CN107441101A - The purposes and powder spray and preparation method of ibandronate - Google Patents

Abstract

The present invention provides the new application of ibandronate and the novel form for inhalation.The ibandronate of described inhalation, including two kinds of modes such as powder spray and atomized drop, it is characterised in that granularity≤7 μm, can include or not comprising auxiliary material.The ibandronate of the inhalation of the present invention, it can directly be played in respiratory tract and promote air flue diastole, anti-inflammatory and pathology improvement result, available for treatment COPD and/or the purposes of asthma, the PFT of COPD mouse can be significantly improved, its airway resistance about 40% is reduced, strengthens its pulmonary dynamic compliance about 90%.

Description

The purposes and powder spray and preparation method of ibandronate

Technical field

The invention belongs to materia medica and galenic pharmacy field, is related to the ibandronate for inhalation, its preparation method And purposes.

Background technology

Ibandronate (Ibandronate sodium, IBA), its chemical name be 1- hydroxyls -3- (methyl amyl amine) - Propane -1,1- disodium phosphonate, molecular formula C9H22NO7P2Na, molecular weight 341.21；It is conventional containing 1 molecular water, point Minor is C9H22NNaO7P2H2O, molecular weight 359.23, is that a kind of biphosphonates bone information of third generation suppresses Agent.U.S. FDA ratifies the preventing and treating for osteoporosis after women's menopause within 2003, in the trade name of American market BONIVA, Chinese name are Bang Luoli, there is 2 kinds of formulations of oral tablet and intravenous fluid.Clinical dosage be oral about 150mg/ pieces/ Month, intravenous injection is 3mg/3 months.The Mean absolute oral bioavilability of ibandronate piece is about 0.6%, by with Bone hydroxyapatite with reference to and suppress osteoclastic activity, the re-absorption of sclerotin and degraded.The side effect of ibandronate is more, bag Including can cause upper digestive tract disorderly, show as dysphagia, esophagitis, esophagus or gastric ulcer, can also cause diarrhoea, stomachache, Nausea, constipation etc., other as hypocalcemia, mineral metabolism obstacle, flu syndrome, headache, dizziness, fash, arthralgia, Lower jaw osteonecrosis etc..

COPD (referred to as " chronic obstructive pulmonary disease " or " COPD "), is characterized by not fully reversible flow limitation Chronic lung disease, clinically often show as the symptoms such as the cough, expectoration, expiratory dyspnea of recurrent exerbation, typically exhibit out The characteristics of row is in progress, includes most chronic bronchitis and pulmonary emphysema.As disease develops, cause airway remodeling, Irreversibility airflow obstruction finally is developed into, or overlapping with asthma generation coexists.Asthma (full name：Bronchial astehma) it is a kind of slow Property respiratory tract disease, it is narrow to be divided into acute bronchus for flow limitation usually as caused by airway inflammation, cause to stridulate, be uncomfortable in chest, Expiratory dyspnea, the recurrent exerbation of cough.Serious threat the health of the public in the world for chronic obstructive pulmonary disease and asthma.The whole world at present Existing 2.1 hundred million patients with COPD and about 300,000,000 asthmatic patients.Chronic obstructive pulmonary disease and asthmatic patient China respectively reach 40,000,000 people and 30000000 people.The epidemiology survey result presided over by Zhong Nanshan academician shows that Chinese chronic obstructive pulmonary disease is overall ill at present Rate is 8.2%, and wherein male's illness rate is 12.4%, and women illness rate is 5.1%.Estimate according to the World Health Organization, in society Under the influence of environment and treatment delay, chronic obstructive pulmonary disease will be one of Etiological of mankind's disablement.Chronic obstructive pulmonary disease is in the whole world In disease death reason, heart disease, cerebrovascular disease and acute pulmonary infection are only second to, 4th arranged side by side together with AIDS.It is and dead Die rate increases year by year, because the dead number of chronic obstructive pulmonary disease just reached 3,000,000 in 2004.

