WO2017124640A1 - Poudre à inhaler d'alendronate sodique utilisée pour l'administration d'un médicament pour le système respiratoire, et application de cette dernière - Google Patents

Poudre à inhaler d'alendronate sodique utilisée pour l'administration d'un médicament pour le système respiratoire, et application de cette dernière Download PDF

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WO2017124640A1
WO2017124640A1 PCT/CN2016/078257 CN2016078257W WO2017124640A1 WO 2017124640 A1 WO2017124640 A1 WO 2017124640A1 CN 2016078257 W CN2016078257 W CN 2016078257W WO 2017124640 A1 WO2017124640 A1 WO 2017124640A1
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alendronate sodium
alendronate
powder
salbutamol
sodium powder
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PCT/CN2016/078257
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Chinese (zh)
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陈燃
陆泉
张婕
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杭州旦杰医学科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles

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  • the invention belongs to the field of pharmacy and preparation, and relates to an alendronate sodium powder for respiratory administration, a preparation method thereof and a use thereof, in particular, alen which mainly exerts pharmacodynamic effects after being inhaled mainly in the respiratory tract after inhalation.
  • Sodium phosphonate powder Sodium phosphonate powder.
  • Sodium Alendronate is a small molecule compound with a molecular weight of 249.97 and is structurally similar to the sodium aminophosphate pyrophosphate.
  • the existing dosage form is oral for tablets, and the main effect is to inhibit bone resorption, and is used for treating and preventing osteoporosis in postmenopausal women.
  • the pharmacological mechanism of its action is based on the affinity of alendronate and bone hydroxyapatite crystals to selectively inhibit osteoclast resorption in the bone reforming cycle.
  • the clinical dose is about 0.2 mg/kg (10 mg/day) orally.
  • Oral alendronate tablets form a stimulating alendronate under the action of gastric acid, which may cause gastrointestinal discomfort, may also cause stomach and esophageal damage and ulcers; even lead to esophageal cancer, therefore, presenting the gastrointestinal Patients with tract problems or esophageal disorders such as sputum sputum should not take alendronate tablets.
  • the local absorption of alendronate is better: subcutaneous and intramuscular injection can be performed.
  • Chronic obstructive pulmonary disease (“slow obstructive pulmonary disease” or “COPD”) is a chronic lung disease characterized by incomplete reversible airflow limitation. It is often clinically characterized by recurrent cough, cough, and difficulty breathing. Symptoms, usually characterized by progressive progression, include most chronic bronchitis and emphysema. As the disease progresses, the airway remodels, eventually developing into irreversible airflow obstruction, or coexisting with asthma. Asthma (full name: bronchial asthma) is a chronic respiratory disease, usually caused by airway inflammation, divided into acute bronchoconstriction, leading to repeated attacks of wheezing, chest tightness, difficulty breathing, and cough. COPD and asthma pose a serious threat to public health on a global scale. There are currently 210 million COPD patients and approximately 300 million asthma patients worldwide.
  • 2-2-receptor agonists are currently the most effective bronchodilators, which can quickly relieve bronchospasm and clinical symptoms, and are the treatment of choice for all ages of COPD and asthma.
  • long-term (1 to 2 weeks or longer) use of a ⁇ 2 receptor agonist can lead to a decrease in drug tolerance and even loss of efficacy.
  • the clinical use of ⁇ 2 receptor agonists has been limited due to the problem of tolerance, and is currently mainly used as a relief drug, either as needed, or in combination with glucocorticoids.
  • Glucocorticoids are currently the most commonly used control drugs (ie, drugs used every day), but glucocorticoids do not cure asthma and require long-term use, which can cause many adverse reactions to patients.
  • alendronate has anti-inflammatory effects on asthma and COPD mice by mouse experiments.
