CN117883418A - Marxiteine capsule type inhalation powder aerosol and preparation method and application thereof - Google Patents

Abstract

The invention discloses a moxiteine capsule type inhalation powder aerosol and a preparation method and application thereof. The Ma Xiteng-tan capsule type inhalation powder spray comprises a capsule shell and capsule contents, wherein the capsule contents comprise the following components in parts by weight: ma Xiteng ultrafine powder 1 part and lactose 1-30 parts; the average D90 particle size of the Ma Xiteng ultrafine powder is 2-5 mu m. The Ma Xiteng capsule type inhalation powder spray does not contain a propellant, is environment-friendly, has no toxic or side effect, and has accurate and controllable administration dosage and small irritation; the auxiliary materials with high compatibility with the raw materials are selected, and the stability of the preparation is high; the drug delivery efficiency is high, the higher lung deposition rate can be realized, the local drug delivery is realized, the dosage is obviously reduced, and the toxic and side effects are small.

Description

Marxiteine capsule type inhalation powder aerosol and preparation method and application thereof

Technical Field

The invention relates to the technical field of medicines, in particular to a moxiteine capsule type inhalation powder aerosol and a preparation method and application thereof.

Background

Pulmonary arterial hypertension (pulmonary arterial hypertension, PAH) is a rare persistent increase in pulmonary arterial pressure caused by progressive pulmonary capillary anterior pulmonary vasculopathy, a rare chronic syndrome. The average survival time from diagnosis of pulmonary hypertension is 2 to 5 years. It is difficult to treat, has poor prognosis, and has a severity that far exceeds that of cancer, and is called "cancer in heart disease" by doctors. The white paper of the present existence state of patients with pulmonary hypertension in China shows that the average time period from the occurrence of symptoms to the diagnosis of patients with pulmonary hypertension in China is 2.2 years, and some patients need 5 years or more; while the average years required for patients with pulmonary hypertension from diagnosis to initiation of treatment is 2.6 years. Among the various pulmonary hypertension types, specific pulmonary hypertension is a type of pulmonary vascular disease characterized by progressive increases in pulmonary vascular resistance with no clear cause, with low incidence, and was included in the first few diseases catalog in 2018.

Treatment of pulmonary hypertension generally uses targeted drugs, commonly known as Endothelin Receptor Antagonists (ERA), phosphodiesterase type 5 inhibitors (PDE 5 i), guanylate cyclase agonists (sGCs) and prostacyclin analogs/prostacyclin receptor agonists (i.v./s.c.). In the latest version of ESC/ERS pulmonary arterial hypertension guidelines, different treatment combination recommendations are given for different risk classes. Clinical trial results show that Ma Xiteng is the first endothelin receptor antagonist targeted therapeutic. However, the existing Ma Xiteng tam medicament is a tablet, and in clinical treatment, the oral administration of the tablet by patients with Pulmonary Arterial Hypertension (PAH) is not very convenient, sometimes even very difficult, and the medicament also has gastrointestinal degradation effect and liver first pass effect in vivo, and has large dosage for oral administration and obvious side effect after being absorbed by gastrointestinal tract. Thus, there is a need for a Ma Xiteng dosage form which can be administered directly by inhalation, which reduces side effects and improves therapeutic efficacy.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides a moxiteine capsule type inhalation powder aerosol and a preparation method and application thereof.

The invention discloses a moxiteine capsule type inhalation powder spray, which comprises a capsule shell and a capsule content, wherein the capsule content comprises the following components in parts by weight: ma Xiteng ultrafine powder 1 part and lactose 1-30 parts;

the average D90 particle size of the Ma Xiteng ultrafine powder is 2-5 mu m.

Further, according to the weight parts, the Ma Xiteng ultrafine powder is 1 part and the lactose is 6-21 parts; the average D90 particle size of the Ma Xiteng ultrafine powder is 2.5-4 mu m.

