CN109771397B - Equipment integration and method for improving pulmonary inhalation medication through lactose micropowder predeposition - Google Patents
Equipment integration and method for improving pulmonary inhalation medication through lactose micropowder predeposition Download PDFInfo
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Abstract
The invention relates to an equipment integration and a method for improving lung inhalation medication by lactose micropowder predeposition, wherein the equipment integration mainly comprises an inhaler, a head and throat part, a breathing pipeline and lung model equipment, an inhalation device comprises two modes of predeposition lactose delivery and normal medication, and the respiratory tract model equipment can simulate the real environment of a human body by wetting the pipe wall during measurement. According to the novel administration method provided by the invention, a lactose micropowder pre-deposition step is arranged one minute before the traditional inhalation administration, and 20-200 mg of anhydrous lactose micropowder such as flower-shaped lactose, amorphous coating lactose and the like is pre-deposited in the wet and viscous head and throat part, respiratory tract and part of lung trachea, so that a smooth inhalation environment is provided for the subsequent inhalation of medicinal powder, and the deposition rate of the medicinal powder in the target area of the lung trachea is improved by 30-200%.
Description
Technical Field
The invention relates to the technical field of dry powder inhalants, in particular to equipment integration and a method for improving pulmonary inhalation medication through lactose micropowder predeposition.
Background
The dry powder inhalant is a pharmaceutical formulation of inhalant, such as tiotropium bromide powder, budesonide powder, beclomethasone dipropionate and cromolyn sodium compound powder, salmeterol and fluticasone propionate compound powder, antibiotic, insulin and other dry powder inhalants. The medicine is prepared by inhaling dry powder of the medicine, and the micro powder of the medicine with the particle size of 1-5 microns reaches the lung from an inhaler, the head and the throat and the respiratory tract, so that the medicine effect is exerted. Particles with the particle size larger than 5 microns are difficult to reach the lung and can be deposited in the oral cavity and the respiratory tract; particles with a particle size of less than 1 micron are difficult to deposit and are easily subsequently exhaled. Therefore, it is the key point of dry powder inhalation technology to allow more powder to reach and deposit in the lungs.
The patent of 'Dry powder inhalant of Interferon alpha' (CN 201210236625.9) and 'Dry powder inhalant of Interferon alpha' (CN 201210236604.7) applied by Beijing ternary genetic engineering Co., Ltd, the Dry powder inhalant is matched with a proper amount of pharmaceutic adjuvants to improve the drug effect, and the pharmaceutic adjuvants comprise an activity protective agent, a dispersion auxiliary agent, a pH stability regulator, a diluent and a large-particle carrier adjuvant. Other patents in the prior art such as inhaled anti-lung cancer targeted pharmaceutical preparation (CN 201710487818.4) also adopt various auxiliary materials to improve the targeting ability of the dry powder inhalant, and the literature describes that the dispersing auxiliary agent is selected from one or more of leucine, phenylalanine and glycine, the pH stabilizing regulator is selected from phosphate buffer solution and citrate buffer solution, and the diluent is selected from lactose or mannitol. The Karim Amighi et al patent Improved pharmaceutical delivery formulations for inhalation (WO 2009050217A 2) also enumerates a number of materials that can be used as carriers for dry powder inhalers, including monosaccharides, polysaccharides, and the like.
The adoption of a plurality of composite auxiliary materials is a method for effectively improving the lung deposition rate of the medicinal powder, but because the safety of the matching of the plurality of auxiliary materials is unknown, the dry powder inhalant approved by the Food and Drug Administration (FDA) basically only admits lactose as the only safe carrier auxiliary material; in recent years, mannitol adjuvant has been used in dry powder inhalants, but there are few cases. The pharmaceutical lactose specifications commonly used are alpha-lactose monohydrate, alpha-lactose anhydrous, beta-lactose anhydrous (both alpha-lactose anhydrous and beta-lactose anhydrous are often present in mixed, or mixed, crystalline forms) and amorphous lactose which is not crystalline.
Based on the principle of practicality, according to the FDA standards, the use of lactose as a carrier for dry powder inhalants is the basis on which products can be industrialized. Hyo-Jung Lee et al, in 2018, published in The Journal of The European Journal of Pharmaceutical Sciences under The name of "The role of lactose carrier on The powder inhaler and aeromechanical performance of sensing microorganisms for dry powder inhaler" (Vol. 117: 279-289), discussed in principle The effect of different morphological sizes of milled or sieved lactose particles on dry powder inhalers, which can result in different drug powder deposition rates (i.e., drug efficacy) using different lactose excipient carriers. Therefore, in the patent of fluticasone propionate and salmeterol xinafoate compound dry powder inhalant and the preparation process thereof (CN 200810204741.6), lactose with two specifications is mixed for use to improve the drug effect.
In conclusion, it is a current problem to be solved to seek a more efficient inhalation administration method, which reduces the deposition of the drug powder at non-target positions (head and throat, respiratory tract), increases the deposition rate of the drug powder at target positions (deep lung and lung trachea), and has a practical and feasible scheme (only lactose is used as a pharmaceutical adjuvant to meet the safety requirement of FDA).
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide equipment integration and a method for improving the medicine inhalation of the lung by predeposition of lactose micropowder, and the efficiency of subsequent medicine administration is enhanced by predeposition of anhydrous lactose micropowder at the head throat, respiratory tract and the like.
In order to achieve the purpose, the technical scheme provided by the invention is as follows:
the equipment integration for improving the lung inhalation medication through lactose micropowder predeposition mainly comprises an inhaler, a head-throat part, a breathing pipeline and lung model equipment, wherein an air outlet of the inhaler is communicated with an air inlet of the head-throat part, an air outlet of the head-throat part is communicated with an air inlet of the breathing pipeline, and an air outlet of the breathing pipeline is communicated with an air inlet of the lung model equipment; the inhaler mainly comprises a filter tip, an inhaler air inlet, a medicine powder compartment, a lactose micro powder compartment, a V-shaped compartment switching baffle, a compartment switching knob and an inhaler air outlet, the head-throat part mainly comprises a head-throat part air inlet, a throat passage and a head-throat part air outlet, the breathing pipeline mainly comprises an air passage and a breathing pipeline air outlet, and the lung model equipment mainly comprises a dendritic air inlet pipe, an air pipe cavity, an inter-cavity grid, an air compression cavity, a manual-automatic air compression plate, an air compression plate moving track and a track electric motor.
