CN114272228B - Tiotropium bromide inhalation microsphere, preparation method thereof and inhalation preparation - Google Patents
Tiotropium bromide inhalation microsphere, preparation method thereof and inhalation preparation Download PDFInfo
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Abstract
The invention relates to the technical field of drug microspheres, in particular to a tiotropium bromide inhalation microsphere, a preparation method thereof and an inhalation preparation. The preparation method of the tiotropium bromide inhalation microsphere comprises the following steps: and mixing a carrier, a tiotropium bromide raw material and acetonitrile, and then performing spray drying, wherein the carrier comprises a polylactic acid-glycolic acid copolymer. The tiotropium bromide inhalation microspheres prepared by the preparation method not only can continuously release tiotropium bromide, but also has higher drug loading and encapsulation efficiency, and meanwhile, the tiotropium bromide inhalation microspheres have good sphericity and uniform granularity.
Description
Technical Field
The invention relates to the technical field of drug microspheres, in particular to a tiotropium bromide inhalation microsphere, a preparation method thereof and an inhalation preparation.
Background
Chronic obstructive pulmonary disease (Chronic Obstructive Pulmonary Diseases, COPD) is a common, chronic progressive respiratory disease of chronic bronchitis or emphysema characterized by airflow obstruction. COPD often causes severe exacerbations of lung function, ultimately leading to disability and death, severely compromising human health, being the fourth leading cause of death in the world, next to heart disease, cerebrovascular and acute lung infections.
The inhalation type preparation has the characteristics of convenient use, rapidness, compact structure, portability and the like, and is widely applied to the treatment of asthma and COPD. In the treatment of COPD, the tiotropium bromide has remarkable treatment effect, belongs to a novel and efficient competitive M cholinergic receptor blocker, is beneficial to relieving abnormal contraction phenomenon of smooth muscle of a patient, can achieve the purposes of reducing the secretion of mucus and reducing respiratory resistance after dilating, and further plays roles of enhancing the pulmonary ventilation function. Meanwhile, researches show that the expansion action time of the tiotropium bromide on the bronchus smooth muscle of the human body can be longer than 24 n. Tiotropium bromide is locally (bronchi) selective upon inhaled administration, whereby therapeutic effects can be achieved without producing systemic anticholinergic effects. Its bronchiectasis is essentially a local (airway) effect, not a systemic effect.
The existing dosage forms of Guan Saituo ammonium bromide on the market only inhale two dosage forms of spray and inhalation powder mist, but neither of the two dosage forms can continuously release the tiotropium bromide. Meanwhile, when the inhalant preparation is prepared, the prepared particles are required to be small in particle size, uniform in particle size, good in particle sphericity, high in drug loading rate, high in encapsulation efficiency and the like. However, the existing inhalant preparation of tiotropium bromide is difficult to meet the above requirements.
In view of this, the present invention has been made.
Disclosure of Invention
The invention aims to provide tiotropium bromide inhalation microspheres, a preparation method thereof and an inhalation preparation. The preparation method of the embodiment of the invention can effectively solve the problems, and the tiotropium bromide inhalation microsphere prepared by the preparation method can continuously release tiotropium bromide, has higher drug loading and encapsulation efficiency, and has the advantages of small particle size, good balling property and uniform particle size.
The invention is realized in the following way:
in a first aspect, the present invention provides a method for preparing tiotropium bromide inhalation microspheres, comprising: and mixing a carrier, a tiotropium bromide raw material and acetonitrile, and then performing spray drying, wherein the carrier comprises a polylactic acid-glycolic acid copolymer.
In an alternative embodiment, the method comprises: adding the carrier into the acetonitrile for mixing and dissolving, adding the tiotropium bromide raw material for mixing, and then carrying out spray drying.
In an alternative embodiment, the spray drying conditions include: inlet flow rate is 2-10ml/min, air suction rate is 60-100%, air flow meter is 30-50mm, inlet temperature is 65-75 ℃, nozzle size is 1-2.8mm.
In an alternative embodiment, the spray drying conditions include: inlet flow rate is 2-5ml/min, air suction rate is 70-100%, air flow meter is 30-40mm, inlet temperature is 65-75 ℃, nozzle size is 1-2mm;
preferably, the conditions of spray drying include: inlet flow rate 3ml/min, air suction rate 100%, air flow meter 40mm, inlet temperature 70 ℃, nozzle size 1.4mm.
In an alternative embodiment, the mass to volume ratio of the carrier to the acetonitrile is 0.5-3%.
In an alternative embodiment, the mass ratio of the carrier to the tiotropium bromide starting material is 100:1-65, preferably 1-12, further preferably 100:9-10.
In an alternative embodiment, the carrier is a polylactic acid-glycolic acid copolymer.
In a second aspect, the present invention provides a tiotropium bromide inhalation microsphere prepared by the method for preparing a tiotropium bromide inhalation microsphere according to any one of the previous embodiments.
In an alternative embodiment, the tiotropium bromide inhalation microsphere has a drug loading of 5-30%.
In a third aspect, the present embodiment provides an inhalable formulation comprising tiotropium bromide inhalable microspheres prepared by the method for preparing tiotropium bromide inhalable microspheres according to any one of the preceding embodiments.
