CN102961409A - Toad skin extract dry powder inhaler, as well as preparation method and application thereof - Google Patents
Toad skin 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 specifically relates to a dry powder inhaler produced by a toad skin extract, a preparation method of the dry powder inhaler and an application of the dry powder inhaler in preparation of medicaments for treating tumors of the lung. The toad skin extract dry powder inhaler is characterized by comprising the toad skin extract and pharmaceutically acceptable excipients, and the weight ratio of the toad skin extract to the excipients is (1:0)-(1:110). The dry powder inhaler produced by the toad skin extract can direct act on patients with lung diseases, reduce the occurrence of toxic and side effects, improve the bioavailability of the medicament, overcome the shortcomings of low effect taking speed, first-pass effect of the liver, systemic toxic and side effects, lower bioavailability and the like of oral preparations, and simultaneously solve the problems of inconvenience in use, poor patient compliance and the like of injections.
Description
Technical field:
The present invention relates to Foradil Aerolizer formoterol fumarate, specifically the preparation method of the Foradil Aerolizer formoterol fumarate made of Cutis Bufonis extract, described Foradil Aerolizer formoterol fumarate and the application in preparation treatment lung tumors medicine.
Background technology:
Cinobufacin is the extract that the dry skin of Bufonidae (Bufonidae) animal Bufo siccus Bufobufo gargarizans Cantor makes through extracting purification, effect with detoxifcation, detumescence, pain relieving, in being used for the treatment of, the disease such as late tumor, chronic hepatitis B, its biological active substances mainly is bufotoxin class (bufotoxins) and hydrolyzate bufotalin class (bufageins), bufotenine class (bufoteinines) etc.Present cinobufacin injection, oral liquid, tablet have been applied to clinical, and hepatocarcinoma, pulmonary carcinoma, gastric cancer etc. are had preferably curative effect.Especially HUACHANSU ZHUSHEYE, from the water soluble preparation of Skin of Bufo bufo gargarizans through being processed into, treatment primary hepatocarcinoma and medium and advanced lung cancer obtain respectively 44% and 56% comprehensive effective percentage, and tumor body minification is respectively 10% and 16%, and chemotherapy and radiation is had synergism.Although the clinical untoward reaction of HUACHANSU ZHUSHEYE is less, but still exist the intravenous drip meeting local vein reaction to occur, cause that the instillation vein shrinks spasm and causes pain, long-time stimulus causes the vein nonspecific inflammation; Dermoreaction, main manifestations are urticaria and the infringement of skin blister sample; Secondly, the cardiovascular system reactions such as premature beat, sinus bradycardia, sinus tachycardia, atrioventricular block appear in small part patient, and the possible cause of generation is the cardiotoxicity that bufotalin a small amount of in the cinobufacin produces.In addition, injection need to use in hospital, and patient compliance is poor.And the cinobufacin oral formulations need be through the first pass effect of liver, and onset is slow, and the preparation bioavailability is lower.
Lung has great surface area, and alveolar wall is comprised of cell monolayer, so that drug molecule very easily enters blood, so the lung inhalation has the plurality of advantages such as rapid-action, that 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, have use convenient, absorb rapidly, without liver firstly cross, the characteristics of rapid release and targeting location, be a kind of novel drug-supplying system.
The sickness rate of pulmonary carcinoma rises rapidly in worldwide, has become first of the cancer cause of the death.Current antitumor drug great majority all are drug administration by injection, and this whole body administering mode is unfavorable for drug accumulation in tumor locus, cause the curative effect of medicine to reduce, and untoward reaction increases.
Adopt site-specific delivery of drugs that antitumor drug is transported to the tumor patient part of human body, medicine is improved in the concentration of patient part, the toxic and side effects that reduces medicine, the therapeutic effect that improves medicine are had great clinical value.Employing can directly be transmitted Cutis Bufonis extract the focus of pulmonary carcinoma through the inhalant of lung administering mode, is conducive to improve Cutis Bufonis extract to the curative effect of pulmonary carcinoma and reduces the toxic and side effects of its normal tissue.The research that has at present the Cutis Bufonis extract Foradil Aerolizer formoterol fumarate 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 Cutis Bufonis extract and preparation method thereof.Another object of the present invention provides 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 Cutis Bufonis extract Foradil Aerolizer formoterol fumarate is characterized in that it is comprised of Cutis Bufonis extract and medically acceptable adjuvant, and Cutis Bufonis extract (according to gained solids quality after the drying) is 1:0-1:110 with the mass ratio of described adjuvant.
