, the preparation of Venenum Bufonis liposoluble extract: get Venenum Bufonis and clean, add 20 times of amount 95%(W/W) ethanol, reflux, extract, 2 times, each 2 hours, merging filtrate was cooled to 40 ℃, filtered, and reclaimed ethanol and concentrated, and concentrated solution carries out spray drying, powder D
50Below 5 microns.
2, the preparation of inhalant: with Venenum Bufonis liposoluble extract powder, happy InhaLac 70 lactose of German U.S. agent, micronization lactose (D
50=5.2 microns) in mass ratio the ratio of 4:90:6 mix, be packaged into after mix homogeneously in capsule or bubble-cap or Diskus, obtain inhalant.
3, the inhalant pulmonary deposition ratio is investigated
Investigate according to People's Republic of China's version pharmacopeia prescriptive procedure in 2010, with the content meter of preparation cinobufagin, its pulmonary deposition ratio reaches 22.3%, places after 18 months under room temperature condition, and the pulmonary deposition ratio of preparation cinobufagin does not have significant change.
Embodiment 11
1, the preparation of Venenum Bufonis liposoluble extract: get Venenum Bufonis and clean, add 20 times of amount 90%(W/W) ethanol, reflux, extract, 2 times, each 2 hours, merging filtrate was cooled to 40 ℃, filtered, and reclaimed ethanol and concentrated, and concentrated solution carries out spray drying, powder D
50Below 5 microns.
2, the preparation of inhalant: with Venenum Bufonis liposoluble extract powder, happy InhaLac 70 lactose of German U.S. agent, micronization lactose (D
50=4.6 microns) in mass ratio the ratio of 6:95:1 mix, be packaged into after mix homogeneously in capsule or bubble-cap or Diskus, obtain inhalant.
3, the inhalant pulmonary deposition ratio is investigated
Investigate according to People's Republic of China's version pharmacopeia prescriptive procedure in 2010, with the content meter of preparation cinobufagin, its pulmonary deposition ratio reaches 20.1%, places after 18 months under room temperature condition, and the pulmonary deposition ratio of preparation cinobufagin does not have significant change.
Embodiment 12
1, the preparation of Venenum Bufonis liposoluble extract: get Venenum Bufonis and clean, add 20 times of amount 85%(W/W) ethanol, reflux, extract, 2 times, each 2 hours, merging filtrate was cooled to 40 ℃, filtered, and reclaimed ethanol and concentrated, and concentrated solution carries out spray drying, powder D
50Below 5 microns.
2, the preparation of inhalant: with Venenum Bufonis liposoluble extract powder, happy InhaLac 70 lactose of German U.S. agent, micronization lactose (D
50=5.5 microns) in mass ratio the ratio of 3:92:2 mix, be packaged into after mix homogeneously in capsule or bubble-cap or Diskus, obtain inhalant.
3, the inhalant pulmonary deposition ratio is investigated
Investigate according to People's Republic of China's version pharmacopeia prescriptive procedure in 2010, with the content meter of preparation cinobufagin, its pulmonary deposition ratio reaches 19.6%, places after 18 months under room temperature condition, and the pulmonary deposition ratio of preparation cinobufagin does not have significant change.
Embodiment 13
1, the preparation of Venenum Bufonis liposoluble extract: get Venenum Bufonis and clean, add 10 times of amount 90%(W/W) ethanol, reflux, extract, 2 times, each 1 hour, merging filtrate filtered, and reclaimed ethanol and concentrated, and concentrated solution carries out spray drying, powder D
50Below 5 microns.
2, the preparation of inhalant: Venenum Bufonis liposoluble extract powder, leucine are mixed the D of granule after mixing in the ratio of 1:5
50Be 205 microns, be packaged in capsule or bubble-cap or Diskus, obtain inhalant.