Chronic obstructive pulmonary disease and asthma are known as the characteristics of medical expenses are high due to needing medication daily throughout one's life and periodically standby medicine.Branch gas Pipe diastole agent is the choice drug of chronic obstructive pulmonary disease and treating asthma.Chinese market estimation at present is 10,000,000,000 yuan.It is expected that keep about 20% Annual growth.Anticholinergic preparation (including Tiotropium Bromide Tiotropium Bromide etc.) and broxaterol (including Salbutamol Salbutamol, salmeterol Salmeterol etc.) be current institute's has age chronic obstructive pulmonary disease preferred bronchodilatation Agent (version diagnosis of chronic obstructive pulmonary disease in 2017, treats and prevents global strategy, GOLD2017).With increasing a certain branch gas The dosage of pipe diastole agent is compared, and different bronchodilators, which are used in combination, can improve drug effect and reduce corresponding side effect. Inhaled is asthma and the most frequently used anti-inflammatory drug of chronic obstructive pulmonary disease.Asthma is than chronic obstructive pulmonary disease to bronchodilators (branch gas Enlargement of pipe agent) and the reaction of inhaled become apparent.Essential difference be present in asthma and the inflammatory mechanisms of chronic obstructive pulmonary disease： Eosinophil is the main airway inflammation cell of asthma, and then main airway inflammation cell is that neutral grain is thin in chronic obstructive pulmonary disease Born of the same parents and macrophage, this be the anti-inflammatory drug effect of glucocorticoid it is obvious for asthma and for chronic obstructive pulmonary disease then unconspicuous reason. GOLD2017 recommends severe and pole severe patients with COPD that long-acting bronchodilators and inhaled are used in combination, but Slight and moderate patients with COPD inhaled is not advocated, does not advocate that the patients with COPD of any degree individually sucks yet Glucocorticoid treatment, reason are not only to improve unobvious to symptom, there is the risk for inducing pneumonia on the contrary.Therefore, chronic obstructive pulmonary disease is controlled Treatment field lacks the anti-inflammatory drug that can effectively improve pathological condition at present.The root of chronic obstructive pulmonary disease is inflammation, patient symptom it is serious Degree mainly also suffers from the influence of inflammatory pathologies factor, related to the degree of flow limitation not always necessarily, sucks branch gas Pipe diastole agent energy relief of airflow obstruction symptom, but the effect of anti-inflammatory drug can not be substituted.Meanwhile patient needs long-term prescription, The low side effect of medicine is also extremely important for improving patients ' life quality.The low anti-inflammatory drug of development good effect, side effect, from Fundamentally improve the pathological condition of patient lungs, be the important development direction of chronic obstructive pulmonary disease treatment, there is very big development space.

Ibandronate is reported without for the research with the incoherent respiratory disease treatment use of sclerotin at present, she Class's Alendronate is also reported without the research of inhalant dosage form such as powder spray or atomized drop.

The content of the invention

The present invention is in order to overcome at least one deficiency of prior art, there is provided new therapeutical uses of ibandronate and new Formulation, by way of powder spray or atomized drop, ibandronate is directly conveyed be deposited on respiratory tract play bronchus relax Open and anti-inflammatory emphysema effect.

To achieve these goals, the present inventor has done numerous studies and practical work, and the specific present invention adopts With following technical scheme：

The invention provides a kind of purposes of ibandronate in COPD and asthma medications.

Further, the ibandronate uses inhalation.

In the formulation of Pulmonary inhalation, the simple production process of powder spray, drugloading rate is big, easy to use -- can it is portable from Exercise and use, be the inhalant dosage form of current main flow.Atomized drop inhalation using powder spray/Diskus for being had difficulties Patient be probably then more preferably to select.This some patients is including getting old and weak, inspiratory flow rate is relatively low, and disease condition is heavier, or Infant etc..Therefore, the preparation method of ibandronate inhalation provided by the invention and the realization way of new therapeutical uses Footpath includes 2 kinds of modes such as powder spray and atomized drop.

The preparation method of described ibandronate inhalation, it by comminuting method can also be dry by spraying that can be Dry method is prepared into powder spray., can be only using her satisfactory class's phosphine of purity in crushing and processing or spray drying process Sour sodium raw materials medicine, auxiliary material, such as lactose, leucine, ammonium hydrogen carbonate can also be added simultaneously.According to the designed use of powder spray, The size distribution of medicinal powder, dissolubility, heap density, angle of repose, atomization, moisture absorption change reach curative effect and must take into consideration. Particle is in respiratory tract sedimentary characteristic：5 μm~20 μm are mainly deposited on trachea-bronchial epithelial cell and tiny bronchus, and≤5 μm can enter Tiny bronchus and alveolar deposit.The administration target of conventional use of powder spray is into alveolar subsequently into blood, and Medicinal powder will pass through considerably long one section of moist respiratory tracts such as trachea-bronchial epithelial cell from oral cavity to lung, and granularity is more than 2.5 μm Particle is easy to be deposited in respiratory tract and can not enter alveolar, therefore granularity (d90) need to be typically controlled below 5 μm, and Be frequently necessary to from good water solubility, excitant is small, good biocompatibility auxiliary material, so that drug diffusion enters alveolar, reduction With avoid the deposition in respiratory tract.These auxiliary materials such as surfactant etc., it is long-term use of, infringement may be produced to lung. It is contemplated that occur to the cardinal symptom of chronic obstructive pulmonary disease and asthma in small airway and the alveolar regions such as bronchus, tiny bronchus, grain Bronchus, tiny bronchus and alveolar can be deposited on by spending moderate and covering certain particle size scope (2.5 μm~10 μm) medicinal powder Effect is directly played, therefore, the fineness ratio of powder spray and atomized drop is relatively adapted to control in 2.5 μm~10 μm this scopes.It is excellent It is d90≤7 μm to select scheme.Preferred scheme, Task-size Controlling is in d90≤5 μm, and particle size is uniform, what particle size analyzer was shown Distribution of peaks is sharp on particle size distribution figure.

Described ibandronate powder spray micro mist processing can use comminuting method, such as use airslide disintegrating mill, pass through 1 time Or the crushing of more than 1 time, ibandronate medicinal powder is processed into the micro mists of granularity d90≤7 μm.Preferably, crushing applied sample amount is 50g~1000g, crushing pressure are 0.7Mpa, and grinding time is 2.5h~3.5h, and it is 2 times to crush number.