The invention has the following beneficial effects: according to the embodiment of the invention, PLGA is adopted as a carrier slow-release material, acetonitrile is adopted as a solvent, and spray drying is adopted in combination, so that the formed tiotropium bromide inhalation microsphere not only can achieve an excellent slow-release effect and can continuously release tiotropium bromide for a long time, but also has higher drug loading and encapsulation rate, and particularly, the tiotropium bromide inhalation microsphere has good balling property and uniform granularity.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the embodiments will be briefly described below, it being understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and other related drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a graph showing the release profile of the tiotropium bromide inhalation microspheres provided in example 1 of the present invention;
fig. 2 is a scanning electron microscope image of a tiotropium bromide inhalation microsphere provided in example 1 of the present invention;
fig. 3 is a scanning electron microscope image of the tiotropium bromide inhalation microsphere provided in example 2 of the present invention;
fig. 4 is a scanning electron microscope image of the tiotropium bromide inhalation microsphere provided in example 3 of the present invention;
fig. 5 is a scanning electron microscope image of the tiotropium bromide inhalation microsphere provided in example 4 of the present invention;
fig. 6 is a scanning electron microscope image of the tiotropium bromide inhalation microsphere provided in example 5 of the present invention;
fig. 7 is a scanning electron microscope image of the tiotropium bromide inhalation microsphere provided in example 6 of the present invention;
fig. 8 is a scanning electron microscope image of the tiotropium bromide inhalation microsphere provided in example 7 of the present invention;
fig. 9 is a scanning electron microscope image of tiotropium bromide inhalation microspheres provided in example 8 of the present invention;
fig. 10 is a scanning electron microscope image of a tiotropium bromide inhalation microsphere according to example 9 of the present invention;
FIG. 11 is a scanning electron microscope image of the tiotropium bromide inhalation microsphere provided in example 10 of the present invention;
fig. 12 is a scanning electron microscope image of the tiotropium bromide inhalation microsphere provided in example 11 of the present invention;
FIG. 13 is a scanning electron microscope image of the tiotropium bromide inhalation microspheres provided in comparative example 1 of the present invention;
FIG. 14 is a scanning electron microscope image of the tiotropium bromide inhalation microspheres provided in comparative example 2 of the present invention;
FIG. 15 is a scanning electron microscope image of the tiotropium bromide inhalation microspheres provided in comparative example 3 of the present invention;
FIG. 16 is a scanning electron microscope image of the tiotropium bromide inhalation microspheres provided in comparative example 4 of the present invention;
FIG. 17 is a scanning electron microscope image of the tiotropium bromide inhalation microspheres provided in comparative example 5 of the present invention;
FIG. 18 is a scanning electron microscope image of the tiotropium bromide inhalation microspheres provided in comparative example 6 of the present invention;
FIG. 19 is a scanning electron microscope image of the tiotropium bromide inhalation microspheres provided in comparative example 7 of the present invention;
FIG. 20 is a scanning electron microscope image of the tiotropium bromide inhalation microspheres provided in comparative example 8 of the present invention;
FIG. 21 is a scanning electron microscope image of the tiotropium bromide inhalation microspheres provided in comparative example 9 of the present invention;
FIG. 22 is a scanning electron microscope image of the tiotropium bromide inhalation microspheres provided in comparative example 10 of the present invention;
FIG. 23 is a scanning electron microscope image of the tiotropium bromide inhalation microspheres provided in comparative example 11 of the present invention;
FIG. 24 is a scanning electron microscope image of the tiotropium bromide inhalation microspheres provided in comparative example 12 of the present invention;
FIG. 25 is a scanning electron microscope image of the tiotropium bromide inhalation microsphere provided in comparative example 13 of the present invention;
FIG. 26 is a scanning electron microscope image of the tiotropium bromide inhalation microsphere provided in comparative example 14 of the present invention;
fig. 27 is a graph showing the release profile of tiotropium bromide inhalation microspheres provided in example 2 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Inhalation microspheres can affect aerodynamic behavior if the particle morphology is irregular, whereas microparticles are spherical: the contact area between particles can be reduced, the cohesive force is weakened, the redispersion of the medicine is facilitated during inhalation administration, the migration and pulling force of the particles under the gas are facilitated, the better airflow compliance is realized, and the deposition rate in the lung is improved. Meanwhile, for the inhaled formulation: the deposition form and position of the medicine in the respiratory system can be different according to the different particle diameters, and specifically: particles with a (aerodynamic) diameter greater than 5.0 μm will be deposited in the pharynx, larynx and upper respiratory tract due to inertial impaction between the particles; particles with diameters between 1.0 and 5.0 μm will reach the deep respiratory tract mainly in the form of gravity deposition, depositing on the tracheal, bronchial and alveolar surfaces; particles with a diameter of 0.5-1.0 μm are deposited on the respiratory bronchioles and alveoli walls; while particles with a diameter of <0.5 μm, typically 80% will be exhaled with the flow of air by brownian motion and will not be deposited substantially in the respiratory tract. Therefore, the inhalant preparation not only requires drug loading capacity, encapsulation efficiency and the like, but also has high requirements on good sphericity, uniform granularity and particle size range.
Tiotropium bromide monohydrate is used as a small-molecule hydrophilic drug, and is different from a large-molecule hydrophilic drug and a small-molecule hydrophobic drug. The preparation of hydrophilic small molecule drugs into sustained release microspheres presents various challenges: on the one hand, the encapsulation efficiency is low, and small molecular substances are easy to escape through the channels in the preparation process because the surfaces and the interiors of the microspheres can have tiny pores or channels. On the other hand, the hydrophilic micromolecule medicine is easy to be suddenly released, and the phenomenon of initial large-dose release is very easy to occur in the release process. Meanwhile, unlike sustained release microspheres for injection, the sustained release microsphere for inhalation of the present invention requires good inhalability of the microsphere, and the key to determine inhalability of the microsphere is that the particle size of the microsphere must be in a proper particle size range (1-10 μm is good), otherwise, the microsphere cannot be used. The limitations in the aspects make the inhalation of the tiotropium bromide monohydrate into the sustained-release microsphere difficult to realize, and related products are not disclosed or marketed until now.
The embodiment of the invention provides a preparation method of tiotropium bromide inhalation microspheres, which comprises the following steps:
the carrier, which includes polylactic acid-glycolic acid copolymer (hereinafter, referred to as PLGA) and the tiotropium bromide raw material, are mixed and then spray-dried.
