CN102247336B - Bufothionine dry powder inhaler, and its preparation method and application - Google Patents
Bufothionine dry powder inhaler, and its preparation method and application Download PDFInfo
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Abstract
The invention relates to a dry powder inhaler, more specifically to a dry powder inhaler prepared by bufothionine, and relates to a preparation method for the drypowder inhaler and application of the dry powder inhaler in preparing medicines for treating tumors of lung. The bufothionine dry powder inhaler is characterized by comprising bufothionine and medically acceptable accessories, wherein the mass ratio of bufothionine to the accessories is in a range of 1:0.01 to 1:100. The application of bufothionine dry powder inhaler is mainly directed at tumors of lung, can directly act on an affected part and is free of first pass effect of liver, thereby reducing adverse reactions and having a great prospect in developing new medicines.
Description
Technical field:
The present invention relates to Foradil Aerolizer formoterol fumarate, specifically the preparation method of the Foradil Aerolizer formoterol fumarate made of bufothionine, described Foradil Aerolizer formoterol fumarate and the application in preparation treatment lung tumors medicine.
Background technology:
Cutis Bufonis is the dry skin of Bufonidae animal Bufo siccus Bufobufo gargarizans Cantor, effect with heat-clearing and toxic substances removing, diuretic relieving distension, the Cutis Bufonis water soluble part mainly contains bufothionine, N-phenyl-ethylnaphthalene amine, amino acids, and wherein bufothionine is one of its main component.Bufothionine is colourless acicular crystal, and its molecular formula is C
12H
14N
2O
4S is water miscible indole alkaloids in the Cutis Bufonis, and antitumor activity in vitro shows that the bufothionine tumor control rate is 87.06%.Water soluble ingredient is the existing a plurality of listings of the medicine of main exploitation in the Cutis Bufonis, and cinobufacin injection, oral liquid, tablet have been applied to clinically at present, and hepatocarcinoma, pulmonary carcinoma, gastric cancer etc. are had preferably effect.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 reason of generation may be that the cardiac toxicity that bufotalin a small amount of in the cinobufacin produces causes; 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.Bufothionine is one of effective ingredient of cinobufacin injection and oral formulations, but the content in existing injection and oral formulations is lower, and above-mentioned preparation can not directly act on lesions position, bufothionine can not be performed to maximum to the inhibitory action of tumor.
Pulmonary is the open organ of body, 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, dies from that pulmonary carcinoma ranks first in the male patient of carninomatosis.Current antitumor drug great majority all are drug administration by injection, and this whole body administering mode causes the curative effect of medicine to reduce so that the targeting of medicine reduces, and untoward reaction increases.
Adopt site-specific delivery of drugs antitumor drug to be transported to the tumor patient part of human body, medicine is improved in the concentration of patient part, can reduce the therapeutic effect of the dosage of medicine, the toxic and side effects that reduces medicine, raising medicine, have great clinical value.Employing can directly be transmitted medicine the focus of pulmonary carcinoma through the inhalant of lung administering mode, is conducive to improve medicine to the curative effect of pulmonary carcinoma and reduces the toxic and side effects of its normal tissue.Through patent and non-patent literature retrieval both at home and abroad, have no the report of relevant this project like product.
Summary of the invention:
Goal of the invention: an object of the present invention is to provide pulmonary's dry powder inhaler formulations of bufothionine 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 bufothionine Foradil Aerolizer formoterol fumarate is characterized in that it is comprised of bufothionine and medically acceptable adjuvant, and the mass ratio of bufothionine and described adjuvant is 1: 0.01-1: 100.
Described bufothionine Foradil Aerolizer formoterol fumarate is characterized in that it is to add the suction powder that adjuvant is made by bufothionine, and the particle diameter of powder is with D
50Meter is between the 0.1-1000 micron.
Described adjuvant is selected one or more mixture in sugar, alcohol, aminoacid, phospholipid, surfactant, cyclodextrin, biodegradable 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 that described adjuvant is the mixture of different-grain diameter lactose, preferred mode is that described adjuvant is for sucking the mixture with lactose granule and micronization lactose, wherein the lactose granule mean diameter is at the 30-250 micron, micronization lactose mean diameter is at the 1-10 micron, the mass ratio of lactose granule and micronization lactose is 1000: 1-1: 1, and most preferred mode is that the mass ratio of lactose granule and micronization lactose is 100: 1-5: 1.
Described bufothionine Foradil Aerolizer formoterol fumarate, its preparation process is as follows:
Bufothionine 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 bufothionine 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 bufothionine 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.
Preferred bufothionine Foradil Aerolizer formoterol fumarate, its preparation process is as follows:
Bufothionine by pulverizing or spray drying is made powder, is made suction with the mixture mix homogeneously of the lactose of different-grain diameter or lactose granule and micronization lactose and used powder, be packaged in capsule or bubble-cap or the Diskus.
The application of described bufothionine Foradil Aerolizer formoterol fumarate in preparation lung tumors medicine.