Described ibandronate powder spray micro mist processing can also use spray drying process, will be dissolved with ibandronate Ethanol water the micro mists of granularity d90≤7 μm is machined to by spray drying.Preferably, spray drying parameters are by her Class's phosphonic acids na concn is 2.0g/L, and ammonium bicarbonate concentration 5.0g/L, concentration of alcohol 40%, inlet temperature is 160 DEG C, 100% suctions out, feed rate 15ml/min, spray rate 500L/h, about 70 DEG C of outlet temperature.

Further, by ibandronate micro mist with 0.5mg~5mg explosive payload individually or with appropriate lactose or leucine Loading capsule is mixed etc. other auxiliary materials, daily medication is once.

The preparation method of described ibandronate inhalation or ibandronate is dissolved in phosphate delayed The aqueous solution of fliud flushing (PBS) or other pH5.0~pH7.0, is carried out by way of atomized drop.For Neulized inhalation she In class's Alendronate solution preparation process, the satisfactory ibandronate bulk drug of purity only can be used, can also added simultaneously Enter auxiliary material, such as propane diols, natrium adetate.Atomising device can use conventional equipment, as Ningbo Hai Shu medical supplies factory gives birth to That produces is peaceful because of YZB1093-2009 medicine atomizers.Preferably, ibandronate is dissolved in PBS, obtains concentration >=1mg/ml's The Neulized inhalation aqueous solution, the solution is added at medicine atomizer sample introduction, is atomized, atomized drop granular size≤7 μm, Gas flow rate~0.1ml/min, administration time 1min.

Compared with prior art, the present invention has the advantage that：

The ibandronate of the inhalation of the present invention, possessing, anticholinergic agent, β 2 receptor agonist etc. are existing While the rapidly and efficiently diastole air flue function of bronchodilators, also improve with the pathology such as air flue anti-inflammatory and emphysema Therapeutic action.

The ibandronate of the inhalation of the present invention, while possessing inhaled anti-inflammatory properties, also has There is the therapeutic action that the pathology such as emphysema improve, be especially suitable for patients with COPD and use.

The ibandronate of the inhalation of the present invention, mainly it is deposited in lung airways and directly plays rush bronchiectasis Improve effect with air flue anti-inflammatory and pathology.Enter blood metabolism rapidly, therefore, systemic side effect is low, and security is good, is adapted to make for a long time With, and because itself being a kind of osteoporosis therapy and prophylactic agent, be expected to develop into chronic obstructive pulmonary disease and asthmatic patient The preferred indispensable good medicine used throughout one's life.

Brief description of the drawings

Fig. 1 is the laser particle analyzer measure figure of IBA-3 samples；

Fig. 2 is the SEM electron microscopes of IBA-3 samples；

Fig. 3 is chronic obstructive pulmonary disease mouse using determination of airway resistance after suction treated with sodium ibandronate；

Fig. 4 is that chronic obstructive pulmonary disease mouse is determined using pulmonary dynamic compliance after suction treated with sodium ibandronate；

Fig. 5 A are the lung tissue H＆E coloration results of untreated chronic obstructive pulmonary disease mouse；

Fig. 5 B are chronic obstructive pulmonary disease mouse lung tissue H＆E coloration results after treated with sodium ibandronate；

Fig. 6 is airway smooth muscle cells protein signal situation of change after ibandronate is handled.

Embodiment

It is cited below particularly preferably real for foregoing description of the invention and other objects, features and advantages can be become apparent Example is applied, and coordinates accompanying drawing, is described in detail below.

Embodiment of the present invention provides the ibandronate for inhalation, and its formulation can be composition for her class's phosphine The powder spray of sour sodium micro mist or the aqueous solution of the atomization dissolved with appropriate ibandronate.

It should be understood that the ibandronate of above-mentioned inhalation can include auxiliary material.The implication of auxiliary material refers to preparing this During the ibandronate of the inhalation of invention, any of the purpose of may advantageously facilitate preparation process or atomization can be added Other compositions, and the impurity contained during for preparing ibandronate bulk drug is not qualified as auxiliary material.

Preferably, the purity of ibandronate in the ibandronate bulk drug used in embodiment of the present invention >= 98%.

According to the preferred embodiment of the invention, the micro mist or droplet size distribution of the ibandronate of the inhalation meet Following condition：d90≤7μm.D90 implication is in this specification：The cumulative particle sizes distribution number of one sample reaches 90% when institute Corresponding granularity, its physical significance are that granularity accounts for 90% less than the particle of the numerical value.

According to one embodiment of the invention, the ibandronate of the inhalation, by by ibandronic acid sodium raw materials Medicinal powder is broken to be prepared.According to another embodiment, the ibandronate of the inhalation, by by ibandronate bulk drug Spray drying is prepared.According to the 3rd embodiment, the ibandronate of the inhalation, by the way that ibandronate is former Material medicine is dissolved in pH5.0-pH7.0 isotonic aqueous solution, obtains the concentration >=1mg/ml Neulized inhalation aqueous solution, through atomization Device nebulisation operation forms atomized drop and obtained.

The ibandronate that embodiment of the present invention additionally provides the inhalation of the present invention is used to treat chronic obstructive The purposes of lung disease and asthma.