The inventor of the invention discovers that the preparation of the tiotropium bromide slow-release inhalation microsphere is special, the problem that the microsphere is difficult to form during the preparation process, the agglomeration and the heavy fusion are easy to occur, and the problem that the granularity is very non-uniform. In order to realize the sustained-release inhalation microsphere with good sphericity and uniform granularity, the invention selects the specific polylactic acid-glycolic acid copolymer as a sustained-release carrier, and prepares the microsphere by combining acetonitrile as a solvent and a spray drying method, thereby finally realizing the sustained-release inhalation microsphere with good sphericity and uniform granularity.
The specific operation is as follows: firstly, the polylactic acid-glycolic acid copolymer is added into the acetonitrile for mixing and dissolving, and the PLGA is adopted as a carrier slow-release material in the embodiment of the invention, which is very critical, and the combination of a specific solvent acetonitrile and a spray drying method not only ensures that the formed tiotropium bromide inhalation microsphere has a slow-release effect, but also ensures that the balling property of the tiotropium bromide inhalation microsphere is good and the granularity is uniform.
In the prior art, lactose, albumin, lecithin, tween and other raw materials may be adopted to promote the formation of microspheres, but in the embodiment of the invention, the inventor finds that if the above materials are added, the formed tiotropium bromide inhalation microspheres are easy to fuse, have non-uniform granularity and the like, so that lactose, albumin, lecithin, tween and other raw materials are not adopted as the raw materials for forming the tiotropium bromide inhalation microspheres.
Furthermore, in the preparation of the tiotropium bromide slow-release inhalation microsphere, the specific acetonitrile is adopted as a solvent, other steps are matched, so that the formation of the tiotropium bromide inhalation microsphere is ensured, if the tiotropium bromide slow-release inhalation microsphere is changed into other solvents, such as dichloromethane and ethyl acetate, the two solvents which are most commonly applied to the field are matched with PLGA for preparing the microsphere, and have relatively stable and better effects proved by a large number of prior arts, when the tiotropium bromide slow-release inhalation microsphere is prepared, the spherical shape is very poor, the sample is easy to adhere, the morphology of the microsphere is irregular, fusion is easy to occur, and thus the tiotropium bromide inhalation microsphere cannot be prepared successfully, and cannot be used for inhalation preparations.
Further, the mass to volume ratio of the polylactic acid-glycolic acid copolymer and the acetonitrile is 0.5 to 3%, i.e., PLGA/acetonitrile (w/v) is 0.5 to 3%, for example, any value between 0.5 to 3%, such as 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, etc.
Then, the tiotropium bromide raw material (hereinafter, referred to as API) is added and stirred to dissolve the tiotropium bromide raw material, wherein the mass ratio of PLGA to tiotropium bromide is 100:1-65, preferably 100:1-50, 100:1-45, 100:1-30, 100:1-25, 100:1-15, 100:1-12, 100:5-12, 100:9-10, for example, may be 100: 1. any number between 100:1-65, 10:1, 5:1, 10:3, 100:35, 2.5:1, 20:9, 2:1, 5:3, and 20:13, etc. The adoption of the mass ratio is beneficial to improving the sphericity and granularity uniformity of the tiotropium bromide microspheres.
It should be noted that, the tiotropium bromide raw material adopted in the embodiment of the invention may be tiotropium bromide hydrate or non-hydrate, the mass ratio is that of tiotropium bromide as monohydrate, and when the non-hydrate tiotropium bromide is adopted, the ratio of the non-hydrate tiotropium bromide to the hyaluronic acid compound or the dosage of the non-hydrate tiotropium bromide may be calculated according to the molecular weights of the monohydrate tiotropium bromide and the non-hydrate tiotropium bromide and the ratio.
Subsequently, spray drying was performed. The inventor researches find that in the preparation process of the tiotropium bromide inhalation microsphere, the microsphere with the particle size reduced to the required particle size cannot be prepared by adopting a conventional emulsification method (comprising a solvent volatilization method or a phase separation method and the like), so that the required tiotropium bromide microsphere cannot be prepared; the tiotropium bromide microsphere prepared by the rapid membrane emulsification method has low drug loading, can not meet the requirements, and has excessive loss of tiotropium bromide, so that the method can not be used for preparing the tiotropium bromide microsphere. The inventor finds that the specific spray drying method is adopted to prepare the tiotropium bromide inhalation microsphere on the basis of adopting the polylactic acid-glycolic acid copolymer as a carrier and acetonitrile as a solvent, and the drug loading capacity, the encapsulation efficiency, the sample sphericity and the granularity of the tiotropium bromide inhalation microsphere can all meet the requirements of the slow release inhalation microsphere.
Further, the spray drying conditions include: inlet flow rate is 2-10ml/min, air suction rate is 60-100%, air flow meter is 30-50mm, inlet temperature is 65-75 ℃, nozzle size is 1-2.8mm.
Preferably, the inlet flow rate is 2-8ml/min, 2-7ml/min, 2-6ml/min, 2-5ml/min, 2-4ml/min or 3-5ml/min.
Preferably, the above-described inhalation rate of the present invention is 70 to 100%, 80 to 100%, 85 to 100%, 90 to 100% or 95 to 100%.
Preferably, the air flow meter of the invention is 30-45mm or 35-45mm or 38-42mm.
Preferably, the inlet temperature of the present invention is 68-72 ℃.
Preferably, the above-mentioned nozzle size of the present invention is 1-2mm, 1-1.8mm, 1-1.6mm or 1.2-1.6mm;
more preferably, the conditions of spray drying include: inlet flow rate 3ml/min, air suction rate 100%, air flow meter 40mm, inlet temperature 70 ℃, nozzle size 1.4mm.
The air flow meter was calculated as Q airflow, and the nozzle size was the diameter of the nozzle.