The inhaler comprises two administration modes, when the V-shaped compartment switching baffle is in the original position, the medicine powder compartment is separated by the baffle, and the inlet air reaches the air outlet of the inhaler through the lactose micropowder compartment; when the V-shaped compartment switching baffle is switched to the dotted line position shown in the figure by the compartment switching knob, the medicine powder compartment is opened, the lactose micro powder compartment is separated by the baffle, and the air inlet reaches the air outlet of the inhaler through the medicine powder compartment.
When the manual-automatic integrated air compressing plate moves left, the air pipe cavity and the whole system form negative pressure to simulate air suction; when the manual-automatic integrated air compressing plate moves rightwards, the air pipe cavity and the whole system form positive pressure to simulate expiration.
When the equipment integration for improving the medicine inhalation of the lung by lactose micropowder predeposition is used, the wall of the whole system is kept in a wet state by breathing in water vapor so as to simulate the actual condition of a human body; the provided apparatus integrates to detect the effect of the provided method and to collect model data for method improvement, experience accumulation and clinical guidance.
The method for improving the lung inhalation medication through lactose micropowder predeposition is characterized in that a lactose micropowder predeposition step is arranged one minute before the traditional inhalation medication, and 20-200 mg of anhydrous lactose micropowder such as flower-shaped lactose, amorphous coating lactose and the like is predeposited in a wet and viscous head and throat part, a breathing pipeline and a part of lung trachea, so that a smooth inhalation environment is provided for the subsequent inhalation of medicinal powder, and the deposition rate of the medicinal powder in a target area of the lung trachea is improved by 30-200%.
For the method for improving the medicine administration by pulmonary inhalation through lactose micropowder predeposition, it should be noted that the anhydrous lactose micropowder such as the flower-shaped lactose and the amorphous coated lactose for predeposition should not be less than 20 mg, otherwise, the amount of the anhydrous lactose micropowder predeposited in the head and throat, the respiratory tract and part of the trachea of the lung is too small, and the part is still wet and viscous, and a large amount of medicine powder for subsequent administration can be deposited; the anhydrous lactose micropowder such as flower-shaped lactose and amorphous coated lactose for predeposition should not be higher than 200 mg, so that discomfort of throat and respiratory tract of patients can be caused by excessive use of the anhydrous lactose micropowder, and the excessive use of the anhydrous lactose micropowder does not change the environment of air wall pipeline obviously, so that the necessity is low.
When the amount of anhydrous lactose micropowder such as floriform lactose, amorphous coated lactose and the like used for pre-deposition is increased from 20 mg to 200 mg, the deposition rate of a target area is increased from 30% to 200%, but the increased proportion is related to the particle size of the anhydrous lactose micropowder; according to the size of the respiratory system pipeline, when the particle size of the anhydrous lactose micropowder for predeposition is 10-50 microns, the anhydrous lactose micropowder is mainly attached to the wall of the head-throat pipeline, so that the deposition of subsequent inhaled medicinal powder on the wall of the head-throat pipeline is reduced, and more medicinal powder reaches the respiratory pipeline and the lung; when the particle size of the anhydrous lactose micropowder for predeposition is 5-10 microns, the anhydrous lactose micropowder is mainly attached to the walls of the head-throat pipeline and the breathing pipeline, so that the deposition of subsequent inhaled medicinal powder on the walls of the head-throat pipeline and the breathing pipeline is reduced, and more medicinal powder reaches the lung; when the particle size of the anhydrous lactose micropowder for predeposition is 1-5 microns and the dosage is 20-50 mg, the anhydrous lactose micropowder can be attached to the trachea of the anterior lung, so that the deposition of the subsequently inhaled medicinal powder in the trachea of the anterior lung is reduced, and more medicinal powder reaches the deep part of the lung.
When the lactose mixed materials with various specifications and sizes are mixed and adopted as the pre-deposited micro powder according to a certain proportion, the environment of moist and viscous whole wall surface can be uniformly and effectively improved, and the optimal pre-deposition effect is achieved. When the anhydrous lactose fine powder used in the pre-deposition step is mixed with the dosages of 80 mg, 10-50 microns, 70 mg, 5-10 microns and 50 mg, 1-5 microns in particle size, the anhydrous lactose fine powder is attached to all airways, and 10-30% of subsequently inhaled medicine powder reaches 30% of the area at the bottom of the lung.
A method for improving pulmonary inhalation by lactose micropowder predeposition as described above, wherein the clinical administration step comprises S1: filling anhydrous lactose with the particle size of 1-50 microns according to the target administration part; s2: inhaling gas, and administering anhydrous lactose micropowder to pre-deposit on respiratory tract; s3: completely exhaling the air, adjusting the inhaler within one minute, and preparing for inhalation; s4: and (4) normally inhaling for administration, and keeping for 5-10 seconds so that the medicinal powder completely reaches the lung.
The flower-shaped lactose is anhydrous alpha/beta composite crystalline lactose, the particle size of the anhydrous alpha/beta composite crystalline lactose is 1-50 microns, and the nitrogen adsorption surface area is 20-50 m2(ii)/g; the amorphous coated lactose is amorphous lactose particles prepared by spray drying or freeze drying, the particle size of the particles is 1-50 microns, and a layer of monohydrate crystal coating is formed on the surface of the particles after the particles are subjected to motion treatment for 30 minutes in an environment with the relative humidity of a fluidized bed being 70%; the flower-shaped lactose and the amorphous coated lactose are very soluble in water and can be stably stored at room temperature.