Described a kind of Cutis Bufonis extract Foradil Aerolizer formoterol fumarate is to add the powder that adjuvant is made by Cutis Bufonis extract, and powder agglomeration forms re-dispersable particles; Or Cutis Bufonis 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 Cutis Bufonis extract, the extract that makes through extracting purification for the skins of Bufonidae animal Bufo siccus or Bufo melanostictus etc.The preparation method of Cutis Bufonis extract is:
Get 1 part of Cutis Bufonis, add 2-100 times of water gaging, backflow or decoction or ultrasonic or microwave or lixiviate or percolation extract 1-10 time, 0.1-48 hour at every turn, merge water extraction liquid, being concentrated into relative density is 1.01-1.50(60-100 ℃), add ethanol (65%-100%, W/W) precipitation, make ethanol content reach 50%(W/W) more than, leave standstill or centrifugal or filtration treatment, get the supernatant Recycled ethanol, obtain obtaining Cutis Bufonis extract after Cutis Bufonis extract or concentrated, the drying.
Perhaps, get 1 part of Cutis Bufonis, add 2-100 times of water gaging, backflow or decoction or ultrasonic or microwave or lixiviate or percolation extract 1-10 time, and each 0.1-48 hour, merging water extraction liquid, being concentrated into relative density is 1.01-1.50(60-100 ℃), add ethanol (65%-100%, W/W) precipitation, make ethanol content reach 50%(W/W) more than, leave standstill or centrifugal or filtration treatment, get the supernatant Recycled ethanol to without the alcohol flavor, add ethanol (65%-100%, W/W) precipitation, make ethanol content reach 60%(W/W) more than, leave standstill or centrifugal or filtration treatment, get the supernatant Recycled ethanol to without the alcohol flavor, obtain Cutis Bufonis extract or concentrated, obtain Cutis Bufonis extract after the drying.
Perhaps, get 1 part of Cutis Bufonis, add 2-100 times of water gaging, backflow or decoction or ultrasonic or microwave or lixiviate or percolation extract 1-10 time, each 0.1-48 hour, merge water extraction liquid, through the ultrafilter membrane ultrafiltration of molecular weight 500-5000, obtain obtaining Cutis Bufonis extract after Cutis Bufonis extract or concentrated, the drying.
Perhaps, get 1 part of Cutis Bufonis, add the certain density ethanol (1%-100%, W/W) that 2-100 doubly measures, reflux or ultrasonic or microwave or lixiviate or percolation extract 1-10 time, each 0.1-48 hour, merge extractive liquid,, Recycled ethanol adds 0-100 times of water to without the alcohol flavor, leave standstill or centrifugal or filtration treatment, obtain obtaining Cutis Bufonis extract after Cutis Bufonis extract or concentrated, the drying.
Perhaps, get 1 part of Cutis Bufonis, add the certain density ethanol (1%-100%, W/W) that 2-100 doubly measures, reflux or ultrasonic or microwave or lixiviate or percolation extract 1-10 time, each 0.1-48 hour, merge extractive liquid,, Recycled ethanol adds 0-100 times of water to without the alcohol flavor, through the ultrafilter membrane ultrafiltration of molecular weight 500-5000, obtain obtaining Cutis Bufonis extract after Cutis Bufonis extract or concentrated, the 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, the Pulvis Talci.
Described sugar can be selected one or more mixture in galactose, lactose, glucose, fructose, sucrose, trehalose, the Raffinose; Described alcohol can be selected one or more mixture in mannitol, xylitol, maltose alcohol, the sorbitol; Described aminoacid can be selected one or more in glycine, Aspartic Acid, alanine, tryptophan, isoleucine, threonine, glutamic acid, phenylalanine, leucine, cystine, lysine, proline, the arginine; Described phospholipid can be selected one or more in soybean phospholipid, lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, the synthetic phospholipid; Described surfactant can be selected one or more mixture in pulmonary surfactant such as dipalmitoyl phosphatidyl choline, DLPC, the 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, the sodium alginate for example.
Preferred mode is described adjuvant for sucking with the lactose granule mean diameter at 45-220 micron and the micronization lactose mean diameter mixture at the 1-10 micron, and wherein the mass ratio of lactose granule and micronization lactose is 1000:1-1:1.Most preferred mode is that the mass ratio of lactose granule and micronization lactose is 100:1-7:1.