Further, the weight of the capsule content is 5-25 mg.

Further, the lactose is one or more of crystalline lactose, spray-dried lactose and commercial inhaled lactose.

Further, the lactose has a D90 average particle diameter of 30-200 mu m;

further, the D90 average particle diameter of the capsule content is 100-200 μm.

The particle size testing method is a laser particle size analyzer.

The invention also discloses a preparation method of the Ma Xiteng tam capsule type inhalation powder spray, which comprises the following steps: pulverizing Ma Xiteng to superfine powder, and mixing with lactose to obtain total mixed powder of moxidectanum; and filling the Ma Xiteng tam total mixed powder into capsules.

Further, the capsules are hydroxypropyl methylcellulose hollow capsules.

Further, the method for crushing the Ma Xiteng is an air flow crushing method.

The invention also discloses application of the Ma Xiteng tam capsule type inhalation powder spray in preparing medicaments for treating pulmonary arterial hypertension.

In conclusion, compared with the prior art, the invention achieves the following technical effects:

1. the Ma Xiteng capsule type inhalation powder spray of the invention takes micronized drug raw materials and proper excipients as capsules, and the atomized drug is actively inhaled into the lung by a patient through a special dry powder inhalation device. The delivery efficiency of the preparation is high, and the lung deposition rate is high; the Ma Xiteng ultrafine powder in the preparation has high particle size and stability and good compatibility between raw materials and auxiliary materials.

2. The Ma Xiteng capsule type inhalation powder spray has no gastrointestinal tract degradation effect and no liver first pass effect, and the medicament can directly act on the lung, is rapidly absorbed and has rapid effect after administration; meanwhile, the local drug administration is realized, the dosage is obviously reduced, and the toxic and side effects are small.

3. The preparation process and the method adopted by the invention are simple and feasible, have no too high requirements on technical equipment, and are suitable for domestic industrial production.

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 schematic diagram showing the morphology of Ma Xiteng tam powder before and after pulverization in example 1 of the present invention; the left graph is before crushing, and the right graph is after crushing;

FIG. 2 is a magnified 1000-fold SEM image of the surface morphology of Ma Xiteng tam powder before and after pulverization according to example 1 of the present invention; the left panel shows the scale 20 μm before pulverization; the right graph shows the scale of 2 μm after crushing;

FIG. 3 is a bar graph of APSD at a flow rate of 100L/min for moxidecteine of example 4 of the present invention;

FIG. 4 is a plot of APSD against flow at 60L/min for moxidecteine of example 4 of the present invention;

FIG. 5 is a bar graph of APSD at a flow rate of Ma Xiteng tan 60L/min under acceleration for 1-3 months in example 5 of the present invention;

FIG. 6 is a bar graph of APSD at a flow rate of Ma Xiteng tan 60L/min at 2 to 3 months in example 5 of the present invention;

FIG. 7 is a bar graph of APSD at a flow rate of Ma Xiteng tan 60L/min for an extended period of 3 months for example 5 of the present invention;

FIG. 8 is a graph of APSD line at a flow rate of Ma Xiteng tan 60L/min under acceleration for 1-3 months for example 5 of the present invention;

FIG. 9 is a graph of APSD line at a flow rate of Ma Xiteng tan 60L/min under the conditions of 2-3 months in example 5 of the present invention;

FIG. 10 is a graph of APSD line at a flow rate of Ma Xiteng tan 60L/min for a long term 3 months for example 5 of the present invention;

FIG. 11 is a bar graph of APSD at a flow rate of Ma Xiteng tan 100L/min under acceleration for 1-3 months in example 5 of the present invention;

FIG. 12 is a bar graph of APSD at a flow rate of Ma Xiteng tan 100L/min for the intermediate 2-3 months in example 5 of the present invention;

FIG. 13 is a bar graph of APSD at a flow rate of Ma Xiteng tan 100L/min for an extended period of 3 months for example 5 of the present invention;

