CN102247337B - Bufotalin dry powder inhalers and preparation method as well as application thereof - Google Patents
Bufotalin dry powder inhalers and preparation method as well as application thereof Download PDFInfo
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- CN102247337B CN102247337B CN 201110147785 CN201110147785A CN102247337B CN 102247337 B CN102247337 B CN 102247337B CN 201110147785 CN201110147785 CN 201110147785 CN 201110147785 A CN201110147785 A CN 201110147785A CN 102247337 B CN102247337 B CN 102247337B
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- Prior art keywords
- bufotalien
- lactose
- powder
- preparation
- dry powder
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Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention relates to dry powder inhalers, in particular to dry powder inhalers prepared from bufotalin, a preparation method of the dry powder inhalers and application of the dry powder inhalers to preparation of medicaments for treating lung tumor medicaments. The bufotalin dry powder inhalers are characterized by consisting of bufotalin and a medically acceptable auxiliary material according to the mass ratio of (1:0.05)-(1:115). The bufotalin is prepared into the dry powder inhalers which can directly act on a focus of lung, so that toxic or side reaction is reduced, bioavailability of the medicament is improved, the defects of slow response, hepatic first-pass effect, systemic toxic or side effect, low bioavailability and the like of an oral preparation can be overcome, meanwhile, the problems of inconvenience for use, poor compliance of a patient and the like of injection can also be solved. Thus, the method of preparing the bufotalin into the dry powder inhalers has broad prospect on development of new medicaments.
Description
Technical field:
The present invention relates to Foradil Aerolizer formoterol fumarate, specifically the preparation method of the Foradil Aerolizer formoterol fumarate made of bufotalien, described Foradil Aerolizer formoterol fumarate and the application in preparation treatment lung tumors medicine.
Background technology:
Bufotalien is the main effective ingredient in the Venenum Bufonis, belongs to the cardiac glycoside material, and white crystals is liposoluble substance, and molecular formula is: C
26H
36O
6, have antitumor, analgesia heart tonifying, antiinflammatory and strengthen the pharmacological actions such as immune.Oral liquid, the tablet that contains at present bufotalien has been applied to clinical, and hepatocarcinoma, pulmonary carcinoma, gastric cancer etc. are had preferably curative effect.Bufotalien toxicity is larger, can produce the toxic and side effects of general after oral, and because the first pass effect of liver be unfavorable for drug accumulation in tumor locus, so onset is slow, the bioavailability of preparation is lower.
Lung has great surface area and abundant blood vessel, 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.
Employing can directly act on bufotalien the focus of pulmonary carcinoma through the inhalant of lung administering mode, can improve bufotalien to the curative effect of pulmonary carcinoma and reduce the toxic and side effects of its normal tissue.Have no at present the research report of the bufotalien Foradil Aerolizer formoterol fumarate with resisting tumor of lung effect.
Summary of the invention:
Goal of the invention: an object of the present invention is to provide pulmonary's dry powder inhaler formulations of bufotalien 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 bufotalien Foradil Aerolizer formoterol fumarate is characterized in that it is comprised of bufotalien and medically acceptable adjuvant, and the mass ratio of bufotalien and described adjuvant is 1: 0.05-1: 115.
Described bufotalien Foradil Aerolizer formoterol fumarate is characterized in that it is to add the suction powder that adjuvant is made by bufotalien, and the particle diameter of powder is with D
50Meter is between the 0.5-1000 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 75-225 micron, micronization lactose mean diameter is at the 1-5 micron, the mass ratio of lactose granule and micronization lactose is 1000: 1-3: 1, and most preferred mode is that the mass ratio of lactose granule and micronization lactose is 100: 1-12: 1.
Described bufotalien Foradil Aerolizer formoterol fumarate, its preparation process is as follows:
Bufotalien 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 bufotalien 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 bufotalien 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 bufotalien Foradil Aerolizer formoterol fumarate, its preparation process is as follows:
Bufotalien 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 bufotalien Foradil Aerolizer formoterol fumarate in preparation lung tumors medicine.