The flower-shaped lactose is anhydrous alpha/beta composite crystalline lactose, the size and the surface area can be changed by changing the production conditions, the size specification for predeposition of the tube wall is 1-50 micrometers, so the flower-shaped lactose product with the same size is adopted, the nitrogen adsorption surface area is inversely proportional to the size, and when the size is increased from 1 micrometer to 50 micrometers, the nitrogen adsorption surface area is 50m2The/g is reduced to 20m2(ii)/g; when the amorphous coated lactose is prepared by spray drying, the particle size can be changed to 1-50 microns by changing the aperture, spraying speed and concentration of the spray drying, and when the amorphous coated lactose is prepared by freeze drying, the particle size needs to be 1-50 microns by grinding; the relative parameter is 30 minutes of movement treatment in the environment with 70 percent of relative humidity adopted in the fluidized bed, the surface of the anhydrous lactose particles can be combined with water molecules and crystallized to form a layer of monohydrate crystalline lactose coating on the outer layer, a thicker monohydrate crystalline lactose coating can be formed by adopting higher humidity and/or time, the solubility of the particles can be reduced, and when the lower humidity and/or time is adopted, the formed monohydrate crystalline lactose coating is too thin, the physical and chemical stability of the particles can be reduced, but the monohydrate crystalline lactose coating with the same thickness can be obtained by changing the humidity and reversely changing the treatment time; it should also be noted that besides floriated lactose, amorphous coated lactose, other anhydrous lactose micropowder, even lactose monohydrate, can be used instead, but because of their relatively poor water solubility, they are not conducive to wall predeposition.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings of the present invention will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art that other drawings can be obtained according to the drawings without inventive labor.
FIG. 1 is a schematic structural diagram of an apparatus integration for improving pulmonary inhalation medication through lactose micropowder pre-deposition, and the apparatus integration comprises an inhaler (1), a filter tip (1-1), an inhaler air inlet (1-2), a powder compartment (1-3), a lactose micropowder compartment (1-4), a V-shaped compartment switching baffle (1-5), a compartment switching knob (1-6), an inhaler air outlet (1-7), a head and throat part (2), a head and throat part air inlet (2-1), a throat passage (2-2), a head and throat part air outlet (2-3), a breathing pipeline (3), a ventilation passage (3-1), a breathing pipeline air outlet (3-2), a pulmonary model apparatus (4), a dendritic air inlet pipe (4-1), an air pipe cavity (4-2), an intercavity grid (4-3), The air compression chamber (4-4), the manual-automatic air compression plate (4-5), the air compression plate moving track (4-6) and the track electric motor (4-7).
Fig. 2 is a flow chart of a method for improving pulmonary inhalation administration by lactose micropowder predeposition according to an embodiment of the present invention, and the clinical administration steps are shown.
Fig. 3 is an electron microscope scanning image of three flower-shaped lactose micro powders with different sizes used in the second, third, fourth and fifth embodiments of the present invention.
Fig. 4 is an electron microscope scan of three different sizes of amorphous coated lactose micropowder (prepared by spray drying) used in examples six, seven, eight, and nine of the present invention.
Fig. 5 is an electron microscope scan of three different sizes of amorphous coated lactose micropowder (prepared by freeze-drying) used in example ten, eleven, twelve and thirteen of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be described below with reference to the embodiments of the present invention and the accompanying drawings, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The first embodiment is as follows:
as shown in fig. 1 (a schematic structural diagram of an apparatus assembly for improving pulmonary inhalation medication by lactose micropowder predeposition), the apparatus assembly for improving pulmonary inhalation medication by lactose micropowder predeposition mainly comprises an inhaler (1), a head and throat part (2), a breathing pipeline (3) and a pulmonary model apparatus (4), wherein an air outlet of the inhaler (1) is communicated with an air inlet of the head and throat part (2), an air outlet of the head and throat part (2) is communicated with an air inlet of the breathing pipeline (3), and an air outlet of the breathing pipeline (3) is communicated with an air inlet of the pulmonary model apparatus (4); the inhaler (1) mainly comprises a filter tip (1-1), an inhaler air inlet (1-2), a medicine powder compartment (1-3), a lactose micropowder compartment (1-4), a V-shaped compartment switching baffle (1-5), a compartment switching knob (1-6) and an inhaler air outlet (1-7), the head and throat part (2) mainly comprises a head and throat part air inlet (2-1), a throat passage (2-2) and a head and throat part air outlet (2-3), the breathing pipeline (3) mainly comprises an air passage (3-1) and a breathing pipeline air outlet (3-2), the lung model equipment (4) mainly comprises a dendritic air inlet pipe (4-1), an air pipe cavity (4-2), an intercavity grid (4-3), a compressed air cavity (4-4), A manual-automatic integrated air compressing plate (4-5), an air compressing plate moving track (4-6) and a track electric motor (4-7).
The inhaler (1) comprises two administration modes, when a V-shaped compartment switching baffle (1-5) is in the original position, a medicine powder compartment (1-3) is separated by the baffle, and the inlet air reaches an inhaler air outlet (1-7) through a lactose micropowder compartment (1-4); when the V-shaped compartment switching baffle (1-5) is switched to the dotted line position shown in the figure by the compartment switching knob (1-6), the medicine powder compartment (1-3) is opened, the lactose micropowder compartment (1-4) is blocked by the baffle, and the air inlet reaches the air outlet (1-7) of the inhaler through the medicine powder compartment (1-3).
When the manual-automatic integrated air compression plate (4-5) moves left, the air tube cavity (4-2) and the whole system form negative pressure to simulate air suction; when the manual-automatic integrated air compression plate (4-5) moves rightwards, the air tube cavity (4-2) and the whole system form positive pressure to simulate expiration.
The equipment integration for improving the medicine inhalation for the lung by lactose micropowder predeposition provided by the embodiment can ensure that the wall of the whole system is kept in a wet state by breathing water vapor when the equipment integration for improving the medicine inhalation for the lung by lactose micropowder predeposition is used, so as to simulate the actual condition of a human body; the provided apparatus integrates to detect the effects of the methods of administration provided below, and to collect model data for process improvement, empirical accumulation, and clinical guidance.