FIG. 14 is a graph of APSD line at a flow rate of Ma Xiteng tan 100L/min under acceleration for 1-3 months for example 5 of the present invention;

FIG. 15 is a graph of APSD line at a flow rate of Ma Xiteng tan 100L/min for 2-3 months in example 5 of the present invention;

FIG. 16 is a graph of APSD line at a flow rate of Ma Xiteng tan 100L/min for a long term 3 months for example 5 of the present invention;

FIG. 17 is a bar graph of APSD at a flow rate of 60L/min for example 6 Ma Xiteng of the present invention;

FIG. 18 is a graph showing APSD line at a flow rate of 60L/min for example 6 Ma Xiteng of the present invention.

Detailed Description

In order that those skilled in the art will better understand the present invention, a technical solution in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in which it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, shall fall within the scope of the invention.

The raw material sources are as follows:

ma Xiteng, laurus Labs Limited;

lactose:

(1) Lactose and lactoseML001, manufacturer DFE;

(2) Lactose and lactose206, manufacturer DFE;

(3) Lactose and lactose300, manufacturer DFE;

lactose monohydrate:guangzhou Tianrun Co., ltd;

and (3) capsules: hydroxypropyl methylcellulose hollow capsules, qualicaps, # 3.

The preparation method of the Ma Xiteng tam capsule type inhalation powder spray comprises the following steps:

crushing Ma Xiteng total mixed powder of the raw material medicine by using an ultrafine powder jet mill, and mixing with lactose reference to prepare total mixed powder of the moxidectanum; the Ma Xiteng total mixed powder is manually filtered through a 0.5mm screen and then placed in a 180mL mixing tank, and then is mixed by a three-dimensional swinging mixer to prepare the moxidectein total mixed powder, and the moxidectein total mixed powder is filled by a hydroxypropyl methylcellulose hollow capsule.

Example 1 detection of Ma Xiteng Tan drug substance

1. Particle size detection before and after crushing Ma Xiteng crude drug

2 parts of a proper amount of Ma Xiteng-tan raw material medicine is weighed, particle size measurement is carried out by using a Talcum laser particle size analyzer, and the dispersion pressure is set to 3bar and R2 lens.

And crushing part of the moxidecteine raw material medicine by using an ultrafine powder jet mill. The dispersion pressure is adjusted within the range of 2-6 bar, and the crushing pressure is adjusted within the range of 2-6 bar. And (5) after crushing, collecting a sample, and detecting the particle size of the micro powder.

2. Determination of stability of Ma Xiteng-content crude drug

Taking 3 parts of crushed Ma Xiteng tam micropowder, respectively placing into constant temperature and humidity boxes at 30 ℃, 65% humidity (RH), 40 ℃,75% RH, 25 ℃ and 60% RH, respectively, sampling and detecting the particle size for 5 days, 15 days and 30 days, and observing the change condition of the particle size.

3. Measurement results

The form of the fine powder was observed by a high-power microscope, the form of the crude drug before and after pulverization was shown in FIG. 1, and the form of the scanning electron microscope was shown in FIG. 2. The coarse particles of the Ma Xiteng-tan raw material before crushing have different shapes, and the whole raw material takes a long strip shape or a cubic-like shape and exists in a crystal form. The shape of the pulverized raw material medicine micro powder is different, and most of the pulverized raw material medicine micro powder is in a long or elliptic cubic-like shape and exists in a crystal form.