According to preferred embodiment, during for treating COPD and asthma, dosage is 0.5mg~5mg Daily, it is administered in the form of powder spray sucks or in the form of atomized drop suction.

One of the preparation method of powder spray of ibandronate of inhalation of the present invention is as follows：

The ibandronate bulk drug for meeting national standard is used production preparation to be carried out with comminuting method, in micro mist for raw material Production preparation process in can use single ibandronate bulk drug, appropriate lactose or other auxiliary can also be mixed Material.Comminuting method is to prepare one of common method of powder spray, but has been spray dried method gradually and has been substituted.Main cause be with Spray drying process is compared, and the powder size that comminuting method is prepared is larger, 2~3 μm be the method the crushing limit, and outside micro mist Shape is irregular.Pulverization can also produce electrostatic, and medicine has higher surface free energy after micronizing, and powder is easily assembled It is agglomerating, cause drug powder viscosity enhancing, poor fluidity, influence the redisperse after medicine discharges from micro mist inhalator.Crush The violent pulverization of method is also possible to the change that can make medicine that unfavorable physicochemical properties occur.Particularly in the crystal of fracture There may be indefinite form on surface.However, inventor's research is thought, for respiratory tract local application, the benefit of comminuting method It is：Powder size is larger and profile is irregular, it is also possible to advantageously reduces medicine and is absorbed into blood volume into alveolar so as to favourable In side effect of the reduction for body；Preparation process is simple, and the production cycle is shorter, and the chance of microorganism pollution is low；In addition, because The auxiliary materials such as solvent need not be used, as long as crushing pressure and time control are proper, then main ingredient is less likely to occur rotten etc..We examine It is to carry out respiratory tract local application to consider this powder spray purpose of design, while reduces as far as possible and enter alveolar absorption, it is not necessary to very strong Mobility, and ibandronate is small-molecule drug simple in construction, and physicochemical properties are more stable, can be pollinated with resistance to The process of broken method.The operating condition of pulverization conditions Primary Reference inhaled tiotropium bromide powder preparation, employ QS100 type air-flows Pulverizer is tested.Stress control is crushed in 0.7MPa, the continuous grinding time of single to be no more than 3.5 hours.In the crushing bar Under part, ibandronate does not go bad.Powder size measure is carried out using Mastersizer2000 laser granulometries, As a result such as table 1 below.

Sample parameters after the crushing of the ibandronate of table 1

From upper table 1, it is no more than the powder of 3.5 hours in 0.7Mpa, the continuous grinding time of single crushing Stress control Under the conditions of broken, size distribution is related to crushing number.Crush 1 time, size distribution fluctuation is larger, 7 μm of d90 ＞, could not reach reason The powder spray granularity thought.Crush 2 times, then granularity d90 can be controlled in 5 μm of ＜, and the result of 2 batches of processing is closely similar, table Bright to crush Stress control under conditions of 0.7MPa, crushing effect keeps stable, crushes 2 times, can stably keep granularity D90 is controlled in 5 μm of ＜, and distribution of peaks is sharply regular, and distribution situation is more satisfactory.Fig. 1 is the MASTERSIZER- of IBA-3 samples The particle size distribution figure of 2000 laser particle analyzers measure, it is seen that distribution main peak is sharp, but granularity have less than 1 μm of part it is one small Secondary peak distribution.Fig. 2 is the SEM electronic microscope photos results of IBA-3 samples.

We have carried out solubility, ninhydrin method identification, molybdenum blue colorimetric method measure, microorganism pollution feelings to IBA-3 samples Condition and various physicochemical properties measure.

2.1 dissolubility：IBA-3 sample 10mg are weighed, are put into the test tube with ground stopper equipped with 2ml water, are vibrated 1 minute, observation Dissolving situation.Powder can be completely dissolved and solution is clarified, and display dissolubility is qualified.

Property Identification：Bulk drug and each 10mg of IBA-3 samples are taken respectively, after adding water 2ml to dissolve, then add 0.2% ninhydrin Test solution 1ml, mixing, heating are boiled 10 minutes, equal displaing amaranth.

2.2 molybdenum blue colorimetric methods determine：

IBA-3 sample 10mg are weighed, add appropriate amount of water to dissolve, add moisture time to move into 100ml measuring bottles, puts in 40 DEG C of water-baths and adds Heat 20 minutes, and constantly shake, let cool to room temperature, be diluted with water to scale, as need testing solution；Ibandronic acid is weighed in addition Sodium raw materials medicine 10mg, puts in 100ml measuring bottles, adds appropriate amount of water to dissolve, and is diluted with water to scale, shakes up, as reference substance solution. Precision measures need testing solution and each 5ml of reference substance solution, puts respectively in 25ml measuring bottles, respectively adds ammonium persulfate solution (1%) 8ml, put in water-bath and heat 20 minutes, let cool to room temperature, add ammonium molybdate solution (to take ammonium molybdate 7.5g, add water 100ml to dissolve, add 5mol/L sulfuric acid solution 100ml, mix) 2.0ml, shake up, after placing 15 minutes, add paramethylaminophenol sulfate solution (to take pair Metol sulfate 0.5g, add 15% solution of sodium bisulfite 195ml, add 20% sodium sulfite solution 5ml, shake up) 2ml, Shake up, after placing 15 minutes, add 34% sodium acetate solution 5ml, add water to scale, shake up.Determined respectively at 710nm wavelength Absorbance, as a result 2 need testing solutions are suitable with reference substance solution absorbance, and display IBA-3 samples are degraded in the absence of main ingredient.