Beneficial effect:
1, lung has great surface area and abundant blood capillary, 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, patient dependence is high, absorptions is rapid, without liver first, rapid release and the targeting characteristics of locating, be a kind of novel drug-supplying system.Existing Foradil Aerolizer formoterol fumarate is multiplex in the infection for the treatment of respiratory tract and pulmonary, has no the treatment for lung tumors.Simultaneously, the research that has a bufotalien Foradil Aerolizer formoterol fumarate of resisting tumor of lung effect also has no report.Oral liquid, the tablet that contains at present bufotalien has been applied to clinical, and hepatocarcinoma, pulmonary carcinoma, gastric cancer etc. are had preferably curative effect, and antitumor activity in vitro shows that its tumor control rate of preparation that contains bufotalien is 26.3-69%.Bufotalien is made Foradil Aerolizer formoterol fumarate, can directly act on pulmonary lesions, there is not simultaneously liver first-pass effect, can improve the bioavailability of medicine, reduce the generation of toxicity, overcome medicine made oral formulations after, need through liver first-pass effect, the shortcomings such as onset is slow, and the toxic and side effects of general is arranged, and the preparation bioavailability is lower.Therefore bufotalien is made Foradil Aerolizer formoterol fumarate, new drug development is had very big prospect.
2, in order to reach the granularity requirements of Foradil Aerolizer formoterol fumarate, need bufotalien is pulverized, find in the practical operation, when being crushed to certain particle size, bufotalien is easy to reunite because electrostatic interaction, cohesiveness etc. between the powder affect medicine, therefore need to carry out proportioning with adjuvant, overcome the problem that medicine is reunited, the applicant is known through great many of experiments, bufotalien 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 bufotalien
50Below=6 microns, mix at 1: 9 in mass ratio with the lactose of particle diameter at the 75-100 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 bufotalien
50=4 microns, mix in 10: 90: 1 ratio at the leucine of 45-65 micron with lactose, the particle diameter of particle diameter at the 75-90 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 bufotalien
50=4 microns, mix in 1: 9 ratio with the leucine of particle diameter 75-125 micron, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 4
The preparation of inhalant: with bufotalien powder, lactose, mannitol, glycine, DLPC, lecithin, magnesium stearate in 1: 3: 4: 3: 0.5: 0.5: 0.3 ratio was mixed, and comminution by gas stream is to powder D
50=6 microns, drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 5
The preparation of inhalant: with the bufotalien comminution by gas stream to powder D
50=5 microns are mixed in 1: 9: 1 ratio with lactose, cholesterol, and drug powder is packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 6
The preparation of inhalant: in bufotalien, add respectively lactose, polyethylene glycol 6000, the albumin of 5 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: bufotalien drug powder, the particle diameter of mean diameter at the 5-10 micron mixed in 7: 80: 12 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: bufotalien drug powder, mannitol, leucine are mixed in 8: 95: 7 ratio, and it is an amount of to add water after the mixing, and spray drying obtains D
50Be 5.0 microns powder, adding mean diameter is the lactose granule mixing of 125-200 micron, is packaged in capsule or bubble-cap or the Diskus, obtains inhalant.
Embodiment 9
The preparation of inhalant: bufotalien powder, mannitol, glycine are mixed in 9: 95: 6 ratio, and it is an amount of to add water after the mixing, and spray drying obtains D
50Be 6.0 microns powder, adding mean diameter is the lactose granule mixing of 80-100 micron, is packaged in capsule or bubble-cap or the Diskus, obtains inhalant.
Embodiment 10
1, the preparation of inhalant: with bufotalien powder (D
50=7.3 microns), German U.S. agent is happy
70 lactose, micronization lactose (D
50=4.5 microns) mix in 2: 60: 4 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 bufotalien reaches 25.1%, places after 18 months under the room temperature condition, and the pulmonary deposition ratio of bufotalien does not have significant change.