Particle size change before and after crushing:

table 1 determination of particle size of Ma Xiteng tan drug substance before pulverization

	D10/μm	D50/μm	D90/μm
				1	1.60	12.83	36.60
2	1.70	13.59	32.02
				Average value of	1.65	13.21	34.31

TABLE 2 determination of the particle size of Ma Xiteng Ten micropowder after pulverization under different pulverizing and dispersing pressures

As can be seen from the results of table 2, when the pulverizing pressure and the dispersing pressure were set to 6bar, the D90 particle size of the Ma Xiteng tan micropowder was measured to be minimum; when the crushing pressure and the dispersing pressure are set to be 2bar, the particle size detection result meets the requirement, but the blockage of the crushing cavity part can be caused by the small dispersing pressure, so that the normal blanking is influenced; when the pulverizing pressure was set to 2bar and the dispersing pressure was set to 4bar, the measured D90 particle size of the fine powder was about 3.87 μm and the discharging was normal, and the particle size detection data were in accordance with the expected results of D90 at 3 to 5. Mu.m.

The stability test results were as follows:

TABLE 3 stability test results for 5 days under different conditions

As can be seen from the results of Table 3, under different conditions of placement, the D90 particle size is increased under each condition, wherein the D90 particle size change of 75% RH is more obvious under the acceleration condition at 40 ℃, the particle size is increased by about 0.3 μm, but the particle size range still meets the expected requirement of D90 in the range of 3-5 μm; compared with the D90 particle size result of 15 days after 5 days of lofting, the D90 particle size basically has no obvious change, namely Ma Xiteng after micronization, the particle size change of the bulk drug tends to be in a stable state before being placed for 5 days or 5 days, and the particle size is not easy to increase or decrease due to the increase of the external temperature or humidity along with the time, so that the particle size stability is high.

Example 2 determination of compatibility of raw materials and auxiliary materials

For Ma Xiteng crude drug and lactoseML001 (adjuvant), lactose->206 (adjuvant), lactose->300 And (5) carrying out a raw and auxiliary material compatibility test, examining the content, the properties and the change conditions of related substances of the raw material medicine and different auxiliary materials under long-term conditions (25 ℃ +/-2 ℃, 60%RH+/-5%RH) and acceleration conditions (40 ℃ +/-2 ℃ and 75%RH+/-5%RH), and providing reference for the feasibility of the preparation prescription.

The particle size of lactose is as follows:

lactose and lactoseML001(D10：4μm、D50：45μm、D90：137μm)；

Lactose and lactose206(D10：31μm、D50：82μm、D90：153μm)；

Lactose and lactose300(D50：3μm、D90：9μm)。

The measuring step comprises the following steps:

the sample is held in an open container and a sealed container, and is placed under long-term conditions (25 ℃ +/-2 ℃ and 60%RH+/-5%RH) and acceleration conditions (40 ℃ +/-2 ℃ and 75%RH+/-5%RH) respectively for 1 month, and relevant items are sampled and detected in 0 day, 5 days, 10 days and 30 days.

The specific measurement conditions are as follows, wherein the sealing condition means that the bottle cap is closed, and the opening condition means that the bottle mouth is opened, and the content is directly contacted with air.

TABLE 4 compatibility determination conditions

The samples were submitted for detection of content, related substances, and properties, and the detection results were as follows, with BQL values referring to values below the lower limit of quantification.

TABLE 5 detection results of different raw material and auxiliary material contents and related substances

As is clear from the test results shown in tables 4 to 5, the content of Ma Xiteng is not greatly reduced with the extension of the standing time, and is maintained at 95% or more basically when the standing time reaches 30 days; under different placing conditions, the related substances show positive increasing trend along with the increase of lactose proportion in the prescription, and the increasing trend also shows different increasing amplitude along with the difference of lactose particle sizes, and is characterized in that the smaller the lactose particle size is, the faster the related substances increase, then compared with two different processing conditions, the samples placed under long-term conditions can be known, the related substances increase slowly, the trend is not obvious,the sample placed under the acceleration condition has relatively intense treatment condition, so that the related substances grow rapidly, but the detection results of all the samples are within the acceptable limit range; from Ma Xiteng tam and lactoseAs shown by the detection result of related substances of ML001 in a ratio of 1:1, the impurity polyene phosphorylcholine only increases by 0.3 percent after being placed for 30 days under the acceleration condition. From the above results, the addition ratio of Ma Xiteng to lactose was 1:1 to 1: the increase range of impurities in the range of 30 is low, and the compatibility is good.