The embodiment also provides a method for improving the lung inhalation medication by lactose micropowder pre-deposition, wherein a lactose micropowder pre-deposition step is arranged one minute before the traditional inhalation medication, and 20-200 mg of anhydrous lactose micropowder such as flower-shaped lactose, amorphous coating lactose and the like is pre-deposited in a wet and viscous head and throat part, a breathing pipeline and a part of lung trachea, so that a smooth inhalation environment is provided for the subsequent inhalation of the medicine powder, and the deposition rate of the medicine powder in a target area of the lung trachea is improved by 30-200%; when the particle size of the anhydrous lactose micropowder for predeposition is 10-50 microns, the anhydrous lactose micropowder is mainly attached to the wall of the pipeline at the head and throat, so that the deposition of subsequent inhaled medicinal powder on the wall of the pipeline at the head and throat is reduced, and more medicinal powder reaches the respiratory pipeline and the lung; when the particle size of the anhydrous lactose micropowder for predeposition is 5-10 microns, the anhydrous lactose micropowder is mainly attached to the walls of the head-throat pipeline and the breathing pipeline, so that the deposition of subsequent inhaled medicinal powder on the walls of the head-throat pipeline and the breathing pipeline is reduced, and more medicinal powder reaches the lung; when the particle size of the anhydrous lactose micropowder for predeposition is 1-5 microns and the dosage is 20-50 mg, the anhydrous lactose micropowder can be attached to the trachea of the anterior lung, so that the deposition of the subsequently inhaled medicinal powder in the trachea of the anterior lung is reduced, and more medicinal powder reaches the deep part of the lung.
Aiming at the method for improving the pulmonary inhalation medication by lactose micropowder predeposition, the invention designs the clinical medication step of the method.
Fig. 2 is a flow chart of a method for improving pulmonary inhalation administration by lactose micropowder predeposition according to an embodiment of the present invention, and the clinical administration steps are shown. As shown in fig. 2, the method for improving pulmonary inhalation administration by lactose micropowder predeposition comprises the following clinical administration steps:
s1: filling anhydrous lactose with the particle size of 1-50 microns according to the target administration part;
s2: inhaling gas, and administering anhydrous lactose micropowder to pre-deposit on respiratory tract;
s3: completely exhaling the air, adjusting the inhaler within one minute, and preparing for inhalation;
s4: and (4) normally inhaling for administration, and keeping for 5-10 seconds so that the medicinal powder completely reaches the lung.
The present invention provides an apparatus integration and method for improved administration by pulmonary inhalation via lactose micropowder predeposition, as further described in the following examples.
Example two:
this example provides a specific clinical administration procedure based on the described device integration and method for improved pulmonary inhalation administration by lactose micropowder predeposition, comprising:
s1: aiming at the respiratory tract and the lung of the target administration part, 20 milligrams of flower-shaped lactose with the grain diameter of 10-50 microns (the nitrogen adsorption surface area of the material is 20-30 m)2/g）；
S2: inhaling gas, and administering anhydrous lactose micropowder to pre-deposit on respiratory tract;
s3: completely exhaling the air, adjusting the inhaler within one minute, and preparing for inhalation;
s4: and (3) normally inhaling and administering the tiotropium bromide powder, and keeping for 5-10 seconds to enable the powder to completely reach the lung.
The simulation was performed using the apparatus shown in fig. 1, and the deposition rate was measured by first sucking the anhydrous lactose fine powder to settle in the wet tube and then sucking the powder. When the particle size of the anhydrous lactose micropowder for predeposition is 10-50 microns, the anhydrous lactose micropowder is mainly attached to the wall of the pipeline at the head and throat, so that the deposition of subsequent inhaled medicine powder on the wall of the pipeline at the head and throat is reduced, and more medicine powder reaches the respiratory tract and the lung. The data show that the deposition rate of the powder at the target site (respiratory tract and lungs) was increased by 30% when using lactose pre-precipitation versus lactose pre-precipitation provided without the method of the present invention.
Example three:
this example provides a specific clinical administration procedure based on the described device integration and method for improved pulmonary inhalation administration by lactose micropowder predeposition, comprising:
s1: aiming at the target administration part, namely lung, 100 mg of flower-shaped lactose with the particle size of 5-10 microns is filled (the nitrogen adsorption surface area of the material is 30-40 m)2/g）；
S2: inhaling gas, and administering anhydrous lactose micropowder to pre-deposit on respiratory tract;
s3: completely exhaling the air, adjusting the inhaler within one minute, and preparing for inhalation;
s4: and normally inhaling the budesonide powder for administration, and keeping for 5-10 seconds so that the powder can completely reach the lung.
The simulation was performed using the apparatus shown in fig. 1, and the deposition rate was measured by first sucking the anhydrous lactose fine powder to settle in the wet tube and then sucking the powder. When the particle size of the anhydrous lactose micropowder for predeposition is 5-10 micrometers, the anhydrous lactose micropowder is mainly attached to the walls of the head-throat pipeline and the breathing pipeline, so that the deposition of subsequent inhaled medicinal powder on the walls of the head-throat pipeline and the breathing pipeline is reduced, and more medicinal powder reaches the lung. The data show that the deposition rate of the powder at the target site (lung) is increased by 100% when using lactose pre-precipitation, relative to lactose pre-precipitation provided without the method of the invention.
Example four:
this example provides a specific clinical administration procedure based on the described device integration and method for improved pulmonary inhalation administration by lactose micropowder predeposition, comprising:
s1: to the targetThe administration part is lung, 50 mg of flower-shaped lactose with the particle size of 1-5 microns is filled in the lung (the nitrogen adsorption surface area of the material is 40-50 m2/g）；
S2: inhaling gas, and administering anhydrous lactose micropowder to pre-deposit on respiratory tract;
s3: completely exhaling the air, adjusting the inhaler within one minute, and preparing for inhalation;
s4: and (3) normally inhaling the beclomethasone dipropionate and cromolyn sodium compound powder, and keeping for 5-10 seconds so that the powder can completely reach the lung.
The simulation was performed using the apparatus shown in fig. 1, and the deposition rate was measured by first sucking the anhydrous lactose fine powder to settle in the wet tube and then sucking the powder. The particle size of the anhydrous lactose micropowder for predeposition is 1-5 microns, so that the anhydrous lactose micropowder can be attached to the trachea of the front lung, the deposition of subsequent inhaled medicine powder on the trachea of the front lung is reduced, and more medicine powder reaches the deep part of the lung. The data show that the deposition rate of the powder at the target site (lung) is improved by 70% when using lactose pre-precipitation, relative to lactose pre-precipitation provided without the method of the invention.