A kind of method for preparing the Cutis Bufonis extract Foradil Aerolizer formoterol fumarate, its preparation process is as follows:
Cutis Bufonis extract is made powder by pulverizing or spray drying, be packaged in capsule or bubble-cap or the Diskus; Cutis Bufonis 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 the Diskus; Perhaps with Cutis Bufonis extract and adjuvant mix homogeneously, make suction by pulverizing or spray drying and use powder, be packaged in capsule or bubble-cap or the Diskus; Perhaps with partial supplementary material mix homogeneously in Cutis Bufonis extract and the prescription, make powder by pulverizing or spray drying, residue adjuvant mix homogeneously is made to suck and is used powder in powder and the prescription, is packaged in capsule or bubble-cap or the Diskus.
A kind of method for preparing the Cutis Bufonis extract Foradil Aerolizer formoterol fumarate, its preparation process is as follows:
Cutis Bufonis 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 the Diskus; Perhaps with Cutis Bufonis 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 the Diskus; Perhaps with partial supplementary material mix homogeneously in Cutis Bufonis extract and the prescription, make powder by pulverizing or spray drying, residue adjuvant mix homogeneously in powder and the prescription, the formation re-dispersable particles of reuniting is packaged in capsule or bubble-cap or the Diskus; Perhaps Cutis Bufonis extract is made powder by pulverizing or spray drying, powder load forms granule on the granules of accessories surface, is packaged in capsule or bubble-cap or the Diskus.
The application of a kind of Cutis Bufonis extract Foradil Aerolizer formoterol fumarate in preparation lung tumors medicine.
Beneficial effect:
1, lung has great surface area, and alveolar wall is comprised of cell monolayer, so that drug molecule very easily enters blood, so the lung inhalation has the plurality of advantages such as rapid-action, that 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, have use convenient, absorb rapidly, without liver firstly cross, the characteristics of rapid release and targeting location, be 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 at lung tumors.Simultaneously, the research that has a Cutis Bufonis extract Foradil Aerolizer formoterol fumarate of resisting tumor of lung effect also has no report.Present Cutis Bufonis extract injection, oral liquid, tablet have been applied to clinical, and hepatocarcinoma, pulmonary carcinoma, gastric cancer etc. are had preferably effect.Especially HUACHANSU ZHUSHEYE, from the water soluble preparation of Skin of Bufo bufo gargarizans through being processed into, treatment primary hepatocarcinoma and medium and advanced lung cancer obtain respectively 44% and 56% comprehensive effective percentage, and tumor body minification is respectively 10% and 16%, and chemotherapy and radiation is had synergism.Although the clinical untoward reaction of HUACHANSU ZHUSHEYE is less, but still exist the intravenous drip meeting local vein reaction to occur, cause that the instillation vein shrinks spasm and causes pain, long-time stimulus causes the vein nonspecific inflammation; Dermoreaction, main manifestations are urticaria and the infringement of skin blister sample; Secondly, the cardiovascular system reactions such as premature beat, sinus bradycardia, sinus tachycardia, atrioventricular block appear in small part patient, and the possible cause of generation is the cardiotoxicity that bufotalin a small amount of in the cinobufacin produces.Injection need to use in hospital in addition, and patient compliance is poor.And the Cutis Bufonis extract oral formulations need be through the first pass effect of liver, and onset is slow, and the preparation bioavailability is lower.Using the Foradil Aerolizer formoterol fumarate of Cutis Bufonis extract mainly is for lung tumors, directly acts on affected part, does not have the first pass effect of liver simultaneously, rapid-action, and does not have above-mentioned untoward reaction, and new drug development is had great prospect.
2, because Cutis Bufonis extract is mixture, wherein contain indole alkaloids, cinobufagin, bufogenin etc., in practical operation, find, when the specific adjuvant that adds certain proportioning can overcome extract and is crushed to certain particle diameter and the reunion that the electrostatic interaction that produces, cohesiveness etc. cause reduces hygroscopicity.The applicant knows that through great many of experiments 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 Cutis Bufonis extract: get dry maxima skin and clean, add 10 times of water gagings, decoct 2 times, each 1.5 hours, merging filtrate, being concentrated into relative density is 1.1-1.2 (85 ℃), be cooled to 40 ℃, add ethanol precipitation, make to contain the alcohol amount and reach 60%, left standstill 24 hours, and got the supernatant Recycled ethanol to without alcohol flavor, concentrated solution adds ethanol to be made and contains the alcohol amount and reach 85%, left standstill 48 hours, and filtered, Recycled ethanol is to thick paste, 60 ℃ of dryings obtain Cutis Bufonis extract.