EXAMPLE 3 Effect of lactose of different particle sizes on quality of formulations

1. Lactose mixtures of different particle sizes were prepared:

(1) 22.800g of lactose ML001 and 1.200g of lactose monohydrate are weighedWill->Placing in about 180mL mixing tank with lactose ML001 therebetween, mixing with three-dimensional swinging mixer, setting mixing speed at 30rpm for 20min to obtain lactose mixture 1, detecting particle size, setting detection dispersion pressure at 3bar, and R5 lens;

weighing 1.000g of moxidecteine, putting Ma Xiteng g of moxidecteine together in a manner of being clamped in the middle of lactose mixture 1 and passing through a 0.5mm screen, putting the mixture into a 180mL mixing tank, then mixing the mixture by using a three-dimensional swinging mixer, setting the mixing rotating speed to be 30rpm, and the time to be 30min, obtaining total mixed powder 1, carrying out particle size detection, setting the detection dispersion pressure to be 3bar, and setting an R5 lens.

(2) Lactose mixture 2 was prepared in the same manner as in (1) except that 21.602g lactose ML001,2.401g lactose monohydrate was weighed; 1.001g of moxidectanum is weighed out, and the total mixed powder 2 is prepared in the mode of reference (1).

(3) 24.000g of lactose ML001 and Ma Xiteng tan 1.000g are weighed, ma Xiteng tan is manually passed through a 0.5mm screen together in a manner of being clamped between lactose ML001, then placed in a 180mL mixing tank, and then mixed by using a three-dimensional swinging mixer, and the mixing rotation speed is set to 30rpm for 30min, so as to obtain total mixed powder 3.

2. The particle size measurement results were as follows:

TABLE 6 determination of particle sizes of different lactose mixtures and total mixed particles

TABLE 7 determination of particle size of Total Mixed powder 3

3. Blend Uniformity (BU) determination:

the measuring step comprises the following steps:

manually sieving a sample of the total mixed powder 3 with a 0.5mm sieve, placing the sample in a 180mL mixing tank, then using a three-dimensional swinging mixer for mixing, setting the mixing speed to be 30rpm, and mixing for 30min to obtain the total mixed powder 4;

taking out the mixing tank filled with the total mixed powder 1-4, respectively placing the upper layer material, the middle layer material and the lower layer material of the mixing tank on weighing paper, sampling according to the sampling modes of 3 points on the upper layer, 4 points on the middle layer and 3 points on the lower layer, wherein the sampling quantity of each point is 30-40 mg, placing the weighed samples in weighing bottles for 10 bottles in total, sealing by using a sealing film, sending to an analyzer for BU detection, and sealing and storing the rest samples for standby.

Table 8BU detection results (Ma Xiteng content of the Tang%)

As shown in the results of table 8, compared with BU of total mixed powder 1 and total mixed powder 3, the Relative Standard Deviation (RSD) of the mixing uniformity of both is greater than 5%, and the mixing uniformity is not satisfactory, i.e. the addition of 4.8% of lactose with fine particle size has no influence on the mixing uniformity in the prescription; the RSD value of the batch is less than 5% and meets the requirement, the single value of the content result is within +/-10% of the average value, the average content is between 90% and 110%, namely, when the lactose with the fine particle size is added to the proportion of 9.6%, the mixing uniformity of the prescription is improved to a certain extent, the RSD value of the total mixed powder 4 is less than 5%, the content is also within the required range, and the fact that the mixing uniformity of the sample can be improved by adding one-time sieving and mixing is shown.

4. Aerodynamic Particle Size Distribution (APSD) detection after capsule filling

The operation steps are as follows: and (3) manually filling the total mixed powder 1,2 and 4 by using a hydroxypropyl methylcellulose hollow capsule, wherein the filling amount is 23.75-26.25 mg, 10 capsules are filled in each batch, and the name of the sample is 1-3 of the inhaled powder aerosol after the filling is finished. And (3) performing inspection analysis after sealing and preserving the sample, and performing APSD detection at a flow rate of 60L/min and 100L/min.