2.4 Micro biological Tests：

IBA-3 sample 3mg are weighed, are dissolved in 10ml purified waters.Press《Pharmacopoeia of People's Republic of China》2010 second Annex XI J Microbe restriction test methods are tested.Assay bacteria colony count≤2/ml；Mould, saccharomycete clump count =0/ml.Testing result is qualified.

2.5 heap density, angle of repose, porosity, critical relative moisture：

Heap density, porosity：Heap density refers to the density that volume of a container V shared by powder quality divided by the powder is tried to achieve. When filling powder, the density measured after certain rule is vibrated or raps claims tap density (tap density) ρ tap.Porosity Refer to the voidage ratio of the total volume formed in matrix.After medicine carries out micronization processes, its heap density, porosity are equal Have greatly changed, the density contrast of medicine and auxiliary material may be caused, cause the difficulty on mixing uniformity.So micronizing Medicine should carry out heap density and porosity measurement.Powder is fitted into volume measured in container includes powder true volume, grain Sub- internal pore, inter-particle voids etc., therefore measure the influence such as shape, size, the packing speed of material and type of feed of container Powder volume.It is most bulk density that when container is measured powder filling is not applied into density measured by any external force, applies external force And powder is set to be under most tight filling state measured density most tight heap density.Tap density is with vibration (tapping) number And change, the final tap density measured during constancy of volume that vibrates is most tight heap density.

A certain amount of powder sample is filled in the 5ml graduated cylinders of the transformation of the way, at the beginning of reading initial volume V, raps and observes graduated cylinder The Volume Changes of middle powder, (typically to be tapped 2500 times) untill volume is without significant change, record final volume V ends.Add Quality difference value before and after sample is to add the quality w of powder.

At the beginning of heap density pb=w/V, tap density ptap=w/V is whole, porosity=1- heaps density/tap density

Angle of repose：The measuring method at angle of repose is to take bore about 6cm, caliber (internal diameter) about 0.4cm one, small funnel, It is fixed on iron stand, paving a blank sheet of paper below funnel, the lower end of funnel and the height of paper are 4-5cm, by medicinal powder from funnel Side is poured slowly into funnel, when the medicinal powder to leak down is close to hopper outlet, measures the height and lower end diameter of the medicinal powder cone, according to This calculates the tangent of an angle that stops, and further calculates angle of repose.

The measure of critical relative moisture.Medicine is after micronization processes are carried out, and due to the increase of specific surface area, hygroscopicity can Can substantially it change, and the inspection project that moisture, which is powder spray, strictly to be controlled, so facing for micronized medicine should be determined Boundary's relative humidity (Critical Relative Humidity, CRH).

Critical relative moisture (CRH) assay method is in two steps：

Firstth, sucting wet curve is made：

Medicine 2mg is weighed, is laid in and dries into the flat measuring cup of constant weight (thickness about 2mm), dries to constant weight, precision and claims It is fixed, bottle cap is opened, is put in the glass desicator for filling concentrated sulfuric acid solution or other salting liquids (relative humidity 75%), in 25 DEG C Preserved in insulating box, measuring cup is taken out respectively at 2,4,8,12,24 ... or other times section, it is accurately weighed, calculate moisture absorption hundred Divide rate, be plotted against time with hydroscopicity and obtain sucting wet curve, find corresponding T days time (or hour) during moisture equilibrium at dry side.

Secondth, CRH measure：

6 parts of medicine 2mg is weighed, is ibid operated, puts the glass of the concentrated sulfuric acid solution or other salting liquids that fill various concentrations In drier, preserved T days in 25 degrees Celsius of insulating box, take out measuring cup, it is accurately weighed, Moisture percentage is calculated, to inhale The moisture equilibrium at dry side curve that moisture is mapped to relative humidity, make two tangent lines in flex point, relative humidity corresponding to tangent line focus, be CRH。

IBA-3 sample experiments measurement results are summarized in table 2.

Ibandronate powder spray of the present invention can the application in the form of capsule.The size of capsule used can be appointed What model, preferable model is less than No. 0, generally selects No. 4.Ibandronic acid natrium capsule can not only easily carry out industrial metaplasia Production, and be easy to carry.The amount of ibandronate powder is certain in capsule, it is ensured that inhalation dose is accurate during use, can Effectively prevent patient from inhaling more or inhaling less.Micro mist is fitted into capsule by 0.5mg~5.0mg single dose, is sealed.Use When taken by single capsule.Anti- moisture sorption effect is good.Satisfied Emptying Rate still can be reached in the environment that relative humidity reaches 90% And atomization., can be by ibandronate micro mist and several times matter for the ease of the needs of industrial a large amount of production auto-fillings (30 μm~100 μm) of the carrier lactose of amount carries out filling after mixing.Residual quantity after atomizing effect and use produces good association Same-action, it can especially reduce the hygroscopicity of ibandronate powder spray.