Beneficial effect:
1, pulmonary is the open organ of body, 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.Multiplex in the infection for the treatment of respiratory tract and pulmonary about Foradil Aerolizer formoterol fumarate at present, but have no report for the Foradil Aerolizer formoterol fumarate of lung tumors treatment.Simultaneously, through patent and non-patent literature retrieval both at home and abroad, have no the report of relevant this project like product.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 that the cardiac toxicity that bufotalin a small amount of in the cinobufacin produces causes.In addition, injection need to use in hospital, and patient compliance is poor.And oral formulations need be through the first pass effect of liver, and onset is slow, and the preparation bioavailability is lower.Bufothionine is one of effective ingredient of cinobufacin injection and oral formulations, but the content in injection and oral formulations is lower, and above-mentioned preparation can not directly act on lesions position, bufothionine can not be performed to maximum to the inhibitory action of tumor.And the dry powder inhaler formulations of bufothionine can directly act on affected part for lung tumors, and does not have the first pass effect of liver, does not have above-mentioned untoward reaction, so its new drug development has very big prospect.
2, bufothionine needs to be mixed into Foradil Aerolizer formoterol fumarate with adjuvant, find in the practical operation, because bufothionine is water soluble ingredient, easily moisture absorption, when bufothionine is crushed to certain particle size because of electrostatic interaction between the powder, cohesivenesss etc. affect medicine and are easy to reunite, and because surface area increases, hygroscopicity strengthens, therefore need to carry out proportioning with adjuvant, overcome the problem of moisture absorption caking, the applicant knows that through great many of experiments bufothionine and ratio of adjuvant are controlled in the particular range, and particularly adjuvant selects the mixture of lactose granule and micronization lactose 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
The preparation of inhalant: adopt comminution by gas stream to D bufothionine
90=5 microns, mix at 1: 8 in mass ratio with the lactose of particle diameter at the 45-100 micron, drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 2
The preparation of inhalant: adopt comminution by gas stream to D bufothionine
90=5 microns, mix in 10: 80: 1 ratio at the leucine of 30-55 micron with lactose, the particle diameter of particle diameter at the 45-110 micron, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 3
The preparation of inhalant: adopt comminution by gas stream to D bufothionine
90=7 microns, mix in 1: 8 ratio with the leucine of particle diameter 50-165 micron, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 4
The preparation of inhalant: with bufothionine powder, lactose, mannitol, glycine, DLPC, lecithin, magnesium stearate in 1: 5: 5: 3: 0.5: 0.5: 0.1 ratio was mixed, and comminution by gas stream is to powder D
50=8 microns, drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 5
The preparation of inhalant: bufothionine, lactose, cholesterol are mixed in 1: 10: 1 ratio, and comminution by gas stream is to powder D
50=7 microns, drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 6
The preparation of inhalant: in bufothionine, add respectively lactose, polyethylene glycol 6000, the albumin of 4 times, 2 times, 3 times of quality, spray drying, powder D
50=8 microns, drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 7
The preparation of inhalant: bufothionine drug powder, the particle diameter of mean diameter at the 5-10 micron mixed in 10: 85: 5 ratio at mannitol, the micronization silica gel of 5-100 micron, be packaged into behind the mix homogeneously in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 8
The preparation of inhalant: bufothionine drug powder, mannitol, leucine are mixed in 10: 90: 3 ratio, and it is an amount of to add water after the mixing, and spray drying obtains D
50Be 4.5 microns powder, with mean diameter be the lactose granule mixing of 125-150 micron, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 9
The preparation of inhalant: bufothionine powder, mannitol, glycine are mixed in 10: 100: 3 ratio, and it is an amount of to add water after the mixing, and spray drying obtains D
50Be 6.8 microns powder, with mean diameter be the lactose granule mixing of 75-125 micron, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 10
1, the preparation of inhalant: with bufothionine powder (D
90=6.7 microns), German U.S. agent is happy
70 lactose, micronization lactose (D
90=5.1 microns) mix in 6: 90: 5 ratio, be packaged into behind the mix homogeneously in capsule or bubble-cap or the Diskus, obtain inhalant.
2, the inhalant pulmonary deposition ratio is investigated
Investigate according to People's Republic of China's version pharmacopeia in 2010 prescriptive procedure, the pulmonary deposition ratio of bufothionine reaches 31.4%, places after 18 months under the room temperature condition, and the pulmonary deposition ratio of bufothionine does not have significant change.
Embodiment 11
1, the preparation of inhalant: with bufothionine powder (D
90=6.2 microns), German U.S. agent is happy
70 lactose, micronization lactose (D
90=5.8 microns) mix in 3: 72: 1 ratio, be packaged into behind the mix homogeneously in capsule or bubble-cap or the Diskus, obtain inhalant.
2, the inhalant pulmonary deposition ratio is investigated
Investigate according to People's Republic of China's version pharmacopeia in 2010 prescriptive procedure, the pulmonary deposition ratio of bufothionine reaches 28.5%, places after 18 months under the room temperature condition, and the pulmonary deposition ratio of bufothionine does not have significant change.