In the embodiment of the invention, the spray drying is really used as one of key elements to realize the excellent effects of small particle size, good sphericity and uniform particle size of the tiotropium bromide inhalation microsphere, and the adoption of specific and proper spray drying conditions is very key. In general, the impact of spray drying on the overall effect of the microspheres is quite limited. However, in the preparation of the tiotropium bromide inhalation microspheres, the inventor finds that the parameters of spray drying have unexpected and significant influence on the spray effect, and when the parameters of spray drying are not proper, the tiotropium bromide inhalation microspheres are not ideal in sphericity or granularity uniformity, and then the tiotropium bromide inhalation microspheres cannot be normally used. The invention adopts the specific spraying condition and is matched with the specific carrier and the solvent, so that the tiotropium bromide inhalation microsphere is ensured to have good balling property and granularity uniformity.
Furthermore, if the inlet temperature of spray drying is too low, the sample is not completely dried, and is easy to adhere to walls and agglomerate. When the sample temperature is too high, melting of the auxiliary material PLGA occurs. It is more advantageous to ensure the sphericity and particle size uniformity within the scope of the embodiments of the present invention.
Further, the spray-dried inlet flow rate is too low, the nozzle size is easy to block, the flow rate is too high, the samples are easy to fuse, and the particle size distribution is uneven. It is more advantageous to ensure the sphericity and particle size uniformity within the scope of the embodiments of the present invention.
Further, the embodiment of the invention provides a tiotropium bromide inhalation microsphere, which is prepared by the preparation method of the tiotropium bromide inhalation microsphere. The drug loading of the tiotropium bromide inhalation microsphere is 5-30%. The tiotropium bromide inhalation microsphere has the advantages of high drug loading and encapsulation rate, sustained release of tiotropium bromide, good sphericity and uniform granularity.
Further, the embodiment of the invention provides an inhalant preparation, which comprises the tiotropium bromide inhalant microsphere prepared by the method for preparing the tiotropium bromide inhalant microsphere according to any one of the previous embodiments.
The detection method provided by the embodiment of the invention comprises the following steps:
1. the drug loading and encapsulation efficiency test method is as follows:
instrument: shimadzu LC-2030C3D, balance.
Chromatographic conditions: mobile phase acetonitrile-2% triethylamine aqueous solution (pH was adjusted to 5.5 with phosphoric acid, 27:73), detection wavelength:237nm, column temperature: 30 ℃, sample injection volume: 20ul, flow rate: 1.0ml/min, analysis time: 12min, column number: LC-065, chromatographic column:Luna 5μm C8(2)/>(250*4.6mm)。
the specific test method comprises the following steps:
(1) Drug content measurement outside sphere (designated M1): the sample is weighed into a triangular flask with about 20mg to 100ml, 50ml of PBS solution is added, the mixture is shaken for 20 seconds, the mixture is shaken evenly, a 0.22 mu M PTFE filter membrane is used for filtration, and the content of the filtrate is detected, namely the content M1 outside the sphere. 2 parts were prepared in parallel.
(2) Whole ball content measurement (drug loading measurement designated M2): the sample is weighed to be about 20mg to 50ml volumetric flask, 10ml DMSO (dimethyl sulfoxide) is added for ultrasound for 5min, then mobile phase is added for dilution and cooling, the volume is fixed, shaking is carried out, and centrifugation is carried out, thus obtaining the content measured as the whole sphere content M2, and the drug loading quantity. 2 parts were prepared in parallel.
Encapsulation efficiency: the simplified calculation formula is [ (M2-M1)/M2 ]. Times.100%, and the encapsulation efficiency is obtained by substituting the calculated formula into corresponding values.
2. In vitro release assay:
instrument: shimadzu LC-2030C3D, balance and water bath shaking table.
Chromatographic conditions: mobile phase acetonitrile-2% triethylamine in water (pH adjusted to 5.5 with phosphoric acid, 27:73), detection wavelength: 237nm, column temperature: 30 ℃, sample injection volume: 20ul, flow rate: 1.0ml/min, analysis time: 12min, column number: LC-065, chromatographic column:Luna 5μm C8(2)/>(250*4.6mm)。
the specific release method comprises the following steps:
cutting a dialysis bag with a length of 6cm, washing with ultrapure water and soaking for half an hour to activate the dialysis bag, clamping one end of the dialysis bag by a clamp, weighing 10mg of sample, adding into the dialysis bag (direct weighing method), adding 1ml of PBS solution into the dialysis bag, clamping the other end of the dialysis bag by the clamp, placing the dialysis bag into a wide-mouth bottle filled with 50ml of PBS solution, covering a cover, and shaking by a water bath shaking table at 37 ℃. 1ml of each of 0h, 1h, 2h, 4h, 24h, 48h, 5d, 7d, 9d, 12d, 14d, 17d, and 20d was sampled, and 1ml of PBS solution was supplemented. 2 parts were measured in parallel.
The features and capabilities of the present invention are described in further detail below in connection with the examples.
Example 1
The embodiment provides a preparation method of tiotropium bromide inhalation microspheres, which comprises the following steps:
2g of PLGA (model: 7525A) was added to 100ml of acetonitrile and dissolved with stirring, 200mg of tiotropium bromide (all of which are referred to as tiotropium bromide monohydrate) powder was added after dissolution, and after complete dissolution of the tiotropium bromide, spray drying was performed. Wherein, the spray drying parameters are set as follows: inlet flow rate 3ml/min, ASP (inspiration rate): 100%, air flow meter: 40mm, inlet temperature 70 ℃, nozzle size: 1.4mm.
The embodiment provides a tiotropium bromide inhalation microsphere, which is prepared by the preparation method.
Detection of
The drug loading, encapsulation efficiency and release condition of the tiotropium bromide inhalation microspheres prepared in the example 1 are detected, and the detection is carried out by a scanning electron microscope.
The theoretical drug loading of the tiotropium bromide inhalation microsphere is 9%, and the actual drug loading is as follows: 9.17%; the encapsulation efficiency was 98.28%. Release profile referring to fig. 1, it can be seen from the release profile that the release can be up to 20 days.