  • these effects are directly added to the culture medium by cell culture or oral administration, and there is no test or direct administration through the respiratory tract. Because the characteristics of alendronate sodium after blood entry are quickly excreted mostly through the kidneys, a small part of it is deposited in the bones, so that the efficiency of inhaling into the bloodstream through absorption into the blood is very low, and the side effects such as kidney toxicity are increased. The risk of such small particle size alendronate micropowder and its powder is not ideal for COPD or asthma medication.
  • the present invention provides a preparation of an alendronate sodium powder spray, which can improve the local utilization rate in the respiratory tract while reducing intra-alveolar inhalation to reduce blood volume and avoid causing Side effects on the body system.
  • the present invention provides an alendronate sodium powder for respiratory administration, wherein the alendronate sodium powder has a single alendronate sodium micropowder and contains no excipients.
  • the alendronate sodium powder is prepared by directly pulverizing the alendronate sodium raw material.
  • the present invention contemplates the preparation and use of a larger particle size of alendronate sodium powder, which has not been reported in the prior literature.
  • the powder loading amount of the powder is large, and the production process is relatively simple.
  • the particle size distribution, solubility, bulk density, angle of repose, atomization performance and moisture absorption of the powder must be considered in order to achieve curative effect.
  • the conventionally used powder is intended to enter the alveoli and then enter the bloodstream, and the powder from the mouth to the lungs passes through a relatively long moist respiratory tract such as the trachea and bronchi, while particles with a particle size of 5 ⁇ m or more are easily deposited in the respiratory tract.
  • the particle size (d90) generally needs to be controlled below 5 ⁇ m, and often need to use water-soluble, irritating, biocompatible excipients to facilitate drug diffusion into the alveoli, reduce and avoid in the respiratory tract The deposition in the middle.
  • excipients such as surfactants, may cause damage to the lungs when used for a long time.
  • the powder with moderate particle size (5 ⁇ 20 ⁇ m) can be directly deposited in the trachea, bronchi and bronchioles, which is equivalent to local application in the respiratory tract. It works faster and avoids or mitigates possible system side effects.
  • 5 ⁇ 20 ⁇ m mainly deposited in the trachea, bronchus and bronchioles, ⁇ 2.5 ⁇ m can enter the small bronchi and in the alveolar deposition, the size of the aerosol applied to the trachea, bronchi and bronchioles (d90) Suitable for control in the range of 5 ⁇ 20 ⁇ m.
  • the fine powder particle size distribution of the alendronate sodium powder is d90 ⁇ 20 ⁇ m, and d50 ⁇ 5 ⁇ m, d10 ⁇ 2.5 ⁇ m.
  • the alendronate sodium micropowder is filled into a capsule with a charge of 0.6 mg to 5 mg, and is administered once a day.
  • the invention also provides a preparation method of the above-mentioned alendronate sodium powder aerosol, which is prepared by directly pulverizing alendronate sodium raw material medicine without adding an auxiliary material or a solvent.
  • the pulverization loading amount is 50 g to 1000 g
  • the pulverization pressure is 0.7 MPa
  • the pulverization time is 2.5 h to 3.5 h
  • the pulverization times are 1 time or more.
  • the present invention also provides the use of the above alendronate sodium powder for the preparation of a medicament for treating chronic obstructive pulmonary disease and asthma.
  • the present invention provides the use of the above-described alendronate sodium powder for the treatment of chronic obstructive pulmonary disease in a patient resistant to a ⁇ 2 receptor agonist.
  • the alendronate sodium powder of the invention is prepared by directly pulverizing the main drug of alendronate, and does not need to use or add any auxiliary materials. Compared with the spray drying method reported in the literature, the method not only produces the method.
  • the preparation process is simple, easy to implement, and avoids the side effects that may be caused by the use of excipients and solvents in the spray drying process.
  • the alendronate sodium powder of the present invention mainly deposits in the respiratory tract to directly exert the bronchodilator effect. Due to the larger particle size, the portion that enters the alveoli is smaller, so the amount of blood entering is low, and deposition into other tissues and kidney pressure is avoided.