It is worth to be noted that, when the particle size of the flower-shaped lactose micropowder is 1-5 microns, the dosage needs to be 20-50 mg, and excessive dosage can cause a large amount of lactose micropowder to be attached to the lung, which is not beneficial to the deposition of subsequent medicinal powder.
Example five:
this example provides a specific clinical administration procedure based on the described device integration and method for improved pulmonary inhalation administration by lactose micropowder predeposition, comprising:
s1: filling 80 mg of flower-shaped lactose with the particle size of 10-50 microns, 70 mg of flower-shaped lactose with the particle size of 5-10 microns and 50 mg of flower-shaped lactose with the particle size of 1-5 microns into a region with a target administration part being 30% of the bottom end of a lung;
s2: inhaling gas, and administering anhydrous lactose micropowder to pre-deposit on respiratory tract;
s3: completely exhaling the air, adjusting the inhaler within one minute, and preparing for inhalation;
s4: normally inhaling and administering the insulin dry powder inhalant, and keeping for 5-10 seconds so that the powdered insulin completely reaches the lung.
The simulation was performed using the apparatus shown in fig. 1, and the deposition rate was measured by first sucking the anhydrous lactose fine powder to settle in the wet tube and then sucking the powder. The anhydrous lactose micropowder can be attached to all airways, 30% of subsequently inhaled medicine powder reaches 30% of the area of the bottom of the lung, and compared with the lactose pre-precipitation provided by the method without the anhydrous lactose micropowder, the deposition rate of the medicine powder at a target position (30% of the area of the bottom of the lung) is improved by 200% (originally 15%) by adopting the lactose pre-precipitation.
The flower-shaped lactose in the second, third, fourth and fifth embodiments is anhydrous alpha/beta composite crystalline lactose, the particle size of the anhydrous alpha/beta composite crystalline lactose is 1-50 micrometers, and the nitrogen adsorption surface area is 20-50 m2(ii)/g; the flower-shaped lactose is anhydrous alpha/beta composite crystalline lactose, the size and the surface area can be changed by changing the production conditions, the size specification for predeposition of the tube wall is 1-50 micrometers, so the flower-shaped lactose product with the same size is adopted, the nitrogen adsorption surface area is inversely proportional to the size, and when the size is increased from 1 micrometer to 50 micrometers, the nitrogen adsorption surface area is 50m2The/g is reduced to 20m2The negative correlation of nitrogen adsorption surface area to particle size is due to the larger area of external air contact per mass of small particles.
Fig. 3 is an electron microscope scanning image of three different sizes of the flower-shaped lactose micropowder used in the second, third, fourth and fifth embodiments of the present invention, which shows that the flower-shaped lactose has a larger surface area, so that the flower-shaped lactose has a larger potential to combine with wet viscous tube walls.
Example six:
this example provides a specific clinical administration procedure based on the described device integration and method for improved pulmonary inhalation administration by lactose micropowder predeposition, comprising:
s1: filling 30 mg of amorphous coated lactose micropowder (prepared by spray drying) with the particle size of 10-50 microns into a target administration part, namely a respiratory tract and a lung;
s2: inhaling gas, and administering anhydrous lactose micropowder to pre-deposit on respiratory tract;
s3: completely exhaling the air, adjusting the inhaler within one minute, and preparing for inhalation;
s4: normally inhaling salmeterol and fluticasone propionate compound powder for administration, and keeping the drug powder to completely reach the lung for 5-10 seconds.
The simulation was performed using the apparatus shown in fig. 1, and the deposition rate was measured by first sucking the anhydrous lactose fine powder to settle in the wet tube and then sucking the powder. When the particle size of the anhydrous lactose micropowder for predeposition is 10-50 microns, the anhydrous lactose micropowder is mainly attached to the wall of the pipeline at the head and throat, so that the deposition of subsequent inhaled medicine powder on the wall of the pipeline at the head and throat is reduced, and more medicine powder reaches the respiratory tract and the lung. The data show that the deposition rate of the powder at the target site (respiratory tract and lung) was increased by 40% when using lactose pre-precipitation versus lactose pre-precipitation provided without the method of the present invention.
Example seven:
this example provides a specific clinical administration procedure based on the described device integration and method for improved pulmonary inhalation administration by lactose micropowder predeposition, comprising:
s1: filling 150 mg of amorphous coated lactose micropowder (prepared by spray drying) with the particle size of 5-10 microns into a target administration part, namely a lung;
s2: inhaling gas, and administering anhydrous lactose micropowder to pre-deposit on respiratory tract;
s3: completely exhaling the air, adjusting the inhaler within one minute, and preparing for inhalation;
s4: and (3) normally inhaling the antibiotic dry powder inhalant for administration, and keeping for 5-10 seconds so that the powder can completely reach the lung.
The simulation was performed using the apparatus shown in fig. 1, and the deposition rate was measured by first sucking the anhydrous lactose fine powder to settle in the wet tube and then sucking the powder. When the particle size of the anhydrous lactose micropowder for predeposition is 5-10 micrometers, the anhydrous lactose micropowder is mainly attached to the walls of the head-throat pipeline and the breathing pipeline, so that the deposition of subsequent inhaled medicinal powder on the walls of the head-throat pipeline and the breathing pipeline is reduced, and more medicinal powder reaches the lung. The data show that the deposition rate of the powder at the target site (lung) is increased by 120% when using lactose pre-precipitation, relative to lactose pre-precipitation provided without the method of the invention.
Example eight:
this example provides a specific clinical administration procedure based on the described device integration and method for improved pulmonary inhalation administration by lactose micropowder predeposition, comprising:
s1: filling 20 mg of amorphous coated lactose micropowder (prepared by spray drying) with the particle size of 1-5 microns into a target administration part, namely a lung;
s2: inhaling gas, and administering anhydrous lactose micropowder to pre-deposit on respiratory tract;
s3: completely exhaling the air, adjusting the inhaler within one minute, and preparing for inhalation;
s4: and (3) normally inhaling the beclomethasone dipropionate and cromolyn sodium compound powder, and keeping for 5-10 seconds so that the powder can completely reach the lung.