As can be seen from FIG. 2, the particle size of the tiotropium bromide inhalation microsphere is 600nm-6 μm, and the particle size is small, the sphericity is very good, and the particle size is very uniform. According to the release degree detection, the tiotropium bromide inhalation microsphere can release the tiotropium bromide continuously, so that the administration times are reduced.
Example 2
This example provides a method for preparing tiotropium bromide inhalation microspheres, which operates substantially in accordance with example 1, except that: the spray drying conditions were as follows: inlet temperature: 70 ℃; ASP (inspiration rate): 100%; inlet flow rate: 5ml/min; an air flow meter: 40mm; nozzle size: 1.4mm.
The detection of the tiotropium bromide inhalation microsphere shows that the theoretical drug loading rate is as follows: 9%; actual drug loading rate: 8.75%; encapsulation efficiency: 98.73%; meanwhile, according to the scanning electron microscope result (see fig. 3), the particle size of the tiotropium bromide inhalation microsphere is 600nm-9 μm, compared with the example 1, the particle size uniformity is slightly reduced, but the tiotropium bromide inhalation microsphere has good sphericity, round and full sphericity and better particle size uniformity. From the release profile (fig. 27), it was found that the release was up to 18 days.
Example 3
This example provides a method for preparing tiotropium bromide inhalation microspheres, which operates substantially in accordance with example 2, except that: the spray drying conditions were as follows: inlet temperature: 65 ℃; ASP (inspiration rate): 100%; inlet flow rate: 5ml/min; an air flow meter: 40mm; nozzle size: 1.4mm.
The detection of the tiotropium bromide inhalation microsphere shows that the theoretical drug loading rate is as follows: 9%; actual drug loading rate: 8.95%; encapsulation efficiency: 98.59%; meanwhile, according to the scanning electron microscope result (see fig. 4), the particle size of the tiotropium bromide inhalation microsphere is 600nm-9 μm, compared with the example 1, the particle size uniformity is slightly reduced, but the tiotropium bromide inhalation microsphere can be well balled, and still has good particle size uniformity.
Example 4
This example provides a method for preparing tiotropium bromide inhalation microspheres, which operates substantially in accordance with example 1, except that: the spray drying conditions were as follows: inlet temperature: 75 ℃; ASP (inspiration rate): 100%; inlet flow rate: 3ml/min; an air flow meter: 40mm; nozzle size: 1.4mm.
The detection of the tiotropium bromide inhalation microsphere shows that the theoretical drug loading rate is as follows: 9%; actual drug loading rate: 8.98%; encapsulation efficiency: 99.08%; meanwhile, according to the scanning electron microscope result (see fig. 5), the particle size of the tiotropium bromide inhalation microsphere is 650nm-6.5 μm, compared with the embodiment 1, the particle size uniformity is slightly reduced, but the tiotropium bromide inhalation microsphere can still be well balled, and the particle size is uniform.
Example 5
This example provides a method for preparing tiotropium bromide inhalation microspheres, which operates substantially in accordance with example 2, except that: the spray drying conditions were as follows: inlet temperature: 70 ℃; ASP (inspiration rate): 100%; inlet flow rate: 5ml/min; an air flow meter: 40mm; nozzle size: 2mm.
The detection of the tiotropium bromide inhalation microsphere shows that the theoretical drug loading rate is as follows: 9%; actual drug loading rate: 8.99%; encapsulation efficiency: 94.71%; meanwhile, according to the scanning electron microscope result (see fig. 6), compared with the example 1, the particle size uniformity of the tiotropium bromide inhalation microsphere is reduced, but the tiotropium bromide inhalation microsphere can be formed into balls, and the balling property is better.
Example 6
This example provides a method for preparing tiotropium bromide inhalation microspheres, which operates substantially in accordance with example 2, except that: the spray drying conditions were as follows: inlet temperature: 70 ℃; ASP (inspiration rate): 100%; inlet flow rate: 5ml/min; an air flow meter: 40mm; nozzle size: 2.8mm.
The detection of the tiotropium bromide inhalation microsphere shows that the theoretical drug loading rate is as follows: 9%; actual drug loading rate: 9.45%; encapsulation efficiency: 96.27%; meanwhile, according to the scanning electron microscope result (see fig. 7), compared with the example 1, the tiotropium bromide inhalation microsphere has reduced granularity uniformity and increased granularity, but the tiotropium bromide inhalation microsphere can be formed into balls with good sphericity.
Example 7
This example provides a method for preparing tiotropium bromide inhalation microspheres, which operates substantially in accordance with example 5, except that: acetonitrile (100 ml), PLGA (2 g), API (253 mg).
The detection of the tiotropium bromide inhalation microsphere shows that the theoretical drug loading rate is as follows: 15%; actual drug loading rate: 14.97%; encapsulation efficiency: 81.77%; meanwhile, according to the scanning electron microscope result (see fig. 8), the particle size of the tiotropium bromide inhalation microsphere is 550nm-8 μm, compared with the example 1, the particle size uniformity is slightly reduced, but the tiotropium bromide inhalation microsphere has better balling property and uniform particle size.
Example 8
This example provides a method for preparing tiotropium bromide inhalation microspheres, which operates substantially in accordance with example 5, except that: acetonitrile (100 ml), PLGA (7525 a) (2 g), API (500 mg).
The detection of the tiotropium bromide inhalation microsphere shows that the theoretical drug loading rate is as follows: 20% of a base; actual drug loading rate: 19.59%; encapsulation efficiency: 73.16%; meanwhile, according to the scanning electron microscope result (see fig. 9), the particle size of the tiotropium bromide inhalation microsphere is 400nm-6 μm, compared with the embodiment 1, the particle size uniformity is reduced, but the tiotropium bromide inhalation microsphere has good sphericity and uniform particle size.