  • the alendronate sodium powder of the present invention can not only enhance the efficacy of the ⁇ 2 receptor agonist, overcome the problem of tolerance, and can reduce the amount of ⁇ 2 receptor agonist used, reduce and avoid ⁇ 2 Side effects of receptor agonists (mainly in the heart).
  • alendronate has an anti-inflammatory effect, the amount of glucocorticoids can be reduced accordingly, and the side effects of glucocorticoids can also be alleviated.
  • the alendronate sodium powder of the present invention contains a small amount of a component having a small particle size and capable of entering the alveolar absorption, and this part of the alendronate which is absorbed into the blood may exert anti-inflammatory and prevent osteoporosis.
  • the alendronate sodium powder of the present invention only needs to control d90 ⁇ 20 ⁇ m, and d50 ⁇ 5 ⁇ m, d10 ⁇ 2.5 ⁇ m, and it is not necessary to exclude the particle size at 2.5 ⁇ m.
  • the alendronate sodium powder of the present invention is expected to develop into a therapeutic drug for COPD and asthma, and is suitable for long-term use in patients with COPD and asthma.
  • Figure 1 is a SEM electron micrograph of an ALE-4 sample.
  • Figure 2 is a SEM electron micrograph of an ALE-6 sample.
  • Figure 3 is a high performance liquid chromatogram of alendronate sodium micropowder.
  • Figure 4 is a H&E staining diagram of rat lung tissue.
  • Figure 5 is a graph showing the relative parameter changes of specific airway resistance after inhalation of a gradient concentration of salbutamol in each rat.
  • Figure 6 is a graph showing the relative parameter changes of specific airway resistance after inhalation of a gradient concentration of alendronate in each rat.
  • Figure 7 is a graph showing the reactivity of four normal rats to salbutamol on day 0.
  • Figure 8 is a graph showing the reactivity of four COPD rats to salbutamol on day 0.
  • Figure 9 is a graph showing the mean response to salbutamol on Day 0 in four normal and four COPD rats.
  • Figure 10 is a graph showing the reactivity of salbutamol in four normal groups of rats after 21 days of salbutamol tolerance induction.
  • Figure 11 is a graph showing the reactivity of salbutamol in four COPD rats after 21 days of salbutamol tolerance induction.
  • Figure 12 is a graph comparing the mean values of salbutamol reactivity in 4 normal groups and 4 COPD rats after 21 days of salbutamol tolerance induction.
  • Figure 13 is a graph comparing the mean values of salbutamol reactivity in 4 COPD rats before and after salbutamol tolerance induction.
  • Figure 14 is a graph showing the reactivity of four normal rats to alendronate after 21 days of salbutamol tolerance induction.
  • Figure 15 is a graph of response to alendronate in 4 COPD rats after 21 days of salbutamol tolerance induction.
  • Figure 16 is a graph showing the mean response to alendronate in four COPD rats after 21 days of salbutamol tolerance induction.
  • Figure 17 is a graph comparing the mean values of reactivity of albendronate to four normal rats and four COPD rats before and after salbutamol tolerance induction.
  • An embodiment of the present invention provides an alendronate sodium powder for respiratory administration, which comprises a single alendronate sodium micropowder and contains no excipients.
  • the purity of alendronate sodium in the alendronate sodium powder or the alendronate sodium drug substance used in the embodiment of the invention is ⁇ 98%.
  • the particle size distribution of the alendronate sodium aerosol satisfies the following conditions: d90 ⁇ 20 ⁇ m, d50 ⁇ 5 ⁇ m, and d10 ⁇ 2.5 ⁇ m.
  • d90, d50 and d10 represent a particle size distribution.
  • the meaning of d90 is: the particle diameter corresponding to a cumulative particle size distribution of a sample of 90%, and its physical meaning is that the particle diameter is smaller than the value (20 ⁇ m). The particles account for 90%.
  • the alendronate sodium powder is prepared by directly pulverizing the alendronate sodium drug substance.