The simulation was performed using the apparatus shown in fig. 1, and the deposition rate was measured by first sucking the anhydrous lactose fine powder to settle in the wet tube and then sucking the powder. The particle size of the anhydrous lactose micropowder for predeposition is 1-5 microns, so that the anhydrous lactose micropowder can be attached to the trachea of the front lung, the deposition of subsequent inhaled medicine powder on the trachea of the front lung is reduced, and more medicine powder reaches the deep part of the lung. The data show that the deposition rate of the powder at the target site (lung) is improved by 30% when using lactose pre-precipitation, relative to lactose pre-precipitation provided without the method of the invention.
It is worth noting that when the particle size of the amorphous coated lactose micropowder (prepared by spray drying) is 1-5 microns, the dosage is 20-50 mg, and excessive dosage can attach to the lung in a large amount, which is not beneficial to the deposition of subsequent medicinal powder.
Example nine:
this example provides a specific clinical administration procedure based on the described device integration and method for improved pulmonary inhalation administration by lactose micropowder predeposition, comprising:
s1: filling amorphous coated lactose micropowder (prepared by spray drying) with 80 mg, 10-50 microns, 70 mg, 5-10 microns and 50 mg, 1-5 microns into a region with a target administration part being 30% of the bottom end of a lung;
s2: inhaling gas, and administering anhydrous lactose micropowder to pre-deposit on respiratory tract;
s3: completely exhaling the air, adjusting the inhaler within one minute, and preparing for inhalation;
s4: the normal inhalation administration of the anticancer active drug dry powder inhalant is carried out, and the medicine powder completely reaches the lung after 5-10 seconds.
The simulation was performed using the apparatus shown in fig. 1, and the deposition rate was measured by first sucking the anhydrous lactose fine powder to settle in the wet tube and then sucking the powder. The anhydrous lactose micropowder can be attached to all airways, 20% of subsequently inhaled medicine powder reaches 30% of the area of the bottom of the lung, and compared with the lactose pre-precipitation provided by the method without the anhydrous lactose micropowder, the deposition rate of the medicine powder at a target position (30% of the area of the bottom of the lung) is improved by 100% (originally 10%) when the lactose pre-precipitation is adopted, so that the anticancer curative effect is enhanced.
The amorphous coated lactose described in the above examples six, seven, eight and nine is amorphous lactose fine particles prepared by spray drying, the particle size of the particles is 1 to 50 micrometers, and a layer of monohydrate crystal coating is formed on the surface of the particles after the particles are subjected to motion treatment in an environment with a relative humidity of a fluidized bed of 70% for 30 minutes; when the amorphous coated lactose is prepared by spray drying, the particle size can be changed to 1-50 microns by changing the aperture, spraying speed and concentration of spray drying; the relative humidity of the fluidized bed is 70%, the relative parameter is 30 minutes of movement treatment, the surface of the anhydrous lactose particles can be combined with water molecules and crystallized to form a layer of monohydrate crystalline lactose coating on the outer layer, a thicker monohydrate crystalline lactose coating can be formed by adopting higher humidity and/or time, the solubility of the particles can be reduced, and when the lower humidity and/or time is adopted, the formed monohydrate crystalline lactose coating is too thin, the physical and chemical stability of the particles can be reduced, but the monohydrate crystalline lactose coating with the same thickness can be obtained by changing the humidity and reversely changing the treatment time.
Fig. 4 is an electron microscope scanning image of three kinds of amorphous coated lactose micropowder (prepared by spray drying) with different sizes and sizes adopted in six, seven, eight and nine embodiments of the present invention, and it can be seen that the amorphous coated lactose micropowder prepared by spray drying is spherical, and under a certain mass, the spherical geometric surface area is extremely large, which is beneficial to the adsorption of the amorphous coated lactose micropowder on the wet viscous tube wall.
Example ten:
this example provides a specific clinical administration procedure based on the described device integration and method for improved pulmonary inhalation administration by lactose micropowder predeposition, comprising:
s1: filling 100 mg of amorphous coated lactose micropowder (prepared by freeze drying) with the particle size of 10-50 microns into a target administration part, namely a respiratory tract and a lung;
s2: inhaling gas, and administering anhydrous lactose micropowder to pre-deposit on respiratory tract;
s3: completely exhaling the air, adjusting the inhaler within one minute, and preparing for inhalation;
s4: and normally inhaling the budesonide powder for administration, and keeping for 5-10 seconds so that the powder can completely reach the lung.
The simulation was performed using the apparatus shown in fig. 1, and the deposition rate was measured by first sucking the anhydrous lactose fine powder to settle in the wet tube and then sucking the powder. When the particle size of the anhydrous lactose micropowder for predeposition is 10-50 microns, the anhydrous lactose micropowder is mainly attached to the wall of the pipeline at the head and throat, so that the deposition of subsequent inhaled medicine powder on the wall of the pipeline at the head and throat is reduced, and more medicine powder reaches the respiratory tract and the lung. The data show that the deposition rate of the powder at the target site (respiratory tract and lung) is improved by 60% when lactose pre-precipitation is used, relative to lactose pre-precipitation provided without the method of the present invention.
Example eleven:
this example provides a specific clinical administration procedure based on the described device integration and method for improved pulmonary inhalation administration by lactose micropowder predeposition, comprising:
s1: filling 20 mg of amorphous coated lactose micropowder (prepared by freeze drying) with the particle size of 5-10 microns into a target administration part, namely a lung;
s2: inhaling gas, and administering anhydrous lactose micropowder to pre-deposit on respiratory tract;
s3: completely exhaling the air, adjusting the inhaler within one minute, and preparing for inhalation;
s4: and (3) normally inhaling the antibiotic dry powder inhalant for administration, and keeping for 5-10 seconds so that the powder can completely reach the lung.
The simulation was performed using the apparatus shown in fig. 1, and the deposition rate was measured by first sucking the anhydrous lactose fine powder to settle in the wet tube and then sucking the powder. When the particle size of the anhydrous lactose micropowder for predeposition is 5-10 micrometers, the anhydrous lactose micropowder is mainly attached to the walls of the head-throat pipeline and the breathing pipeline, so that the deposition of subsequent inhaled medicinal powder on the walls of the head-throat pipeline and the breathing pipeline is reduced, and more medicinal powder reaches the lung. The data show that the deposition rate of the powder at the target site (lung) is improved by 30% when using lactose pre-precipitation, relative to lactose pre-precipitation provided without the method of the invention.