The content uniformity of 3.1 capsules.Method：30 capsules of sampling, balance weigh, and true using molybdenum blue colorimetric method Determine the content of ibandronate in capsule.

The Emptying Rate measure of 3.2 capsules.Method：Carried out by 2010 editions Chinese Pharmacopoeias (two) annex IL methods.Emptying Rate It is required that >=90%

Capsule stability, it is primarily upon the influence that capsule softgel shell absorbs water to preparation performance

Method：Take accelerated test.Take capsule 3 batches (30/batch), be placed in climatic chamber (40 ± 2 DEG C, 75 ± 5% phases To humidity) in preserve, respectively at 0,1,2,3 the end of month sample, investigate outward appearance, Emptying Rate, deposition, content.

3.3 powder retentions and atomization：By the ibandronate inhalation powder spray precise weighing (W1) of trial-production, it is put into In special inhalator (production of Shanghai balance pharmaceutical factory), capsule is punched, then inhalator is connected with 5000ml vials, is connected Place is equipped with switching knob, and this knob begins in the closed position.Vacuumized with 60l/min throughputs, open above-mentioned knob, in capsule Medicinal powder i.e. sprayed from inhalator, continuously three times.If powder forms uniform smog, exist after deposition without big particle, explanation Atomization is excellent；If most of powder is atomized, bottom of bottle only has a small amount of particle, and atomization is medium.If most of powder It is not atomized, deposited into bulk in bottom of bottle, illustrate that atomization is poor.Used capsule shells are taken out from suction apparatus, Precise weighing (W2), is wiped the residual powder of inside capsule wall only with small brushes, then claims capsulae vacuus weight (W3).Capsule 's content powder The computational methods of last residual quantity are：[(W2-W3)/(W1-W3)] × 100%

Humidity influences and capsule wall attaches experiment：Ibandronate inhalation powder spray is taken, accurately weighed, 25 DEG C of room temperatures are underlying In the environment of relative humidity 75%, taken out after 24 hours, weigh capsules weight again.Then powder is poured out, observes characters powder Change, and determine the residual quantity of powder in capsule by upper method and attach situation to understand capsule wall.

Following table is to screen the experimental conditions of ibandronate dust cloud agent prescription：

The prescription screening and parametric measurement of the ibandronate powder spray of table 2

The nature difference for the capsule being made up of above IBA-3 mixing is little.Two can be promoted by being used as auxiliary material using lactose Level distribution bottle deposition, illustrates that lactose can promote ibandronate micro mist mobility.

The content of capsule provided by the present invention by granularity d90≤7 μm ibandronate micro mist or ibandronic acid Sodium micro mist mixes composition with appropriate auxiliary material lactose.Granularity d90≤5 μm of preferable ibandronate micro mist, it is most preferably micro- The Task-size Controlling of powder is in d90≤5 μm, and distribution of peaks is sharp.The dissolubility of micro mist, heap density, angle of repose, Emptying Rate are all preferable, Atomization is good, and moisture absorption is not easy during processing, storage, use.General treatment chronic obstructive pulmonary disease and the medicinal powder of asthma are drawn into Air flue is compared with can produce predetermined curative effect at center.Because the atomizing effect of the ibandronate powder spray prepared by the present invention is good It is good, it is possible to utilize the inhalation of dust device of commercially available treatment chronic obstructive pulmonary disease and asthma.Such as use Shanghai balance pharmaceutical factory Inhalator.What the device actually play a part of is to rack capsule.The device for racking capsule can be with Reusability.One Ghost can be abandoned after capsule 's content extinction, next time in use, being further filled with a capsule into the device.The present invention's Ibandronate capsule can also be struck with the hand open, and micro mist therein can enter respiratory tract by airflow function during breathing and send out The effect of waving.This is advantageous to outdoor or in emergency circumstances patient's self-administration.

Here is the lung function tests result treated using the ibandronate of inhalation to chronic obstructive pulmonary disease mouse.

Chronic obstructive pulmonary disease mouse modeling is using sootiness combination elastoser perfusion structure.After modeling about 7 days through PFT and Pathology determines, and confirms to have established stable chronic obstructive pulmonary disease symptom.It is using FinePointe RC airway resistances and lung compliance detection System (Buxco companies) carries out therapeutic response measure.Step is as follows：

1. inspection apparatus sealing, adjust baseline.

2. pair mouse carries out airway intubation, insert in instrument enclosure, connect relevant device circuit and pipeline.

3. determine lung function parameter, according to the following period, using the medicine of PBS and various concentrations (concentration by it is low to It is high),

Carry out relevant data acquisition：

A:Laundering period 5min

B:Take 20 μ lPBS or medicine to add at instrument setting-out, carry out atomization 1min

C:To the data determination 5min of PBS or medicinal atomized reactions

D:After Restoration stage 3min, next group of determination of drug concentration reaction is carried out

4. export data are excel forms, analyze data.