Example 9
This example provides a method for preparing tiotropium bromide inhalation microspheres, which operates substantially in accordance with example 5, except that: acetonitrile (100 ml), PLGA (7525 a) (2 g), API (857 mg).
The detection of the tiotropium bromide inhalation microsphere shows that the theoretical drug loading rate is as follows: 30%; actual drug loading rate: 29.20%; encapsulation efficiency: 55.49%; meanwhile, according to the scanning electron microscope result (see fig. 10), the particle size of the tiotropium bromide inhalation microsphere is 700nm-9 μm, compared with the embodiment 1, the particle size uniformity is reduced, but the tiotropium bromide inhalation microsphere has good sphericity and uniform particle size.
Example 10
This example provides a method for preparing tiotropium bromide inhalation microspheres, which operates substantially in accordance with example 1, except that: the spray drying conditions were as follows: inlet flow rate 3ml/min, ASP (inspiration rate): 70%, air flow meter (Q airflow): 40mm, inlet temperature 70 ℃, nozzle size: 1.4mm.
According to the scanning electron microscope result (see figure 11), the particle size of the tiotropium bromide inhalation microsphere is 600nm-6 mu m, the particle size uniformity is good, and the balling property of the tiotropium bromide inhalation microsphere is good.
Example 11
This example provides a method for preparing tiotropium bromide inhalation microspheres, which operates substantially in accordance with example 1, except that: the spray drying conditions were as follows: inlet flow rate 10ml/min, ASP (inspiration rate): 100%, air flow meter (Q airflow): 40mm, inlet temperature 70 ℃, nozzle size: 1.4mm.
As can be seen from the scanning electron microscope result (see FIG. 12), the particle size of the tiotropium bromide inhalation microsphere is 600nm-8 μm, the uniformity of the particle size is slightly reduced compared with that of the example 1, but the tiotropium bromide inhalation microsphere has good sphericity and uniform particle size.
Comparative example 1
This comparative example provides a process for the preparation of tiotropium bromide inhalation microspheres, which process operates substantially in accordance with example 1, except that: acetonitrile was replaced with dichloromethane.
Experimental results: the sample is mostly deposited in a cyclone separator, the recovery rate is low, and meanwhile, according to the scanning electron microscope result (the result is shown in fig. 13) of the tiotropium bromide inhalation microsphere, the sample of the tiotropium bromide inhalation microsphere is fused, and the fusion is serious, can not be formed into balls basically, and can not be used for an adsorption preparation.
Comparative example 2:
this comparative example provides a process for the preparation of tiotropium bromide inhalation microspheres, which process operates substantially in accordance with example 1, except that: the acetonitrile was replaced with ethyl acetate.
Experimental results: the sample was mostly deposited in the cyclone separator, and at the same time, according to the scanning electron microscope result of the tiotropium bromide inhalation microsphere (result see fig. 14), it is known that the sample of tiotropium bromide inhalation microsphere is incomplete in sphere, very bad in sphere shape, and also serious fusion and agglomeration occur.
Comparative example 3
This comparative example provides a process for the preparation of tiotropium bromide inhalation microspheres, which process operates substantially in accordance with example 1, except that: PLGA was replaced with povidone K90.
Experimental results: according to the scanning electron microscope result (the result is shown in fig. 15) of the tiotropium bromide inhalation microsphere, it is known that the sample of the tiotropium bromide inhalation microsphere is seriously agglomerated, the sphericity is extremely poor, the fusion is very serious, and even the particle size of the sample cannot be measured.
Comparative example 4
This comparative example provides a process for the preparation of tiotropium bromide inhalation microspheres, which process operates substantially in accordance with example 1, except that: the spray drying conditions were as follows: inlet temperature: 60 ℃; ASP (inspiration rate): 70% of the total weight of the steel sheet; inlet flow rate: 15ml/min; an air flow meter: 60mm; nozzle size: 1.4mm.
Theoretical drug loading of tiotropium bromide inhalation microspheres formed in this comparative example: 9%; actual drug loading rate: 8.94%; encapsulation efficiency: 98.12%. From the scanning electron microscope results (see fig. 16) of the tiotropium bromide inhalation microspheres, it is clear that the sample of tiotropium bromide inhalation microspheres is severely agglomerated, mostly settled at the bottom of the separator, and severely fused, and is difficult to be used for preparing inhalation preparations.
Comparative example 5
This comparative example provides a process for the preparation of tiotropium bromide inhalation microspheres, which process operates substantially in accordance with example 1, except that: the spray drying conditions were as follows: inlet temperature: 80 ℃; ASP (inspiration rate): 100%; inlet flow rate: 3ml/min; an air flow meter: 40mm; nozzle size: 1.4mm.
Experimental results: the detection of the tiotropium bromide inhalation microsphere shows that the theoretical drug loading rate is as follows: 9%; actual drug loading rate: 9.05%; encapsulation efficiency: 98.60%. According to the scanning electron microscope result (see fig. 17), the particle size of the tiotropium bromide inhalation microsphere is less uniform, and the fusion phenomenon occurs.
Comparative example 6
This comparative example provides a process for the preparation of tiotropium bromide inhalation microspheres, which process operates substantially in accordance with example 1, except that: the spray drying conditions were as follows: inlet temperature: 70 ℃; ASP (inspiration rate): 70% of the total weight of the steel sheet; inlet flow rate: 15ml/min; an air flow meter: 60mm; nozzle size: 1.4mm.
The air flow meter and inlet flow rate of this comparative example were not within the scope of the examples of the present invention, theoretical drug loading: 23%; actual drug loading rate: 16.98%; encapsulation efficiency: 64.67% based on the scanning electron microscope results of the tiotropium bromide inhalation microspheres (see fig. 18 for results), it is clear that the tiotropium bromide inhalation microspheres are poorly spheronized and severely fused and agglomerated.