Example twelve:
this example provides a specific clinical administration procedure based on the described device integration and method for improved pulmonary inhalation administration by lactose micropowder predeposition, comprising:
s1: filling 40 mg of amorphous coated lactose micropowder (prepared by freeze drying) with the particle size of 1-5 microns into a target administration part, namely a lung;
s2: inhaling gas, and administering anhydrous lactose micropowder to pre-deposit on respiratory tract;
s3: completely exhaling the air, adjusting the inhaler within one minute, and preparing for inhalation;
s4: normally inhaling and administering curcumin dry powder inhalant, and keeping for 5-10 seconds so that the curcumin dry powder completely reaches the lung.
The simulation was performed using the apparatus shown in fig. 1, and the deposition rate was measured by first sucking the anhydrous lactose fine powder to settle in the wet tube and then sucking the powder. The particle size of the anhydrous lactose micropowder for predeposition is 1-5 microns, so that the anhydrous lactose micropowder can be attached to the trachea of the front lung, the deposition of subsequent inhaled medicine powder on the trachea of the front lung is reduced, and more medicine powder reaches the deep part of the lung. The data show that the deposition rate of the powder at the target site (lung) is increased by 50% when using lactose pre-precipitation, relative to lactose pre-precipitation provided without the method of the invention.
It is worth noting that when the particle size of the amorphous coated lactose micropowder (prepared by spray drying) is 1-5 microns, the dosage is 20-50 mg, and excessive dosage can attach to the lung in a large amount, which is not beneficial to the deposition of subsequent medicinal powder.
Example thirteen:
this example provides a specific clinical administration procedure based on the described device integration and method for improved pulmonary inhalation administration by lactose micropowder predeposition, comprising:
s1: filling amorphous coated lactose micropowder (prepared by freeze drying) with 80 mg, 10-50 microns, 70 mg, 5-10 microns and 50 mg, 1-5 microns into a region with a target administration part being 30% of the bottom end of a lung;
s2: inhaling gas, and administering anhydrous lactose micropowder to pre-deposit on respiratory tract;
s3: completely exhaling the air, adjusting the inhaler within one minute, and preparing for inhalation;
s4: normally inhaling the traditional Chinese medicine dry powder inhalant for administration, and keeping for 5-10 seconds so that the powder can completely reach the lung.
The simulation was performed using the apparatus shown in fig. 1, and the deposition rate was measured by first sucking the anhydrous lactose fine powder to settle in the wet tube and then sucking the powder. The anhydrous lactose micropowder can be attached to all airways, 10% of subsequently inhaled medicine powder reaches 30% of the area of the bottom of the lung, and compared with the lactose pre-precipitation provided by the method without the anhydrous lactose micropowder, the deposition rate of the medicine powder at a target position (30% of the area of the bottom of the lung) is improved by 100% (originally 5%) when the lactose pre-precipitation is adopted, so that the anticancer curative effect is enhanced.
The amorphous coated lactose described in the above examples ten, eleven, twelve and thirteen is amorphous lactose particles prepared by freeze drying, the particle size of the particles is 1-50 microns, and a layer of monohydrate crystal coating is formed on the surface of the particles after the particles are subjected to motion treatment in an environment with a relative humidity of a fluidized bed of 70% for 30 minutes; when the amorphous coated lactose is prepared by freeze drying, the particle size of the amorphous coated lactose needs to be 1-50 microns by grinding; similarly, the relative humidity of the fluidized bed is 70% and the movement treatment for 30 minutes is a relative parameter, the surface of the anhydrous lactose particles can be combined with water molecules and crystallized to form a crystalline lactose monohydrate coating on the outer layer, a thicker crystalline lactose monohydrate coating can be formed by adopting higher humidity and/or time, the solubility of the particles can be reduced, and when the humidity and/or time is lower, the formed crystalline lactose monohydrate coating is too thin, the physical and chemical stability of the particles can be reduced, but the crystalline lactose monohydrate coating with the same thickness can be obtained by changing the humidity and reversely changing the treatment time.
Fig. 5 is an electron microscope scan of three different sizes of amorphous coated lactose micropowder (prepared by freeze-drying) used in example ten, eleven, twelve and thirteen of the present invention. It can be seen that the amorphous coated lactose micropowder particles prepared by spray drying are approximately spherical, and under a certain mass, the spherical geometric surface area is extremely large, which is beneficial to the adsorption of the amorphous coated lactose micropowder on the wet viscous pipe wall.
The floral lactose and amorphous coated lactose described in the various examples above are very soluble in water and stable at room temperature. It is also worth mentioning that besides floriform lactose and amorphous coated lactose, other anhydrous lactose fine powders, even lactose monohydrate, can be used instead, but because of their relatively poor water solubility, they are not favorable for the predeposition of the tube wall, and the optimization results obtained are poor.
Example fourteen:
according to the equipment integration for improving the lung inhalation medication by lactose micropowder predeposition provided by the invention, other inhalation medication methods can also be used for simulation measurement, and the wall of the whole system is kept in a wet state by breathing in water vapor to simulate the actual condition of a human body; the provided apparatus integrates to detect the effect of the provided method and to collect model data for method improvement, experience accumulation and clinical guidance.
In addition, according to the method for improving the pulmonary inhalation medication through lactose micropowder predeposition provided by the invention, similar optimization results can be obtained by adopting other model equipment, animal models and clinical experiments, and the method belongs to the scope of applying the method of the invention by a person skilled in the art.
Although the embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and those skilled in the art can make changes, modifications, substitutions and alterations to the above embodiments within the scope of the present invention without departing the essence of the corresponding embodiments from the scope of the embodiments of the present invention, which should be covered in the claims and the specification of the present invention.