The detection results are as follows:

table 9 APSD results at a flow rate of 60L/min at 9 Ma Xiteng

From the above results, the FPD value of the inhalation powder aerosol 3 is higher than that of the inhalation powder aerosol 2 under the condition that the total accumulated amount is lower than that of the inhalation powder aerosol 2, which means that the drug delivery efficiency of the inhalation powder aerosol 3 is the highest and the lung deposition amount is high; in contrast to the FPD value of inhalation powder aerosol 1, since the total cumulative amounts of the two samples are not consistent, if the total cumulative amount of the first sample is increased to be consistent with the third sample, the FPD value may still be lower than that of inhalation powder aerosol 3; description of lactose monohydrateRatio of (3)The increase of (3) does not exert an increasing effect on the FPD value of Ma Xiteng, and the delivery effect is better and the lung deposition amount is higher when lactose with a small particle size is not added.

EXAMPLE 4 Effect of different particle size Ma Xiteng tam micropowder on delivery Effect

And crushing Ma Xiteng-shaped coarse powder by using a Ma Xim jet mill to prepare Ma Xiteng-shaped fine powder with low, medium and high different particle sizes respectively, mixing the fine powder with the three different particle sizes with corresponding auxiliary materials to prepare a sample, and examining delivery conditions of Ma Xiteng-shaped fine powder with different particle sizes.

The preparation steps of Ma Xiteng tam micro powder with different particle sizes are as follows:

(1) Weighing 3.010g of moxidecteine raw material, crushing by using a Ma Xim jet mill, setting crushing pressure to 4bar, dispersing pressure to 4bar, and screw rotating speed to 100rpm, and closing the blanking and crushing for 2min when almost no material is in the screw part, so as to obtain moxidecteine micro powder 1;

(2) Ma Xiteng the preparation process of the fine powder 2 is the same as that of the step (1), except that the crushing pressure is 3bar and the dispersing pressure is 3bar.

(3) Ma Xiteng the preparation process of the fine powder 3 is the same as that of the step (1), except that the pulverizing pressure is 2bar and the dispersing pressure is 2bar.

Mixing the Ma Xiteng total mixed powder 1-3 with 24.001g lactose ML001 according to the mode of reference example 1, wherein the mixing speed is 30rpm, and the mixing time is 30min, so as to prepare the total mixed powder 1-3 of the moxidectanium; and (3) manually sieving the Ma Xiteng total mixed powder 1-3 with a 0.5mm screen, placing the powder in a 180mL mixing tank, then mixing the powder by using a three-dimensional swinging mixer, setting the mixing speed to be 30rpm, and mixing the powder for 30min to obtain the moxidectanum total mixed powder 1 '-3'.

And (3) manually filling capsules into Ma Xiteng-content total mixed powder 1 '-3', filling 25mg, and then carrying out APSD detection.

The Ma Xiteng tam micropowder particle size information is as follows:

table 10 different Ma Xiteng tan micropowder particle size information

Sample of	D10/μm	D50/μm	D90/μm
				Ma Xiteng Ten micropowder 1	0.7	1.37	2.54
Ma Xiteng Ten micropowder 2	0.72	1.55	3.14
				Ma Xiteng Ten micropowder 3	0.64	1.64	3.79

The measurement results were as follows:

TABLE 11 APSD test results at 100L/min flow Rate of Ma Xiteng Ten micropowder formulations with different particle sizes