2, the preparation of inhalant: adopt comminution by gas stream to D Cutis Bufonis extract
50Below 5 microns, with particle diameter the lactose of 45-70 micron in mass ratio 1:10 mix, drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 2
1, the preparation of Cutis Bufonis extract: get dry maxima skin and clean, add 12 times of water gagings, decoct 2 times, each 2 hours, merging filtrate, being concentrated into relative density is 1.2-1.3 (85 ℃), be cooled to 40 ℃, add ethanol precipitation, make to contain the alcohol amount and reach 70%, left standstill 24 hours, and got the supernatant Recycled ethanol to without alcohol flavor, concentrated solution adds ethanol to be made and contains the alcohol amount and reach 85%, left standstill 48 hours, and filtered, Recycled ethanol is to distinguishing the flavor of without alcohol, spray drying obtains the Cutis Bufonis extract powder, powder D
50Below 5 microns.
2, the preparation of inhalant: with Cutis Bufonis extract powder, particle diameter the lactose of 45-80 micron, particle diameter the leucine of 20-50 micron in mass ratio the ratio of 10:100:1 mix, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 3
1, the preparation of Cutis Bufonis extract: get dry maxima skin and clean, add 30 times of water gagings, microwave-assisted extracts 3 times, and each 1 hour, merge extractive liquid,, through the ultrafilter membrane ultrafiltration of molecular weight 1000, the ultrafiltrate spray drying obtains the Cutis Bufonis extract powder, powder D
50Below 5 microns.
2, the preparation of inhalant: the Cutis Bufonis extract powder packets is packed in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 4
1, the ethanol preparation of Cutis Bufonis extract: get Cutis Bufonis and clean, add 12 times of amount 60%(W/W), reflux, extract, 2 times, each 2 hours, merge extractive liquid,, Recycled ethanol is to distinguish the flavor of deepfreeze 48 hours without alcohol, filter, the active carbon (W/V) of adding 0.3% boiled 30 minutes, filtered, spray drying obtains the Cutis Bufonis extract powder.
2, the preparation of inhalant: with Cutis Bufonis extract powder, lactose, mannitol, glycine, DLPC, lecithin, magnesium stearate in mass ratio the ratio of 1:5:5:2:0.5:0.5:0.1 mix, comminution by gas stream is to powder D
50Below 5 microns, drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 5
1, the preparation of Cutis Bufonis extract: get Cutis Bufonis and clean, the dehydrated alcohol that adds 20 times of amounts, reflux, extract, 2 times, each 1 hour, merge extractive liquid,, Recycled ethanol, ultrafilter membrane ultrafiltration through molecular weight 3000, ultrafiltrate vacuum concentration to proportion is 1.20 (45 ℃), and 50 ℃ of vacuum dryings of extractum obtain Cutis Bufonis extract.
2, the preparation of inhalant: Cutis Bufonis extract, lactose, cholesterol are mixed in the ratio of 1:8:1, and comminution by gas stream is to powder D
50Below 5 microns, drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 6
1, the preparation of Cutis Bufonis extract: get Cutis Bufonis and clean, add the 60%(W/W of 15 times of amounts) ethanol, reflux, extract, 3 times, each 1 hour, merge extractive liquid,, Recycled ethanol is to distinguishing the flavor of without alcohol, and it is heavy that concentrated solution adds 2 times of water gagings, left standstill 24 hours, high speed centrifugation is got supernatant and is obtained Cutis Bufonis extract.
2, the preparation of inhalant: lactose, polyethylene glycol 6000, the albumin with 5 times, 1 times, 2 times of contained solid qualities in the above-mentioned Cutis Bufonis extract adds in the Cutis Bufonis extract spray drying, powder D respectively
50Below 5 microns, drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 7
1, the preparation of Cutis Bufonis extract: get Cutis Bufonis and clean, add the 10%(W/W of 10 times of amounts) ethanol, reflux, extract, 2 times, each 1 hour, merge extractive liquid,, Recycled ethanol is to distinguishing the flavor of without alcohol, and the concentrated solution high speed centrifugation is got supernatant and is obtained Cutis Bufonis extract, spray drying obtains Cutis Bufonis extract, powder D
50Below 5 microns.