  • the alendronate sodium powder is prepared directly during the preparation of the alendronate sodium bulk drug, that is, the particle size distribution of the powder is obtained directly without a tableting operation.
  • Embodiments of the present invention also provide the use of the alendronate sodium powder of the present invention for the treatment of chronic obstructive pulmonary disease and asthma, and chronic obstructiveness of a patient for resistance to a ⁇ 2 receptor agonist The use of lung disease.
  • the dose is from 0.6 mg to 5 mg per day, and is administered in the form of a capsule.
  • the invention adopts alendronate sodium raw material medicine which meets the national standard as a raw material, is prepared by mechanical pulverization method, and is not used or involved in other auxiliary materials in the production and preparation process of the fine powder.
  • the present invention employs a mechanical pulverization method.
  • Mechanical pulverization is one of the common methods for preparing powders, but it has gradually been replaced by spray drying.
  • the fine powder prepared by the mechanical pulverization method has a larger particle size, 2 to 3 ⁇ m is the pulverization limit of the method, and the shape of the fine powder is irregular; the pulverization can also generate static electricity, and after the micronization of the drug, The higher surface free energy, the particles tend to aggregate, resulting in enhanced viscosity of the drug micropowder, poor fluidity, affecting the redispersion of the drug after release from the micropowder inhaler.
  • the severe pulverization of the mechanical pulverization process may also cause adverse physicochemical properties of the drug.
  • amorphous crystals may be formed on the surface of the fractured crystal.
  • the mechanical pulverization method is advantageous in that the fine powder has a large particle size and irregular shape, which is favorable for local deposition in the respiratory tract; the preparation process is simple, the production cycle is short, and the chance of microbial contamination is very high. Low; since it is not necessary to use an auxiliary material such as a solvent, as long as the pulverization pressure and time are properly controlled, the main drug is not easily deteriorated.
  • this powder is designed for local administration of the respiratory tract. It does not require strong fluidity.
  • the fine particle size is larger and more favorable, and alendronate is a small molecule drug with simple structure, and its physical and chemical properties are relatively stable. It can withstand the processing of mechanical pulverization. Therefore, we choose mechanical pulverization.
  • the pulverization conditions mainly refer to the operating conditions of the tiotropium bromide inhalation powder, and two kinds of pulverizers such as QS100 and AO type were used for the test.
  • the pulverization pressure is controlled at 0.7 MPa, and the single continuous pulverization time does not exceed 3.5 hours. Under the pulverization conditions, alendronate did not deteriorate.
  • the fine powder particle size was measured using a Mastersizer 2000 laser particle size analyzer, and the results are shown in Table 1 below.
  • the particle size distribution is related to the amount of the sample and the number of pulverization under the pulverization conditions in which the pulverization pressure is controlled at 0.7 MPa and the single continuous pulverization time is not more than 3.5 hours.
  • the loading amount of 1000 g and pulverization 3 times or more (3.0 to 3.5 h) can control the particle size D90 to be less than 20 nm (19.58 to 19.59 ⁇ m).
  • the pulverization effect of 3 times and 3 times or more is basically equivalent, so the number of pulverization of 1000 g can be selected 3 times.
  • the particle size D90 can be controlled to about 12 ⁇ m (11.43 to 12.32 ⁇ m).
  • the pulverization and the pulverization particle size reduction were small, indicating that the pulverization effect of one time and one time is basically equivalent under the condition of 1000 g of the sample loading amount, so the number of pulverization of 50 g can be selected once.
  • the particle size of 7 ⁇ 20nm belongs to the range of the respiratory tract (trachea and bronchus). Therefore, these two conditions (1000g sample loading smash 3 times or more, 50g sample loading smash 1 time or more) are consistent.
  • Our requirement. We took ALE-4 and ALE-6 samples as representative samples of the two preparation conditions, respectively, and performed SEM electron microscopy analysis, as shown in Fig. 1 and Fig. 2.
  • 1 is a SEM electron micrograph of an ALE-4 sample
  • FIG. 2 is a SEM electron micrograph of an ALE-6 sample.