	Ma Xiteng Tan Total Mixed powder 1'	Ma Xiteng Tan Total Mixed powder 2'	Ma Xiteng Tan Total Mixed powder 3'
				Capsule shell (mug)	16.1182	18.6104	24.4666
Inhalation device (mug)	43.6829	28.5544	27.8471
				Adapter-artificial larynx (mug)	80.9216	84.5118	95.5484
Preseparator (mug)	214.5842	201.2726	163.2768
				S1(μg)	67.8023	71.3037	91.5536
S2(μg)	115.1684	153.1555	182.9802
				S3(μg)	155.7304	168.6526	164.0697
S4(μg)	156.3164	129.1953	118.3465
				S5(μg)	70.8883	60.0437	51.3499
S6(μg)	32.0030	24.2082	21.8690
				S7(μg)	17.5780	9.3074	10.6876
S8(μg)	6.0178	2.8919	4.6414
				Accumulation (mug)	976.812	951.708	956.637
Total dose per(μg)	960.7	933.097	932.171
				Calc.Delivered(μg)	917.0	904.543	904.324
FPD(μg)	521.7	505.7	502.2
				FPF(％)	56.89	55.91	55.54
MMAD(μm)	2.360	2.729	3.006
				GSD	2.133	1.956	1.941
ISM：S2～S8(μg)	553.702	547.455	553.944

As is clear from Table 11 and the results of FIGS. 3 to 4, the drug delivery efficiency was highest when the average particle diameter of Ma Xiteng tan D90 was 2.54. Mu.m. As the particle size of Ma Xiteng is increased, the FPD value of the preparation is in a decreasing trend, and the smaller the particle size of the moxidecteine is, the higher the deposition amount is obviously shown at the preseparator; overall, the delivered dose of Ma Xiteng tends to decrease as its particle size increases.

EXAMPLE 5 Ma Xiteng determination of stability of inhalation powder

1. Ma Xiteng preparation of an inhalation powder spray:

according to the prescription, lactose ML001 is 240.00g, ma Xiteng is 10.001g, ma Xiteng is clamped between lactose ML001, then manual sieving treatment of a 0.5mm screen is carried out, the sieved material is collected and placed in a 1L mixing tank, then a two-dimensional mixer is used for mixing, the mixing speed is set to be 25rpm, and the mixing time is set to be 45min, so that the total mixed powder of the moxidectantan is prepared. And then, manually filling capsules into Ma Xiteng-tan total mixed powder to prepare the moxidecteine inhalation powder aerosol. And subpackaging Ma Xiteng of the inhaled powder aerosol into 8 aluminum foil bags, wherein each aluminum foil bag has a subpackage amount of about 55 grains, heat-sealing the packaged samples, lofting according to the lofting plan, sampling and inspecting at corresponding time, and carrying out APSD (advanced metering and standard deviation) measurement.

2. Measurement standard:

the impurity polyene phosphorylcholine must not exceed 0.6% of the marked amount, the other single impurity peak must not exceed 0.2% of the marked amount, and the total impurity must not exceed 2.0% of the marked amount, which is a qualified sample.

Table 12 Ma Xiteng inhalation powder spray lofting plan

Table 13 Ma Xiteng test results of different conditions for placing inhalation powder

As is clear from the results in Table 13, under the acceleration conditions, the impurity polyene phosphorylcholine tended to increase in 1 month, 2 months and 3 months, but from 2 months, the increase of polyene phosphorylcholine began to decrease, i.e., the increase of total impurities also decreased; from the results of the related substances accelerated for 3 months, the final results of the related substances, namely the polyene phosphorylcholine and other unknown single impurities and total impurities, are within the standard limit of quality, namely the product is relatively stable in quality when the product is placed for 3 months under the accelerated condition, and the related substances do not show a large increase. In general, related substances of the current products are not obviously increased temporarily, and the stability of the products is high.