Claims (4)
1. An equipment integration for improving medicine inhalation of lung by lactose micropowder predeposition, which is characterized in that: the equipment integration for improving the lung inhalation medication through lactose micropowder predeposition mainly comprises an inhaler (1), a head and throat part (2), a breathing pipeline (3) and lung model equipment (4), wherein the air outlet of the inhaler (1) is communicated with the air inlet of the head and throat part (2), the air outlet of the head and throat part (2) is communicated with the air inlet of the breathing pipeline (3), and the air outlet of the breathing pipeline (3) is communicated with the air inlet of the lung model equipment (4); the inhaler (1) mainly comprises a filter tip (1-1), an inhaler air inlet (1-2), a medicine powder compartment (1-3), a lactose micropowder compartment (1-4), a V-shaped compartment switching baffle (1-5), a compartment switching knob (1-6) and an inhaler air outlet (1-7), the head and throat part (2) mainly comprises a head and throat part air inlet (2-1), a throat passage (2-2) and a head and throat part air outlet (2-3), the breathing pipeline (3) mainly comprises an air passage (3-1) and a breathing pipeline air outlet (3-2), the lung model equipment (4) mainly comprises a dendritic air inlet pipe (4-1), an air pipe cavity (4-2), an intercavity grid (4-3), a compressed air cavity (4-4), A manual-automatic integrated air compressing plate (4-5), an air compressing plate moving track (4-6) and a track electric motor (4-7); the inhaler (1) comprises two administration modes, when a V-shaped compartment switching baffle (1-5) is in the original position, a medicine powder compartment (1-3) is separated by the baffle, and the inlet air reaches an inhaler air outlet (1-7) through a lactose micropowder compartment (1-4); when the V-shaped compartment switching baffle (1-5) is switched to the dotted line position shown in the figure by the compartment switching knob (1-6), the medicine powder compartment (1-3) is opened, the lactose micropowder compartment (1-4) is separated by the baffle, and the air inlet reaches the air outlet (1-7) of the inhaler through the medicine powder compartment (1-3); when the manual-automatic integrated air compression plate (4-5) moves left, the air tube cavity (4-2) and the whole system form negative pressure to simulate air suction; when the manual-automatic integrated air compressing plate (4-5) moves rightwards, the air tube cavity (4-2) and the whole system form positive pressure to simulate expiration; when the device is used for integration, a lactose micropowder pre-deposition step is set one minute before traditional inhalation administration, 20-200 mg of flower-shaped lactose and amorphous coated lactose are pre-deposited in the head and throat part (2), the breathing pipeline (3) and part of the trachea of the lung model device (4) which are wet and viscous and integrated by the device, a smooth inhalation environment is provided for the inhalation of subsequent medicinal powder, and the deposition rate of the medicinal powder in the trachea target area of the lung model device (4) is improved by 30-200%; when the particle size of the anhydrous lactose micropowder for predeposition is 10-50 microns, the anhydrous lactose micropowder is mainly attached to the pipeline wall of the head throat (2) of the equipment assembly, so that the deposition of subsequent inhaled medicine powder on the pipeline wall of the head throat (2) is reduced, and more medicine powder reaches a breathing pipeline (3) and a lung model device (4) of the equipment assembly; when the particle size of the anhydrous lactose micropowder for predeposition is 5-10 microns, the anhydrous lactose micropowder is mainly attached to the pipeline wall of the head throat (2) and the wall of the breathing pipeline (3) of the equipment assembly, so that the deposition of subsequent inhaled medicinal powder on the pipeline wall of the head throat (2) and the wall of the breathing pipeline (3) of the equipment assembly is reduced, and more medicinal powder reaches the lung; when the particle size of the anhydrous lactose micropowder used for predeposition is 1-5 microns and the using amount is 20-50 mg, the anhydrous lactose micropowder can be attached to the trachea of the anterior lung model equipment (4) integrated with the equipment, so that the deposition of subsequent inhaled medicine powder in the trachea of the anterior lung model equipment (4) is reduced, and more medicine powder reaches the deep part of the lung model equipment (4).
2. The device assembly of claim 1, wherein the model device for simulating clinical drug delivery comprises:
s1: filling anhydrous lactose with the particle size of 1-50 microns according to the target administration part;
s2: simulating inhalation gas, and administering anhydrous lactose micropowder to be pre-deposited in a breathing pipeline (3);
s3: simulating complete exhalation, adjusting the inhaler (1) within one minute, and preparing for re-inhalation;
s4: and (3) simulating normal inhalation administration, and keeping for 5-10 seconds to enable the medicinal powder to completely reach the lung model equipment (4).
3. The device assembly of claim 1 for improved administration by pulmonary inhalation through lactose micropowder predeposition, wherein: the flower-shaped lactose is anhydrous alpha/beta composite crystalline lactose, the particle size of the anhydrous alpha/beta composite crystalline lactose is 1-50 micrometers, and the nitrogen adsorption surface area is 20-50 m 2/g; the amorphous coated lactose is amorphous lactose particles prepared by spray drying or freeze drying, the particle size of the particles is 1-50 microns, and a layer of monohydrate crystal coating is formed on the surface of the particles after the particles are subjected to motion treatment for 30 minutes in an environment with the relative humidity of a fluidized bed being 70%; the flower-shaped lactose and the amorphous coated lactose are very soluble in water and can be stably stored at room temperature.
4. The device assembly of claim 1 for improved administration by pulmonary inhalation through lactose micropowder predeposition, wherein: when the particle size of the anhydrous lactose micropowder used in the pre-deposition step is mixed with dosages of 80 mg, 10-50 microns, 70 mg, 5-10 microns and 50 mg, 1-5 microns, the anhydrous lactose micropowder is attached to all air passages of the equipment integration, and 10-30% of subsequently inhaled medicine powder reaches 30% of the area at the bottom end of the lung model equipment (4).
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Effective date of registration: 20211210 Address after: 410000 room 001, 5 / F, professional building and incubation building, software center building, 662 Lugu Avenue, high tech Development Zone, Changsha, Hunan (cluster registration) Patentee after: Hunan Zhiya Biotechnology Co.,Ltd. Address before: 410000 Room 102, building 66, Yueshu, phase 4a, Yingfeng cuidi, No. 229, section 4, Jinxing North Road, Wangcheng District, Changsha City, Hunan Province Patentee before: Tan Songwen |