Embodiment 11
1, the preparation of inhalant: with bufotalien powder (D
50=6.5 microns), German U.S. agent is happy
70 lactose, micronization lactose (D
50=5.5 microns) mix in 12: 87: 2 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 bufotalien reaches 26.2%, places after 18 months under the room temperature condition, and the pulmonary deposition ratio of bufotalien does not have significant change.
Embodiment 12
1, the preparation of inhalant: with bufotalien powder (D
50=6.3 microns), German U.S. agent is happy
70 lactose, micronization lactose (D
50=4.4 microns) mix in 4: 98: 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 bufotalien reaches 22.7%, places after 18 months under the room temperature condition, and the pulmonary deposition ratio of bufotalien does not have significant change.
Embodiment 13
The preparation of inhalant: with bufotalien powder (D
50=7.0 microns), leucine (D
50=245 microns) mix the D of granule after mixing in 1: 10 ratio
50Be 256 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 14
The preparation of inhalant: bufotalien is mixed comminution by gas stream, powder D with leucine in 1: 1 ratio
50Below 5 microns, this powder is mixed again the D of granule after mixing with the mannitol of 9 times of amounts
50Be 289 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 15
The preparation of inhalant: bufotalien is mixed comminution by gas stream, powder D with poloxamer in 5: 1 ratio
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 553 microns, be packaged in capsule or bubble-cap or the Diskus, obtain inhalant.
Embodiment 16
The preparation of inhalant: with the bufotalien comminution by gas stream, powder D
50=4 microns, this powder is mixed again the D of granule after mixing with the lactose granule of 13 times of amounts
50Be 254 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 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 0.5mg bufotalien/kg; The 17th group of gavage gives bufotalien, and dosage is 0.5mg bufotalien/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 22% that the pulmonary of rat of each group of inhalant administration the incidence rate of lump or nodular lesion occurs minimum, is up to 37%; Bufotalien gavage group is 59%, and the normal saline group is 100%, and each group of inhalant administration has significant difference (P＜0.05) with bufotalien 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 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 0.5mg bufotalien/kg; The 17th group of gavage gives bufotalien, and dosage is 0.5mg bufotalien/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 42.1%, is up to 60.2%; The tumour inhibiting rate of bufotalien gavage group is 31.7%, and normal saline does not almost have inhibition to tumor, and each group of inhalant administration has significant difference (P＜0.05) with the tumour inhibiting rate of bufotalien gavage group, normal saline group.
Claims (5)
1. a bufotalien Foradil Aerolizer formoterol fumarate is characterized in that it is by D
50Be that 7.3 microns bufotalien powder, German U.S. agent are happy
70 lactose, D
50The micronization lactose that is 4.5 microns forms, and three's ratio is 2: 60: 4.
2. a bufotalien Foradil Aerolizer formoterol fumarate is characterized in that it is by D
50Be that 6.5 microns bufotalien powder, German U.S. agent are happy
70 lactose, D
50The micronization lactose that is 5.5 microns forms, and three's ratio is 12: 87: 2.
3. a bufotalien Foradil Aerolizer formoterol fumarate is characterized in that it is by D
50Be that 6.3 microns bufotalien powder, German U.S. agent are happy
70 lactose, D
50The micronization lactose that is 4.4 microns forms, and three's ratio is 4: 98: 1.
4. method for preparing claim 1 or 2 or 3 described a kind of bufotalien Foradil Aerolizer formoterol fumarates, its preparation process is as follows: bufotalien 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 bufotalien Foradil Aerolizer formoterol fumarate of 3 in preparation treatment lung tumors medicine.
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| CN101785777A (en) * | 2010-03-30 | 2010-07-28 | 上海现代药物制剂工程研究中心有限公司 | Application of bufotalin std. in preparing medicament for treating lung tumors |
| CN101822832A (en) * | 2010-04-16 | 2010-09-08 | 马宏跃 | Composition with anti-tumor effect and application thereof in preparing medicament for treating tumor |
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