  • ALE-4 and ALE-6 we performed two methods for ALE-4 and ALE-6, such as solubility, ninhydrin identification, HPLC identification, molybdenum blue colorimetric determination, microbial contamination and various physical and chemical properties.
  • Solubility 10 mg of each of the experimentally prepared ALE-4 and ALE-6 alendronate sodium powders were weighed and placed in a stoppered tube containing 2 ml of water, and shaken for 1 minute to observe the dissolution. Both powders were completely soluble and the solution was clear, indicating that the solubility was acceptable.
  • Alendronate sodium was determined by pre-column derivatization.
  • the molecular structure of alendronate is relatively simple and lacks corresponding chromophores.
  • the amino group in the alendronate molecule is combined with the FMOC reaction to form a fluorescent group.
  • Solution A acetonitrile
  • Solution B 0.01 M disodium hydrogen phosphate, gradient elution procedure: 0 to 24 Min, 86% A; 24 to 29 min, 30% A; 29 to 30 min, 86% A; column temperature: 35 ° C; Flow rate: 1.0 mL•min-1.
  • Loading volume 1 uL or 2 uL.
  • Fluorescence excitation wavelength 260 nm
  • fluorescence emission wavelength 310 nm.
  • the chromatogram was obtained by eluting with a gradient of 25 mM pyrophosphate of acetonitrile-25 mM citric acid as shown in FIG. Among them 3.5min - The alendronate peak was at 4 min and the Fmoc peak at 13 min-14.5 min. Both ALE-4 and ALE-6 showed alanine sodium peak, and the peak height was comparable to that of the drug substance, indicating that there was no main drug degradation of ALE-4 and ALE-6.
  • ALE-4 and ALE-6 dissolve in water, add water to the 100ml volumetric flask, heat in a 40°C water bath for 20 minutes, shake constantly, let cool to room temperature, dilute with water to the mark, serve as The test solution; another accurately weighed 10 mg of alendronate sodium raw material, placed in a 100 ml volumetric flask, dissolved in water, diluted with water to the mark, shaken, as a reference solution.
  • the bulk density is the density obtained by dividing the mass of the powder by the volume V of the container occupied by the powder.
  • the density measured after a certain regular vibration or tapping is called the tap density ⁇ tap .
  • Porosity refers to the ratio of the volume of voids formed in the matrix to the total volume. After the micronization treatment of the drug, the bulk density and porosity of the drug change greatly, which may cause the density difference between the drug and the auxiliary material, which causes difficulty in mixing uniformity. Therefore, micronized drugs should be tested for bulk density and porosity.
  • the volume measured by filling the powder into the container includes the true volume of the powder, the voids in the particles, the voids between the particles, and the like.
  • the shape and size of the measuring container, the filling speed of the material, and the filling method affect the volume of the powder.
  • the density measured is the loosest bulk density without applying any external force
  • the density measured by applying an external force to make the powder in the tightest filling state is called the tightest packing density.
  • the tap density changes with the number of tapping times, and the tap density measured when the final oscillation volume is constant is the tightest packing density.
  • Angle of repose The angle of repose is measured by taking a small funnel with a diameter of about 6 cm and a diameter of about 0.4 cm. It is fixed on the iron frame, and a white paper is placed under the funnel. The lower end of the funnel and the height of the paper are 4-5cm, slowly pour the powder from the top of the funnel into the funnel. When the powder to be leaked is close to the funnel outlet, measure the height of the cone and the diameter of the lower end of the powder, calculate the tangent of the angle of repose, and further calculate the angle of repose. .
  • the critical relative humidity (CRH) determination method is divided into two steps:
  • the powder forms a uniform smoke, no large particles are present after deposition, indicating that the atomization performance is excellent; if most of the powder is atomized, there is only a small amount of particles at the bottom of the bottle, and the atomization performance is moderate. If most of the powder is not atomized, it is deposited in the form of a block at the bottom of the bottle, indicating poor atomization performance.