2, the preparation of inhalant: with Cutis Bufonis extract drug powder, particle diameter the mannitol of 10-90 micron, micronization silica gel in mass ratio the ratio of 10:89:1 mix, be packaged into behind the mix homogeneously in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 8
1, the preparation of Cutis Bufonis extract: get Cutis Bufonis and clean, add the 50%(W/W of 10 times of amounts) ethanol, reflux, extract, 2 times, each 1 hour, merge extractive liquid,, Recycled ethanol is to distinguish the flavor of the concentrated solution high speed centrifugation without alcohol, get supernatant and obtain Cutis Bufonis extract, spray drying obtains the Cutis Bufonis extract powder.
2, the preparation of inhalant: with Cutis Bufonis extract drug powder, mannitol, leucine in mass ratio the ratio of 10:100:3 mix, it is an amount of to add water after the mixing, spray drying obtains D
50Be 4.8 microns powder, mix with the rotary blender that polymer inner liner is arranged, make loose aggregate, the D of aggregate
50Be 390 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 9
1, the preparation of Cutis Bufonis extract: get Cutis Bufonis and clean, add the 40%(W/W of 10 times of amounts) ethanol, reflux, extract, 3 times, each 0.5 hour, merge extractive liquid,, Recycled ethanol is to distinguish the flavor of the concentrated solution high speed centrifugation without alcohol, get supernatant and obtain Cutis Bufonis extract, spray drying, powder D
50Below 5 microns.
2, the preparation of inhalant: with Cutis Bufonis extract powder, mannitol, leucine in mass ratio the ratio of 10:80:2 mix, mix with the rotary blender that polymer inner liner is arranged, make loose aggregate, the D of aggregate
50Be 120 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 10
1, the preparation of Cutis Bufonis extract: get dry maxima skin and clean, add 20 times of water gagings, decoct 2 times, each 2 hours, merging filtrate, being concentrated into relative density is 1.2-1.3 (85 ℃), be cooled to 40 ℃, add ethanol precipitation, make to contain the alcohol amount and reach 70%, left standstill 24 hours, and got the supernatant Recycled ethanol to without alcohol flavor, concentrated solution adds ethanol to be made and contains the alcohol amount and reach 85%, left standstill 48 hours, and filtered, Recycled ethanol is to distinguishing the flavor of without alcohol, spray drying, powder D
50Below 5 microns.
2, the preparation of inhalant: with Cutis Bufonis extract powder, happy InhaLac 70 lactose of German U.S. agent, micronization lactose (D
50=5.1 microns) in mass ratio the ratio of 5:90:5 mix, be packaged into behind the mix homogeneously in capsule or bubble-cap or the Diskus, obtain inhalant.
3, the inhalant pulmonary deposition ratio is investigated
Investigate according to People's Republic of China's version pharmacopeia in 2010 prescriptive procedure, with bufothionine content meter in the preparation, its pulmonary deposition ratio reaches 32.6%, places after 18 months under the room temperature condition, and the pulmonary deposition ratio of bufothionine does not have significant change in the preparation.
Embodiment 11
1, the preparation of Cutis Bufonis extract: get dry maxima skin and clean, add 20 times of water gagings, decoct 2 times, each 2 hours, merging filtrate, being concentrated into relative density is 1.2-1.3 (85 ℃), be cooled to 40 ℃, add ethanol precipitation, make to contain the alcohol amount and reach 70%, left standstill 24 hours, and got the supernatant Recycled ethanol to without alcohol flavor, concentrated solution adds ethanol to be made and contains the alcohol amount and reach 85%, left standstill 48 hours, and filtered, Recycled ethanol is to distinguishing the flavor of without alcohol, spray drying, powder D
50Below 5 microns.
2, the preparation of inhalant: with Cutis Bufonis extract powder, happy InhaLac 70 lactose of German U.S. agent, micronization lactose (D
50=4.9 microns) in mass ratio the ratio of 3:95:1 mix, be packaged into behind the mix homogeneously in capsule or bubble-cap or the Diskus, obtain inhalant.