Comparative example 7
This comparative example provides a process for the preparation of tiotropium bromide inhalation microspheres, which process operates substantially in accordance with example 1, except that: the spray drying conditions were as follows: inlet temperature: 70 ℃; ASP (inspiration rate): 100%; inlet flow rate: 10ml/min; an air flow meter: 25mm; nozzle size: 1.4mm.
The air flow meter of this comparative example is not within the scope of the examples of the present invention, theoretical drug loading: 9%; actual drug loading rate: 9.11%; encapsulation efficiency: 96.13%, and according to the scanning electron microscope result (the result is shown in fig. 19), the particle size of the tiotropium bromide inhalation microsphere is 900nm-50 μm, and the particle size of the tiotropium bromide inhalation microsphere is very non-uniform.
Comparative example 8
The comparative example uses a solvent evaporation process to prepare a sample, specifically, 3 grams of PLGA is placed in a beaker, and 12 grams of methylene chloride is added and mixed well to form a stable oil phase. 1 gram of API (powder for 30min milling) was removed from the oil phase and sheared with a homogenizer at high speed for 3min (18000 rpm). A suspension is formed. The suspension was then added dropwise to the external aqueous phase (0.5% PVA solution 1L) and sheared with an emulsifier (10230 rpm for 6 min) to form an o/w emulsion. The o/w emulsion was transferred to a stirrer and stirred for 5h to allow the dichloromethane to evaporate naturally. After the completion of stirring, the mixture was filtered through a Buchner funnel, rinsed with ultrapure water, the pellet was collected, 4g of a 1% aqueous mannitol solution was added, and the collected pellets were placed in a freeze dryer. After lyophilization, the microsphere samples were collected by sieving.
Experimental results: theoretical drug loading 24.7%, actual drug loading 6.86% encapsulation efficiency: 94.44%, the sample has better balling property according to the scanning result of an electron microscope (see FIG. 20), but the granularity is not uniform, and the granularity is 1-50 mu m. The method has the advantages that the particle size required by inhalation microspheres cannot be reduced when the preparation is carried out by adopting a solvent volatilization method, the drug loading is low, and the method is difficult to be used for preparing tiotropium bromide inhalation microspheres.
Comparative example 9
The comparative example uses a rapid membrane emulsification method to prepare a sample, specifically, 2.5 grams of PLGA is first placed in a beaker, then 10 grams of methylene chloride is added and mixed well to form a stable oil phase. 695mg of API was weighed into the oil phase and sheared with a homogenizer at high speed for 3min (18000 rpm) to form a suspension. The suspension was poured directly into the external aqueous phase (300 ml of 1% PVA solution) and passed through a membrane (10 μm) emulsifier 5 times. An o/w emulsion was formed, transferred to a stirrer, stirred for 5h, and dichloromethane was allowed to evaporate naturally. After completion of stirring, the mixture was filtered through a Buchner funnel, rinsed with ultrapure water, and the pellet was collected and 1g of a 1% aqueous mannitol solution was added. The collected microspheres were placed in a lyophilizer. After lyophilization, the microsphere samples were collected by sieving.
Experimental results: theoretical drug loading rate: 21%, actual drug loading: 0.06%, encapsulation efficiency: 61.65 according to the scanning result of the electron microscope (see FIG. 21), the sample has good balling property, good dispersibility, uniform granularity and particle size of 3-9 μm, but the drug loading is very low and cannot meet the requirement, so the method cannot be adopted.
Comparative example 10
The preparation provided in this comparative example is substantially identical to example 5, except that: acetonitrile (100 ml), PLGA (7525 a) (750 mg), API (500 mg).
Experimental results: theoretical drug loading rate: 40%; actual drug loading rate: 39.67%; encapsulation efficiency: 35.25%; from its scanning electron microscope results (see fig. 22), the sample collapsed severely and could not be balled.
Comparative example 11
The comparative example provides a preparation method, which comprises the following steps: adding 2g of PLGA into 100ml of acetonitrile for dissolution, adding 500mg of API after dissolution, stirring until dissolution, and spray drying to obtain primary particles; spray drying parameters: inlet temperature: 70 ℃; ASP (inspiration rate): 100%; inlet flow rate: 5ml/min; q air flow meter: 40mm; nozzle size: 2.8mm.
In the second step, a 5% lactose-water solution (w/v) is prepared, and the final sample is obtained by spray drying after adding the primary particles to suspension.
Inlet temperature: 70 ℃; ASP (inspiration rate): 100%; inlet flow rate: 5ml/min; an air flow meter: 40mm; nozzle size: 2.8mm.
Experimental results: theoretical drug loading rate: 2.0%; actual drug loading rate: 2.09%; from a scanning electron microscope image (see fig. 23) of the sample, it is known that the sample has poor balling property, has a collapse phenomenon, and has non-uniform particle size. It can be seen that when lactose is added to the raw material, the sample particle size is not uniform and the sphericity is poor, so that lactose is not suitable to be added when the tiotropium bromide inhalation microsphere is formed by the method.
Comparative example 12
The comparative example provides a preparation method, which comprises the following steps: firstly, adding 2g of PLGA into 100ml of acetonitrile, stirring and dissolving, adding 450m g of tiotropium bromide (all tiotropium bromide refer to tiotropium bromide monohydrate) powder after dissolving, adding 25mg of albumin powder after the tiotropium bromide is completely dissolved, and performing spray drying after the albumin is completely dissolved, wherein the spray drying parameters are set as inlet flow rate of 4ml/min and ASP (air suction rate): 100%, air flow meter: 40mm, inlet temperature 75 ℃, nozzle size: 2.2mm.
Experimental results: theoretical drug loading rate: 18%; actual drug loading rate: 17.99%; encapsulation efficiency: 69.48 according to the scanning electron microscope image (see FIG. 24) of the sample, the sample has poor balling property and fusion phenomenon, and the phenomenon of uneven granularity and fusion phenomenon of the sample can be caused when albumin is added into the raw material, so that the method is not suitable for adding albumin when tiotropium bromide is formed into the inhalation microsphere.