  • the used capsule shell was taken out from the inhalation device, accurately weighed (W2), and the residual powder on the inner wall of the capsule was wiped off with a small brush, and the weight of the capsule (W3) was weighed.
  • the calculation method of the residual amount of the capsule contents is: [(W2-W3)/(W1-W3)] ⁇ 100%
  • Humidity effect and capsule wall adhesion test Take alendronate sodium inhalation powder, accurately weighed, set the relative humidity of 75% at room temperature at 25 ° C, take it out after 24 hours, and weigh the capsule again. The powder was then poured out, the change in powder properties was observed, and the residual amount of the powder in the capsule was measured by the above method to understand the adhesion of the capsule wall.
  • the above capsules composed of ALE-4, ALE-6 or ALE-4 mixed with ALE-6 have little difference in properties.
  • the supernatant was removed by 3000 rpm for 5 minutes.
  • the resulting precipitate was dissolved in 1 mL of a 0.2 mol/L sodium acetate buffer solution (pH 4.5).
  • Bond Elut-DEA Company Agilent, Cat. No. 12102016
  • bed volume 300 uL
  • the solid phase extraction column was activated with 1 ml of methanol, and the solid phase extraction column was washed twice with 1 ml of pure water.
  • the first spray is calculated as 0.32 mg Rat Lung leaf Weight (g) Grinding volume (mL) ALN concentration (ug/mL) Total amount (mg) % of total drug intake Left one 0.196 0.5 52.6 0.026 8.10% Left two 0.266 0.5 134.5 0.067 20.90% No.1 Right one 0.322 0.5 165.2 0.083 25.90% Right two 0.283 0.5 118.8 0.059 18.40% Right three 0.214 0.5 63.4 0.032 10.00% total 1.281 0.267 83.40% Left one 0.232 0.5 93.3 0.047 14.70% Left two 0.274 0.5 113.6 0.057 17.80% No.2 Right one 0.314 0.5 134.4 0.067 20.90% Right two 0.343 0.5 145.4 0.073 22.80% Right three 0.276 0.5 102.5 0.051 15.90% total 1.439 0.295 92.20% Left one 0.214 0.5 72.95 0.036 11.30% Left two 0.27 0.5 124.05 0.062 19.40% average Right one
  • Alendronate sodium aerosol (ALN) non-clinical pharmacodynamics study (pharmacodynamic animal experiment)
  • the sampling situation is as follows:
  • Two normal rats (348g ⁇ 5%) were selected, male and female, and two model rats, male and female.
  • the respiratory condition of the rats was measured using a breath meter.
  • the small drug copy was made by using hard alloy foil, and it was used for lung administration.
  • the fixed capacity of the drug was 1.3 mm 3 .
  • the alendronate sodium powder powder was continuously taken 10 times, dissolved in 1 mL of 0.2 M citrate buffer, and the content of alendronate in the solution was determined by HPLC. The results are shown in Table 5:
  • the rat lung mist applicator In order to dose the powder of the micro-drug to the rat, the rat lung mist applicator must be calibrated to mainly calibrate the dose of the first spray.
  • the dose of the first spray of the rat lung powder mist administration kit is 0.32 ⁇ 0.12 mg. Rat lung administration will be carried out based on this.
  • COPD rats S+E: smoking + elastase modeling
  • aerosol inhalation 0, 0.125 Mg/ml, 0.25 mg/ml, 0.5 mg/ml, 1 mg/ml, 2 mg/ml salbutamol-physiological saline solution, and respiratory parameters such as airway resistance were measured using a Buxco animal respiratory monitoring system.
  • the measurement time was 5 minutes after the aerosol administration, and 150 to 250 respiratory cycles were measured.
  • Rat grouping Take SE (smoking + Elastase) Four COPD rats modeled by the method (ear label: S-1 (#53), S-2 (#52), S-3 (#51), S-4 (#74)) As an experimental group, all were female. Another 4 normal rats of the same age (early number control-1 (#70), control-2 (#71), control-3) (#72), control-4 (#73), female, as a control.