Embodiment 12
1, the preparation of inhalant: with bufothionine powder (D
90=6.5 microns), German U.S. agent is happy
70 lactose, micronization lactose (D
90=5.4 microns) mix in 1: 65: 13 ratio, be packaged into behind the mix homogeneously in capsule or bubble-cap or the Diskus, obtain inhalant.
2, the inhalant pulmonary deposition ratio is investigated
Investigate according to People's Republic of China's version pharmacopeia in 2010 prescriptive procedure, the pulmonary deposition ratio of bufothionine reaches 29.4%, places after 18 months under the room temperature condition, and the pulmonary deposition ratio of bufothionine does not have significant change.
Embodiment 13
The preparation of inhalant: with bufothionine powder (D
50=5.5 microns), leucine (D
50=215 microns) mix the D of granule after mixing in 1: 8 ratio
50Be 225 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 14
The preparation of inhalant: bufothionine is mixed comminution by gas stream, powder D with leucine in 1: 1 ratio
90Below 5 microns, this powder is mixed again the D of granule after mixing with the mannitol of 8 times of amounts
50Be 279 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 15
The preparation of inhalant: bufothionine is mixed comminution by gas stream, powder D with poloxamer in 8: 1 ratio
90Below 8 microns, this powder is mixed again the D of granule after mixing with the lactose granule of 10 times of amounts, the magnesium stearate of 1 times of amount
50Be 301 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 16
The preparation of inhalant: with the bufothionine comminution by gas stream, powder D
90=6 microns, this powder is mixed again the D of granule after mixing with the lactose granule of 15 times of amounts
50Be 75 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.
Effect experiment:
The method of benzopyrene percutaneous puncture pulmonary injection is set up the induced lung animal model for tumour, gets 190 of modeling rats, is divided at random 19 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 1mg bufothionine/kg; The 17th group of lumbar injection bufothionine, dosage is 1mg bufothionine/kg; The 18th group of gavage gives bufothionine, and dosage is 1mg bufothionine/kg; The 19th 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 15% that the pulmonary of rat of each group of inhalant administration the incidence rate of lump or nodular lesion occurs minimum, is up to 35%; Bufothionine injection group is 55%, bufothionine gavage group is 65%, the normal saline group is 100%, and each group of inhalant administration has significant difference (P＜0.05) with bufothionine injection group, bufothionine gavage group, normal saline group in 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 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 RPMI-1640, 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, pharmacodynamic experiment
Get successfully 190 of modeling rabbit, be divided at random 19 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 1mg bufothionine/kg; The 17th group of lumbar injection bufothionine, dosage is 1mg bufothionine/kg; The 18th group of gavage gives bufothionine, and dosage is 1mg bufothionine/kg; The 19th 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, and calculates tumour inhibiting rate.
Experimental result: the tumour inhibiting rate minimum of each group of inhalant administration is 55.9%, is up to 65.9%; The tumour inhibiting rate of bufothionine injection group is 48.7%, the tumour inhibiting rate of bufothionine gavage group is 28.6%, without obvious inhibition, each group of inhalant administration has significant difference (P＜0.05) with the tumour inhibiting rate of bufothionine injection group, bufothionine gavage group, normal saline group to the normal saline group to tumor.
Claims (5)
1. a bufothionine Foradil Aerolizer formoterol fumarate is characterized in that it is by D
50Be that 6.7 microns bufothionine powder, German U.S. agent are happy
70 lactose, D
50The micronization lactose that is 5.1 microns forms, and three's ratio is 6: 90: 5.
2. a bufothionine Foradil Aerolizer formoterol fumarate is characterized in that it is by D
50Be that 6.2 microns bufothionine powder, German U.S. agent are happy
70 lactose, D
50The micronization lactose that is 5.8 microns forms, and three's ratio is 3: 72: 1.
3. a bufothionine Foradil Aerolizer formoterol fumarate is characterized in that it is by D
50Be that 6.5 microns bufothionine powder, German U.S. agent are happy
70 lactose, D
50The micronization lactose that is 5.4 microns forms, and three's ratio is 1: 65: 13.
4. method for preparing claim 1 or 2 or 3 described a kind of bufothionine Foradil Aerolizer formoterol fumarates, its preparation process is as follows: bufothionine is made powder by pulverizing or spray drying, make suction with the mixture mix homogeneously of lactose granule and micronization lactose and use powder, be packaged in capsule or bubble-cap or the Diskus.
5. according to claim 1 and 2 or the application of a kind of bufothionine Foradil Aerolizer formoterol fumarate of 3 in preparation treatment lung tumors medicine.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US9763965B2 (en) | 2012-04-13 | 2017-09-19 | Glaxosmithkline Intellectual Property Development Limited | Aggregate particles |
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| CN1068043A (en) * | 1991-06-22 | 1993-01-20 | 吴玉琢 | A kind of method and special implement thereof that extracts Venenum Bufonis |
| CN101176739A (en) * | 2006-11-08 | 2008-05-14 | 山东绿叶制药有限公司 | Toadpoison ligand extract as well as preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US9763965B2 (en) | 2012-04-13 | 2017-09-19 | Glaxosmithkline Intellectual Property Development Limited | Aggregate particles |
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