Comparative example 13
The comparative example provides a preparation method, which comprises the following steps: firstly, adding 2g of PLGA into 100ml of acetonitrile, stirring and dissolving, adding 450m g of tiotropium bromide (all tiotropium bromide refer to tiotropium bromide monohydrate) powder after dissolving, adding 50mg of lecithin after the tiotropium bromide is completely dissolved, and performing spray drying after the lecithin is completely dissolved, wherein the spray drying parameters are set as inlet flow rate of 4ml/min and ASP (air suction rate): 100%, air flow meter: 40mm, inlet temperature 75 ℃, nozzle size: 2.2mm.
Experimental results: theoretical drug loading rate: 18%; actual drug loading rate: 17.71%; encapsulation efficiency: 73.37 according to the scanning electron microscope image (see FIG. 25) of the sample, the particle size of the sample is 800nm-18 μm, the particle size is not uniform, and the sphericity is extremely poor, therefore, when lecithin is added into the raw material, the sphericity of the sample is poor, and therefore, the method of the invention is not suitable for adding lecithin when the tiotropium bromide inhalation microsphere is formed.
Comparative example 14
The comparative example provides a preparation method, which comprises the following steps: adding 2g of PLGA into 100ml of acetonitrile for dissolution, adding 500mgAPI after dissolution, stirring until dissolution, and spray drying to obtain primary particles; inlet temperature: 70 ℃; ASP (inspiration rate): 100%; inlet flow rate: 5ml/min; an air flow meter: 40mm; nozzle size: 2.8mm.
And a second step of: adding 0.5ml Tween 80 into purified water to make its solubility 1%, adding 5g lactose, stirring to dissolve to give 10%, adding primary particles, suspending, and spray drying. Inlet temperature: 100 ℃; ASP (inspiration rate): 100%; inlet flow rate: 1.5ml/min; an air flow meter: 40mm; nozzle size: 2.2mm.
According to a scanning electron microscope image (see FIG. 26) of the sample, the particle size of the sample is 800nm-30 mu m, the particle size is nonuniform, the sphericity is extremely poor, and collapse phenomenon exists, and the particle size is nonuniform, the sphericity is poor and collapse phenomenon exists when lactose and Tween 80 are added into the raw materials, so that the method is not suitable for adding sugar and Tween when the tiotropium bromide is formed into the tiotropium bromide inhalation microsphere.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (8)
1. A method for preparing tiotropium bromide inhalation microspheres, which is characterized by comprising the following steps: mixing a carrier, a tiotropium bromide raw material and acetonitrile, and then spray drying, wherein the carrier is selected from polylactic acid-glycolic acid copolymer; the conditions of spray drying include: inlet flow rate is 2-10ml/min, air suction rate is 60-100%, air flow meter is 30-50mm, inlet temperature is 65-75 ℃, nozzle size is 1-2.8mm; the mass-volume ratio of the carrier to the acetonitrile is 0.5-3%; the mass ratio of the carrier to the tiotropium bromide raw material is 100:1-65.
2. The method of manufacturing according to claim 1, comprising: adding the carrier into the acetonitrile for mixing and dissolving, adding the tiotropium bromide raw material for mixing, and then carrying out spray drying.
3. The method of preparation according to claim 1 or 2, wherein the spray drying conditions comprise: the inlet flow rate is 2-5ml/min, the air suction rate is 70-100%, the air flow meter is 30-45mm, the inlet temperature is 65-75 ℃, and the nozzle size is 1-2mm.
4. The method of preparation according to claim 1 or 2, wherein the spray drying conditions comprise: inlet flow rate 3ml/min, air suction rate 100%, air flow meter 40mm, inlet temperature 70 ℃, nozzle size 1.4mm.
5. The preparation method according to claim 1 or 2, characterized in that the mass ratio of the carrier and the tiotropium bromide raw material is 100:1-12.
6. Tiotropium bromide inhalation microsphere, characterized in that it is prepared by the process for the preparation of tiotropium bromide inhalation microsphere according to any one of claims 1-5.
7. The tiotropium bromide inhalation microsphere according to claim 6, wherein the drug loading of the tiotropium bromide inhalation microsphere is between 5-30%.
8. An inhalable formulation comprising tiotropium bromide inhalable microspheres prepared by a method of preparing tiotropium bromide inhalable microspheres according to any one of claims 1 to 5.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1557308A (en) * | 2004-01-19 | 2004-12-29 | 复旦大学 | Tiotropium aerosol inhalant and its preparation method |
| CN102429876A (en) * | 2011-12-14 | 2012-05-02 | 深圳翰宇药业股份有限公司 | Liraglutide sustained-release microsphere preparation and preparation method thereof |
| CN105324106A (en) * | 2013-04-01 | 2016-02-10 | 普马特里克斯营业公司 | Tiotropium dry powders |
| CN112353765A (en) * | 2020-11-09 | 2021-02-12 | 山东华辰制药有限公司 | Preparation method of ceftiofur microspheres |
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| WO2009150136A1 (en) * | 2008-06-09 | 2009-12-17 | Boehringer Ingelheim International Gmbh | Novel embedment particles for inhalation |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1557308A (en) * | 2004-01-19 | 2004-12-29 | 复旦大学 | Tiotropium aerosol inhalant and its preparation method |
| CN102429876A (en) * | 2011-12-14 | 2012-05-02 | 深圳翰宇药业股份有限公司 | Liraglutide sustained-release microsphere preparation and preparation method thereof |
| CN105324106A (en) * | 2013-04-01 | 2016-02-10 | 普马特里克斯营业公司 | Tiotropium dry powders |
| CN112353765A (en) * | 2020-11-09 | 2021-02-12 | 山东华辰制药有限公司 | Preparation method of ceftiofur microspheres |
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