  • Salbutamol sulfate aerosol (Vantolin, GlaxoSmithKline, 200 spray / bottle, 50ug / spray), salbutamol original drug, alendronate sodium powder spray.
  • the reactivity of four normal rats to salbutamol on day 0 is shown in Figure 7.
  • the reactivity of four COPD rats to salbutamol on day 0 is shown in Figure 8.
  • the reactivity (mean) of salbutamol on day 0 of the four normal and four COPD rats is shown in FIG.
  • alendronate sodium raw material drug produced by Shaanxi Hanjiang Pharmaceutical Group Co., Ltd.
  • the pulverization conditions were a crushing pressure of 0.7 MPa, and the mixture was pulverized 4 times for 3 hours to obtain a fine powder of alendronate.
  • the alendronate content was determined and dispensed in hard capsules at 6 mg/capsule.
  • Laser particle size measurement results Malvern, UK The Instrument Co. laser granulometer was used to determine the particle size of the capsule contents of different batches. As a result, the percentage of the sample having a particle size of less than 20 ⁇ m was greater than 90%, and the percentage of the portion having a particle size of less than 5 ⁇ m was less than 50%.
  • the powder content of the capsule was observed by electron microscopy. Under the 10000-times SEM electron microscope, the powder was a single fine particle, no adhesion, no agglomerate, and good dispersion, and was an irregular three-dimensional structure.
  • the raw material of alendronate sodium before pulverization and the powder after pulverization were determined by molybdenum blue colorimetry.
  • the method is to take 8 mg of the raw material medicine or powder, and prepare a solution having a concentration of alendronate sodium equivalent to 0.08 mg/ml, and measure the absorbance of the corresponding wavelength according to the analysis method.
  • the absorbance of the powder after pulverization (0.071 ⁇ 0.007) was comparable to that of the raw material before pulverization (0.067 ⁇ 0.006), and it was found that the content of alendronate did not change significantly.
  • alendronate sodium raw material produced by Shaanxi Hanjiang Pharmaceutical Group Co., Ltd.
  • the pulverization conditions were a crushing pressure of 0.7 MPa, 2.5 hours, and pulverization twice.
  • a fine powder of alendronate is obtained.
  • the alendronate content was determined and dispensed in hard capsules at 2 mg/capsule.
  • the powder content of the capsule was observed by electron microscopy. Under the 10000-times SEM electron microscope, the powder was a single fine particle, no adhesion, no agglomerate, and good dispersion, and was an irregular three-dimensional structure.
  • the results of the rat COPD model showed that the dose of alendronate sodium aerosol inhaler was 0.6 ⁇ 5.0 mg, once a day, can improve the respiratory function of COPD rats ⁇ 40%, better than the effect of salbutamol sulfate ( ⁇ 20%) .
  • the continuous application of the alendronate sodium powder of the present invention for 3 weeks still improves the respiratory function of COPD rats by ⁇ 30%, indicating that there is no drug resistance problem.

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Abstract

L'invention concerne une poudre à inhaler d'alendronate sodique utilisée pour l'administration d'un médicament pour le système respiratoire, et l'application de cette dernière. La poudre à inhaler d'alendronate sodique contient un seul constituant, la micropoudre d'alendronate sodique, et ne contient pas d'agent auxiliaire. La poudre à inhaler d'alendronate sodique peut améliorer d'environ 40 % la fonction respiratoire de rats atteints de BPCO, une efficacité supérieure à celle du sulfate de salbutamol dans un dosage classique, et permet de contrer le problème de la résistance au médicament posé par le sulfate de salbutamol et autres agonistes des récepteurs bêta-2.
PCT/CN2016/078257 2016-01-18 2016-04-01 Poudre à inhaler d'alendronate sodique utilisée pour l'administration d'un médicament pour le système respiratoire, et application de cette dernière WO2017124640A1 (fr)

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