3, the inhalant pulmonary deposition ratio is investigated
Investigate according to People's Republic of China's version pharmacopeia in 2010 prescriptive procedure, with bufothionine content meter in the preparation, its pulmonary deposition ratio reaches 30.2%, places after 18 months under the room temperature condition, and the pulmonary deposition ratio of bufothionine does not have significant change in the preparation.
Embodiment 12
1, the preparation of Cutis Bufonis extract: get dry maxima skin and clean, add 20 times of water gagings, decoct 2 times, each 2 hours, merging filtrate, being concentrated into relative density is 1.2-1.3 (85 ℃), be cooled to 40 ℃, add ethanol precipitation, make to contain the alcohol amount and reach 70%, left standstill 24 hours, and got the supernatant Recycled ethanol to without alcohol flavor, concentrated solution adds ethanol to be made and contains the alcohol amount and reach 85%, left standstill 48 hours, and filtered, Recycled ethanol is to distinguishing the flavor of without alcohol, spray drying, powder D
50Below 5 microns.
2, the preparation of inhalant: with Cutis Bufonis extract powder, happy InhaLac 70 lactose of German U.S. agent, micronization lactose (D
50=5.5 microns) in mass ratio the ratio of 3:77:11 mix, be packaged into behind the mix homogeneously in capsule or bubble-cap or the Diskus, obtain inhalant.
3, the inhalant pulmonary deposition ratio is investigated
Investigate according to People's Republic of China's version pharmacopeia in 2010 prescriptive procedure, with bufothionine content meter in the preparation, its pulmonary deposition ratio reaches 29.8%, places after 18 months under the room temperature condition, and the pulmonary deposition ratio of bufothionine does not have significant change in the preparation.
Embodiment 13
1, the preparation of Cutis Bufonis extract: get dry maxima skin and clean, add 10 times of water gagings, decoct 2 times, each 1 hour, merging filtrate, being concentrated into relative density is 1.3-1.4 (85 ℃), be cooled to 40 ℃, add ethanol precipitation, make to contain the alcohol amount and reach 60%, left standstill 48 hours, and got the supernatant Recycled ethanol to without alcohol flavor, concentrated solution adds ethanol to be made and contains the alcohol amount and reach 80%, left standstill 48 hours, and filtered, Recycled ethanol is to distinguishing the flavor of without alcohol, spray drying, powder D
50Below 5 microns.
2, the preparation of inhalant: Cutis Bufonis extract powder, leucine are mixed the D of granule after mixing in the ratio of 1:5
50Be 292 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 14
1, the preparation of Cutis Bufonis extract: get dry maxima skin and clean, add 6 times of water gagings, decoct 5 times, each 1 hour, merging filtrate, being concentrated into relative density is 1.05 (70 ℃), be cooled to 40 ℃, add ethanol precipitation, make to contain the alcohol amount and reach 65%, left standstill 48 hours, and got the supernatant Recycled ethanol to without alcohol flavor, concentrated solution adds ethanol to be made and contains the alcohol amount and reach 70%, left standstill 48 hours, and filtered, Recycled ethanol is to distinguishing the flavor of without alcohol, concentrating under reduced pressure, vacuum drying obtains Cutis Bufonis extract.
2, the preparation of inhalant: Cutis Bufonis 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 9 times of amounts
50Be 328 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 15
1, the preparation of Cutis Bufonis extract: get dry maxima skin and clean, add 30 times of water gagings, decocted 1 hour, it is 1.30 (60 ℃) that extracting solution is concentrated into relative density, is cooled to 20 ℃, adds the ethanol precipitation, make to contain alcohol amount and reach 70%, left standstill 24 hours, get the supernatant Recycled ethanol to without the alcohol flavor, concentrated solution adds ethanol to be made and contains alcohol amount and reach 90%, left standstill 48 hours, and filtered, Recycled ethanol is to distinguishing the flavor of without alcohol, concentrating under reduced pressure, vacuum drying obtains Cutis Bufonis extract.
2, the preparation of inhalant: with Cutis Bufonis 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 8 times of amounts, the magnesium stearate of 1 times of amount
50Be 653 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 16
1, the preparation of Cutis Bufonis extract: get Cutis Bufonis and clean, add 10 times of water gagings, decocted 1 hour, it is 1.20 (50 ℃) that extracting solution is concentrated into relative density, is cooled to room temperature, adds the ethanol precipitation, make to contain alcohol amount and reach 50%, left standstill 24 hours, get the supernatant Recycled ethanol to without the alcohol flavor, concentrated solution adds ethanol to be made and contains alcohol amount and reach 70%, left standstill 48 hours, and filtered, Recycled ethanol is to distinguishing the flavor of without alcohol, concentrating under reduced pressure, vacuum drying obtains Cutis Bufonis extract.