Fig. 3 is airway resistance (sRaw) measurement result.It can be seen that with suction ibandronate, chronic obstructive pulmonary disease airway of mice resistance Decline, when ibandronate solution concentration >=1.25mg/ml (1.25mg/ml, 2.5mg/ml, 5mg/ml), chronic obstructive pulmonary disease mouse gas Road drop in resistance reflects that the inhalation of ibandronate promotes chronic obstructive pulmonary disease airway of mice diastole to 60% during non-medication. The pulmonary dynamic compliance measure carried out simultaneously shows (Fig. 4), when as ibandronate solution concentration >=2.5mg/ml (2.5mg/ Ml, 5mg/ml), the pulmonary dynamic compliance (Cdyn) of chronic obstructive pulmonary disease mouse rises about 90%, reflect the suction of ibandronate to Medicine not only improves airway resistance situation, while significantly improves chronic obstructive pulmonary disease mouse lung tissue elasticity, namely significantly improves it Pulmonary emphysema situation.Fig. 5 A are the lung tissue H＆E coloration results of untreated chronic obstructive pulmonary disease mouse.Fig. 5 B are chronic obstructive pulmonary disease mouse through her class Lung tissue H＆E coloration results after Alendronate treatment.Wherein COPD：The chronic obstructive pulmonary disease mouse of untreated, Ibandronate：Through her Chronic obstructive pulmonary disease mouse after class's Alendronate treatment.From coloration result it can be seen that after treated with sodium ibandronate, alveolar wall substantially increases Thickness, the improvement namely pulmonary emphysema situation for showing alveolar spring function are improved.

Here is using ibandronate processing airway smooth muscle cells, then determines gas using Western Blot (WB) The situation of change of road smooth muscle contraction/diastole regulation and control stream signal protein molecule.As a result such as Fig. 6 is shown, works as ibandronate (IBAedronate) concentration brings up to 12.5 μM or higher, and MLC phosphorylations are significantly inhibited, meanwhile, the albumen of its upstream swashs Enzyme MLCK and the ROCK of more upstream amount are all remarkably decreased, and display ibandronate is by suppressing airway smooth muscle contraction ROCK-MLCK-MLC phosphorylation signals path and promote the diastole of airway smooth muscle.

Embodiment

Embodiment 1

One step comminuting method

Ibandronate bulk drug 1000g is taken, is loaded in QS100 type pulverizers.Pulverization conditions are that 0.7MPa crushes pressure Power, 2 hours, crush 1 time, obtain ibandronate micro mist.Preliminary observation, micro mist are well dispersed without adhesion, no agglomerate.

Micropowder samples about 1g is taken, using Britain's Malvern Instruments Ltd. laser granulometries to micro mist powder End has carried out granulometry, and as a result above-mentioned sample granularity d90 is 5.55 μm, and d50 is 2.73 μm, and d10 is 0.90 μm.

The destruction of ibandronate whether is caused to be degraded to investigate preparation process, with molybdenum blue colorimetric method to her class before crushing Alendronate bulk drug is determined with the powder after crushing.Ibandronate is made to take bulk drug or each 8mg of powder in method Solution of the concentration equivalent to 0.08mg/ml, the absorbance measurement of respective wavelength is carried out by analysis method.As a result, the powder after crushing Last absorbance (0.258 ± 0.035) is suitable with the bulk drug (0.266 ± 0.042) before crushing, it is seen that the content of ibandronate Change without obvious.

Embodiment 2

Two step comminuting methods

Ibandronate bulk drug 1000g is taken, is loaded in QS100 type pulverizers.Pulverization conditions are that 0.7MPa crushes pressure Power, crush 2 times.First time grinding time 1.5 hours, second grinding time 2 hours.Obtain ibandronate micro mist.Tentatively Observation, micro mist are well dispersed without adhesion, no agglomerate.

Micropowder samples about 1g is taken, using Britain's Malvern Instruments Ltd. laser granulometries to micro mist powder End has carried out granulometry, and as a result above-mentioned sample granularity d90 is 2.73 μm, and d50 is 1.61 μm, and d10 is 0.58 μm.

The destruction of ibandronate whether is caused to be degraded to investigate preparation process, with molybdenum blue colorimetric method to her class before crushing Alendronate bulk drug is determined with the powder after crushing.Ibandronate is made to take bulk drug or each 8mg of powder in method Solution of the concentration equivalent to 0.08mg/ml, the absorbance measurement of respective wavelength is carried out by analysis method.As a result, the powder after crushing Last absorbance (0.249 ± 0.026) is suitable with the bulk drug (0.266 ± 0.042) before crushing, it is seen that the content of ibandronate Change without obvious.

Embodiment 3

Spray drying process

0.5g ibandronate is dissolved in 200ml water, 2.5g ammonium bicarbonate solubilities mix 2 in 100ml water Solution, add 200ml ethanol and be mixed to form 40% ethanol water for spraying.Ammonium hydrogen carbonate is during spray drying Degradable volatilization so that produce aperture in the ibandronate solid micro-powder eventually formed.