Embodiment 14
1, the preparation of Venenum Bufonis liposoluble extract: get Venenum Bufonis and clean, add 6 times of amount 95%(W/W) ethanol, reflux, extract, 5 times, each 1 hour, merging filtrate filtered, and reclaimed ethanol extremely without the alcohol flavor, and concentrating under reduced pressure, vacuum drying obtain the Venenum Bufonis liposoluble extract.
2, the preparation of inhalant: the Venenum Bufonis liposoluble extract is mixed comminution by gas stream, powder D with leucine in the ratio of 1:1
50Below 5 microns, this powder is mixed again the D of granule after mixing with the mannitol of 10 times of amounts
50Be 199 microns, be packaged in capsule or bubble-cap or Diskus, obtain inhalant.
Embodiment 15
1, the preparation of Venenum Bufonis liposoluble extract: get Venenum Bufonis and clean, add 30 times of amount 90%(W/W) ethanol, reflux, extract, 1 hour, extracting solution filters, and reclaims ethanol extremely without the alcohol flavor, and concentrating under reduced pressure, vacuum drying obtain the Venenum Bufonis liposoluble extract.
2, the preparation of inhalant: with Venenum Bufonis liposoluble extract and poloxamer in mass ratio the ratio of 10:1 mix, comminution by gas stream, powder D
50Below 5 microns, this powder is mixed again the D of granule after mixing with the lactose granule of 9 times of amounts, the magnesium stearate of 1 times of amount
50Be 157 microns, be packaged in capsule or bubble-cap or Diskus, obtain inhalant.
Embodiment 16
1, the preparation of Venenum Bufonis liposoluble extract: get Venenum Bufonis and clean, add 10 times of amount 95%(W/W) ethanol, reflux, extract, 3 times, each 1 hour, extracting solution filtered, and reclaimed ethanol extremely without the alcohol flavor, and concentrating under reduced pressure, vacuum drying obtain the Venenum Bufonis liposoluble extract.
2, the preparation of inhalant: with Venenum Bufonis liposoluble extract comminution by gas stream, powder D
50Below 5 microns, this powder is mixed again the D of granule after mixing with the lactose granule of 22 times of amounts
50Be 236 microns, be packaged in capsule or bubble-cap or Diskus, obtain inhalant.
Embodiment 17
Obtain inhalant according to embodiment 1-16, carry out pharmacodynamic experiment.
Effect experiment:
The method of benzopyrene percutaneous puncture pulmonary injection is set up the induced lung animal model for tumour, gets 180 of modeling rats, is divided at random 18 groups, 10 every group.Every day 1 time, medication 7 days.The inhalant inhalation that administering mode: 1-16 group obtains for embodiment 1-16, dosage is 3mg crude drug/kg; The 17th group of gavage gives the Venenum Bufonis liposoluble extract, and dosage is 3mg crude drug/kg; The 18th group is the normal saline matched group that contains 0.5% sodium carboxymethyl cellulose, lumbar injection 10mL/kg.Next day is put to death rat in drug withdrawal, dissects lungs, observes the lung lesion situation.
Experimental result: it is 20% that the pulmonary of rat of each group of inhalant administration the incidence rate of lump or nodular lesion occurs minimum, is up to 39%; Venenum Bufonis liposoluble extract gavage group is 58%, and the normal saline group is 100%, and each group of inhalant administration has significant difference (P＜0.05) with Venenum Bufonis liposoluble extract gavage group, normal saline group on the pulmonary lesion incidence rate.
Embodiment 18
Obtain inhalant according to embodiment 1-16, carry out pharmacodynamic experiment.
1, the foundation of rabbit VX2 original position lung cancer model
1) the freezing cell suspension of the conventional recovery VX2 tumor of the making of lotus tumor kind rabbit, make 10
6The living cells suspension of/mL is got 1mL and is inoculated in 1 rabbit right rear leg outside intramuscular, can lay one's hand on and the lump of a diameter 30cm in inoculation position after 3 weeks, namely makes lotus tumor kind rabbit.