2, the preparation of inhalant: with the Cutis Bufonis 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 20 times of amounts
50Be 286 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 17
Obtain inhalant according to embodiment 1-16, carry out pharmacodynamic experiment, wherein drugs compared is HUACHANSU ZHUSHEYE (commercially available), Cutis Bufonis injection A and B, and Cutis Bufonis injection A and B prepare in accordance with the following methods:
Cutis Bufonis injection A:
Get dry maxima skin and clean, add 15 times of water gagings, decoct each 2 hours 2 times, merging filtrate, being concentrated into relative density is 1.2 (85 ℃), is cooled to 20 ℃, adds the ethanol precipitation, make to contain alcohol amount and reach 60%, left standstill 24 hours, get the supernatant Recycled ethanol to without the alcohol flavor, concentrated solution adds ethanol to be made and contains alcohol amount and reach 85%, leaves standstill 48 hours, filters, Recycled ethanol adds water to every milliliter and is equivalent to crude drug in whole 5g to without the alcohol flavor, regulates pH to 6.5,0.45 the micron membrane filtration, embedding, pressure sterilizing and get final product.
Cutis Bufonis injection B:
Get dry maxima skin and clean, add 20 times of amount 60% ethanol, reflux, extract, 2 times, each 2 hours, merge extractive liquid,, Recycled ethanol is to distinguishing the flavor of without alcohol, add 3 times of water gagings, deepfreeze 48 hours filters, the active carbon (W/V) of adding 0.3% boiled 30 minutes, filtered, add water to every milliliter and be equivalent to crude drug in whole 5g, regulate pH to 7,0.45 micron membrane filtration, embedding, pressure sterilizing and get final product.
Effect experiment:
The method of benzopyrene percutaneous puncture pulmonary injection is set up the induced lung animal model for tumour, gets 200 of modeling rats, is divided at random 20 groups, 10 every group.Every day 1 time, medication 7 days.Administering mode: 1-16 group is that the inhalant inhalation of embodiment 1-16, dosage are 15g crude drug/kg; The 17th group of lumbar injection HUACHANSU ZHUSHEYE (commercially available), dosage: 15g crude drug/kg; The 18th group of lumbar injection Cutis Bufonis injection A, dosage: 15g crude drug/kg; The 19th group of lumbar injection Cutis Bufonis injection B, dosage: 15g crude drug/kg; The 20th group is physiology saline control group, 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 10.5% that the pulmonary of rat of each group of inhalant administration the incidence rate of lump or nodular lesion occurs minimum, is up to 30.3%; HUACHANSU ZHUSHEYE group (commercially available) is 60.5%, Cutis Bufonis injection A group is 50.1%, Cutis Bufonis injection B group is 60.8%, the normal saline group is 100%, and each group of inhalant administration has significant difference (P＜0.05) with HUACHANSU ZHUSHEYE group (commercially available), Cutis Bufonis injection A group, Cutis Bufonis injection B group, normal saline group in the pulmonary lesion incidence rate.
Embodiment 18
Obtain inhalant according to embodiment 1-16, carry out pharmacodynamic experiment, wherein drugs compared is HUACHANSU ZHUSHEYE (commercially available), Cutis Bufonis injection A and B, and Cutis Bufonis injection A and B prepare in accordance with the following methods:
Cutis Bufonis injection A:
Get dry maxima skin and clean, add 15 times of water gagings, decoct each 2 hours 2 times, merging filtrate, being concentrated into relative density is 1.2 (85 ℃), is cooled to 20 ℃, adds the ethanol precipitation, make to contain alcohol amount and reach 60%, left standstill 24 hours, get the supernatant Recycled ethanol to without the alcohol flavor, concentrated solution adds ethanol to be made and contains alcohol amount and reach 85%, leaves standstill 48 hours, filters, Recycled ethanol adds water to every milliliter and is equivalent to crude drug in whole 5g to without the alcohol flavor, regulates pH to 6.5,0.45 the micron membrane filtration, embedding, pressure sterilizing and get final product.