B-290 type spray dryers, the 2- liquid shower nozzles equipped with 0.7mm.Condition is：Inlet temperature be 160 DEG C, 100% Suction out, feed rate 15ml/min, spray rate 500L/h.Dry powder sample is stored in drier at room temperature.Outlet temperature is about 70℃。

Embodiment 4

Atomized drop

0.5g ibandronate is dissolved in 100ml pH7.0 phosphate buffer (PBS), the solution is added At medicine atomizer sample introduction, it is atomized, atomized drop granular size≤7 μm, gas flow rate~0.1ml/min.To chronic obstructive pulmonary disease The administration time 1min of mouse.After 5min, with FinePointe RC airway resistances and lung compliance detecting system, (Buxco is public Department) carry out lung function tests.As a result show, airway resistance (sRaw) declines about 40%, and dynamic compliance (Cdyn) strengthens about 90%.

Embodiment 5

Single ibandronate dust cloud agent capsules

5mg ibandronate micro mists are weighed with balance, are fitted into No. 4 capsules.Continuously load 100 capsules, record capsule Actual explosive payload, is accurate to one decimal place.

30 capsules are extracted, carrying out droplet distribution using Chinese Pharmacopoeia (2,010 2) method (annex XH/ annex 89) surveys It is fixed, and the unified recovery of capsule shells is immersed in 10ml purified waters, after stirring and dissolving retained drug powder, 1ml liquid is taken out, with molybdenum blue ratio Color method determines OD710, converts to obtain ibandronic acid na concn further according to standard curve, is multiplied by cumulative volume (10ml), divided by capsule Dosage number (30), then divided by the average explosive payload (5mg) of capsule, obtaining the average residual quantity of ibandronate micro mist in capsule is 9.3%, therefore, average capsule Emptying Rate is 90.7%.Each 1ml of liquid in one-level distribution bottle and two level distribution bottle is drawn respectively, It is same to carry out molybdenum blue colorimetric method measure OD710, obtained also according to liquid volume (10ml) conversion in standard curve and distribution bottle The medicinal powder amount that deposits in distribution bottle, then divided by capsule dosage number (30) and average explosive payload (5mg), obtain one-level distribution bottle and deposit Rate is 62.4%, and two level distribution bottle deposition is 20.2%.

Embodiment 6

It is mixed with the ibandronate dust cloud agent capsules of lactose auxiliary material

Weigh 700mg ibandronates micro mist, 2.1g lactose respectively with balance, insert in 50ml centrifuge tubes, cover tightly lid 5min is acutely shaken afterwards, is then overturned and is mixed 2500 times repeatedly, then, is weighed with balance, by 20mg/, wherein containing her class Alendronate micro mist 5mg, it is fitted into No. 4 capsules.Continuously load 100 capsules, record the actual explosive payload of capsule, be accurate to decimal point Latter position.

30 capsules are extracted, carrying out droplet distribution using Chinese Pharmacopoeia (2,010 2) method (annex XH/ annex 89) surveys It is fixed, and the unified recovery of capsule shells is immersed in 10ml purified waters, after stirring and dissolving retained drug powder, 1ml liquid is taken out, with molybdenum blue ratio Color method determines OD710, converts to obtain ibandronic acid na concn further according to standard curve, is multiplied by cumulative volume (10ml), divided by capsule Dosage number (30), then divided by the average explosive payload (5mg) of capsule, obtaining the average residual quantity of ibandronate micro mist in capsule is 5.5%, therefore, average capsule Emptying Rate is 94.5%.Each 1ml of liquid in one-level distribution bottle and two level distribution bottle is drawn respectively, It is same to carry out molybdenum blue colorimetric method measure OD710, obtained also according to liquid volume (10ml) conversion in standard curve and distribution bottle The medicinal powder amount that deposits in distribution bottle, then divided by capsule dosage number (30) and average explosive payload (5mg), obtain one-level distribution bottle and deposit Rate is 42.6%, and two level distribution bottle deposition is 4

0.8%.

Claims (10)

1. ibandronate is in treatment COPD and/or the purposes of asthma.

2. purposes as claimed in claim 1, it is characterised in that the ibandronate inhalation.

3. purposes as claimed in claim 1, it is characterised in that ibandronate is powder spray or atomized drop.

4. purposes as claimed in claim 2, it is characterised in that ibandronate powder spray is also comprising pharmaceutically acceptable auxiliary Material.

5. with purposes described in claim 1 ibandronate powder spray, it is characterised in that in ibandronate powder spray she The granularity of class's Alendronate micro mist is 2.5 μm~10 μm.

6. with purposes described in claim 5 ibandronate powder spray, it is characterised in that in ibandronate powder spray she The size distribution of class's Alendronate micro mist is d90≤7 μm.

7. with purposes described in claim 5 ibandronate powder spray, it is characterised in that in ibandronate powder spray she The Task-size Controlling of class's Alendronate micro mist is in d90≤5 μm, and particle size is uniform.

8. ibandronate powder spray as claimed in claim 5, it is characterised in that the powder spray uses comminuting method or spraying It is prepared by seasoning.

9. the preparation method of the ibandronate powder spray with purposes described in claim 1, it is characterised in that the powder spray Using comminuting method, crushing pressure is 0.7MPa, and the continuous grinding time of single is no more than 3.5 hours, crushes twice.

10. the ibandronate atomized drop with purposes described in claim 1, it is characterised in that the ibandronate mist It is that ibandronate is dissolved in PBS solution to change drop, atomized drop granular size≤7 μm.