2) cut the intramuscular tumor in the lotus tumor kind rabbit leg outside under the preparation aseptic condition of piece of tissue suspension, get to be and oppress the eugonic tumor tissues of sample, be cut into the mud shape.RPMI 1640 culture fluid rinse 30 mesh sieves, remove individual cells and too small piece of tissue, and on sieve, part is crossed 20 mesh sieves under the RPMI RPMI-1640 rinses, and removes excessive piece of tissue.Get the lower part of screen and divide, after centrifugation, taking precipitate 2mL adds the RPMI RPMI-1640 and is mixed with piece of tissue suspension 20mL.
3) all rabbit right thoracic wall depilations of inoculation in lung, intramuscular injection speed is slept and is fixed after new mixture 0.8mL/kg anaesthetizes, routine disinfection, get aseptic three way cock, connecing respectively No. 12 injection needles, suctions has the 1mL syringe of rabbit self blood clot and the syringe that suction has VX2 tumor tissue's suspension or cell suspension 1mL.Under X-ray examination, No. 12 syringe needles are thrust in the rabbit inferior lobe of right lung, after the resorption depletion of blood, inject 0.4mL piece of tissue suspension or cell suspension, then inject 0.2mL rabbit self blood clot, extract syringe needle, inoculate complete.
4) the whole rabbit of the observation of growth of xenografted situation were from after inoculation the 3rd day, and carry out to chest the CT scan that layer is wide, bed thickness is 5mm every day, observed transfer case in tumor growth, thoracic cavity.
5) rabbit VX2 original position lung cancer model is set up as a result rabbit all tumor growth in lung, success ratio of inoculation 100%.
2, pharmacodynamic experiment
Get successfully 180 of modeling rabbit, be divided at random 18 groups, 10 every group.Every day 1 time, medication 12 days.The inhalant inhalation that administering mode: 1-16 group obtains for embodiment 1-16, dosage is 3mg crude drug/kg; The 17th group of gavage gives the Venenum Bufonis liposoluble extract, and dosage is 3mg crude drug/kg; The 18th group is the normal saline matched group that contains 0.5% sodium carboxymethyl cellulose, lumbar injection 10mL/kg.Next day is put to death rabbit in drug withdrawal, dissects the rabbit lungs, peels off tumor tissues, weighs.
Experimental result: the tumour inhibiting rate minimum of each group of inhalant administration is 48.9%, is up to 66.2%; The tumour inhibiting rate of Venenum Bufonis liposoluble extract gavage group is 37.6%, and the normal saline group does not almost have inhibitory action to tumor, and each group of inhalant administration has significant difference (P＜0.05) with the tumour inhibiting rate of Venenum Bufonis liposoluble extract gavage group, normal saline group.
Claims (1)
1. Senso fat-soluble extract dry powder inhalation is characterized in that it is comprised of Venenum Bufonis liposoluble extract and medically acceptable adjuvant;
The preparation of described Venenum Bufonis liposoluble extract: get Venenum Bufonis and clean, add 10 times of amount 95% ethanol, reflux 2 times, each 1.5 hours, merging filtrate after filtering reclaimed ethanol, is concentrated into thick paste, and 60 ℃ of dryings obtain the Venenum Bufonis liposoluble extract;
The preparation of described inhalant: adopt comminution by gas stream to D the Venenum Bufonis liposoluble extract
50Below 6 microns, with the lactose of particle diameter 50-80 micron in mass ratio 1:12 mix, drug powder is packaged in capsule or bubble-cap or Diskus, obtain inhalant.
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| CN104337844A (en) * | 2013-08-02 | 2015-02-11 | 北京因科瑞斯医药科技有限公司 | Venenum bufonis extractive and application of preparation of venenum bufonis extractive to preparing medicines for treating melanoma |
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| CN104337844A (en) * | 2013-08-02 | 2015-02-11 | 北京因科瑞斯医药科技有限公司 | Venenum bufonis extractive and application of preparation of venenum bufonis extractive to preparing medicines for treating melanoma |
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