Cutis Bufonis injection B:
Get dry maxima skin and clean, add 20 times of amount 60% ethanol, reflux, extract, 2 times, each 2 hours, merge extractive liquid,, Recycled ethanol is to distinguishing the flavor of without alcohol, add 3 times of water gagings, deepfreeze 48 hours filters, the active carbon (W/V) of adding 0.3% boiled 30 minutes, filtered, add water to every milliliter and be equivalent to crude drug in whole 5g, regulate pH to 7,0.45 micron membrane filtration, embedding, pressure sterilizing and get final product.
Effect 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 makes 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.30 mesh sieves were descended in the flushing of RPMI 1640 culture fluid, removed individual cells and too small piece of tissue, and part was descended 20 mesh sieves in the flushing of RPMI RPMI-1640 on the sieve, removed excessive piece of tissue.Get the lower part of screen and divide, after the 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 the 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 suspension or cell suspension 1mL.Under X-ray examination, No. 12 syringe needles are thrust in the rabbit inferior lobe of right lung, behind 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 the inoculation the 3rd day, and carry out layer wide, bed thickness be 5mm CT scan to chest every day, observed transfer case in tumor growth, the thoracic cavity.
5) rabbit VX2 original position lung cancer model is set up as a result rabbit all tumor growth in the lung, success ratio of inoculation 100%.
2, effect experiment:
Get successfully 200 of modeling rabbit, be divided at random 20 groups, 10 every group.Every day 1 time, medication 12 days.Administering mode: 1-16 group is the inhalant inhalation of embodiment 1-16, dosage: 15g crude drug/kg; The 17th group of lumbar injection HUACHANSU ZHUSHEYE (commercially available), dosage: 15g crude drug/kg; The 18th group of lumbar injection Cutis Bufonis injection A, dosage: 15g crude drug/kg; The 19th group of lumbar injection Cutis Bufonis injection B, dosage: 15g crude drug/kg; The 20th group is physiology saline control group, 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 the rabbit of each group of inhalant administration is 58.7%, is up to 64.3%; HUACHANSU ZHUSHEYE group (commercially available) is 56.3%, Cutis Bufonis injection A group is 45.1%, Cutis Bufonis injection B group is 48.9%, normal saline is to almost unrestraint effect of tumor, and each group of inhalant administration has significant difference (P＜0.05) with the tumour inhibiting rate of HUACHANSU ZHUSHEYE group (commercially available), Cutis Bufonis injection A group, Cutis Bufonis injection B group, normal saline group.
Claims (1)
1. Cutis Bufonis extract Foradil Aerolizer formoterol fumarate is characterized in that it is comprised of Cutis Bufonis extract and medically acceptable adjuvant;
Being prepared as of described Cutis Bufonis extract: get Cutis Bufonis and clean, the dehydrated alcohol that adds 20 times of amounts, reflux, extract, 2 times, each 1 hour, merge extractive liquid,, Recycled ethanol, ultrafilter membrane ultrafiltration through molecular weight 3000, ultrafiltrate vacuum concentration to 45 ℃ lower proportion is 1.20, and 50 ℃ of vacuum dryings of extractum obtain Cutis Bufonis extract;
Being prepared as of described inhalant: Cutis Bufonis extract, lactose, cholesterol are mixed in the ratio of 1:8:1, and comminution by gas stream is to powder D
50Below 5 microns, drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106432401A (en) * | 2016-09-20 | 2017-02-22 | 安徽华润金蟾药业股份有限公司 | Method for preparing cinobufagin through membrane separation |
| CN106518948A (en) * | 2016-09-20 | 2017-03-22 | 安徽华润金蟾药业股份有限公司 | Method for ultrasonic extraction of cinobufagin |
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| CN1813802A (en) * | 2005-02-04 | 2006-08-09 | 安徽金蟾生化股份有限公司 | Bufonid skin extract production process |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1813802A (en) * | 2005-02-04 | 2006-08-09 | 安徽金蟾生化股份有限公司 | Bufonid skin extract production process |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106432401A (en) * | 2016-09-20 | 2017-02-22 | 安徽华润金蟾药业股份有限公司 | Method for preparing cinobufagin through membrane separation |
| CN106518948A (en) * | 2016-09-20 | 2017-03-22 | 安徽华润金蟾药业股份有限公司 | Method for ultrasonic extraction of cinobufagin |
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