TABLE 14 APSD results at 60L/min flow rate

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TABLE 15 APSD results at 100L/min flow rate

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As can be seen from table 14 and fig. 5 to 10, the FPD value of the preparation was significantly reduced after being placed under accelerated conditions for 1 month, and the drug delivery amount was reduced by about 70 μg, because the difference in cumulative amounts resulted in a slightly higher FPD value at 2 months of acceleration than at 1 month of acceleration, and the same value was obtained at 3 months of acceleration; under the condition that the cumulative amount is the same, the FPD value of Ma Xiteng is reduced, and the reduction range is about 70 mug; the maximum reduction amplitude is achieved in acceleration for 1 month and acceleration for 2 months; with the prolonged standing time, the FPD value of Ma Xiteng is reduced, and the reduction amplitude is about 60 mug; the FPD value of Ma Xiteng is also reduced in the long term condition, but the reduction is not high in comparison with the acceleration and intermediate conditions. As is clear from Table 15 and FIGS. 11 to 16, the Ma Xiteng is the greatest in the reduction of about 50 to 70. Mu.g in the acceleration for 1 month and 2 months, and the change in the acceleration for 2 months to 3 months is initiated to be reduced by about 20. Mu.g; from the change of the FPD value from 2 months to 3 months, the decreasing amplitude of the Ma Xiteng dose gradually decreases with the increase of the standing time; as can be seen from the results under the intermediate and long-term conditions, the FPD value of Ma Xiteng is reduced by both different treatment conditions; from the viewpoint of the reduction amplitude, the long-term condition has a greater influence on the FPD value of Ma Xiteng, and the reduction amplitude of the intermediate condition is similar to the acceleration condition. The Ma Xiteng inhalation powder can be stably placed for more than three months under a long-term condition, and the reduction of the conveying efficiency and the lung deposition rate is low.

EXAMPLE 6 Effect of different amounts of Ma Xiteng Tan drug substance on delivery Effect

(1) Weighing 23.000g of lactose ML001 and 2.001g of Ma Xiteng of lactose ML001, clamping Ma Xiteng of lactose ML001 in the middle, then manually sieving with a 0.5mm sieve, collecting the sieved material, placing the sieved material in a 180mL mixing tank, then mixing with a three-dimensional swinging mixer, setting the mixing speed to be 30rpm, mixing time to be 30min, manually sieving with a 0.5mm sieve, placing the sieved material in the 180mL mixing tank, then mixing with the three-dimensional swinging mixer, setting the mixing speed to be 30rpm, and mixing time to be 30min, thus obtaining the total mixed powder 1 of moxibustein; and (3) manually filling the Ma Xiteng-unit total mixed powder 1 into capsules, wherein the filling amount is 25mg, the filling amount difference is +/-5%, 8 capsules are filled in each batch, the names of the filled capsules are Ma Xiteng-unit inhalation powder aerosol 1, and APSD (advanced metering device) under the flow velocity of 60L/min and 100L/min is carried out.

(2) Ma Xiteng A inhalation powder aerosol 2 is prepared in the same step as (1) except that the lactose ML001 is 21.000g and the lactose ML Ma Xiteng is 4.001g.

Table 16 determination results of APSD of various dosage Ma Xiteng tan drug substance preparations

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The results in Table 16 and FIGS. 17 to 18 show that the residual amounts of the Ma Xiteng tam preparations with different contents are different, the FPD values meet the expected requirements, and the FPF values of the both preparations are above 70%; as the Ma Xiteng standard increases from 2mg to 4mg, the FPD value and the deposition amount of the capsule shells S1 to S8 levels also increase correspondingly, specifically, the increase of the FPD value increases about 2 times, the deposition amount in the S1 to S8 levels obviously shows about 2 times increase at the S2 to S6 levels, and the general increase trend is positive correlation with the change of the standard.

The foregoing description of the preferred embodiments of the invention is not intended to limit the invention to the precise form disclosed, and any such modifications, equivalents, and alternatives falling within the spirit and scope of the invention are intended to be included within the scope of the invention.

Claims (10)

1. The moxiteine capsule type inhalation powder spray is characterized by comprising a capsule shell and a capsule content, wherein the capsule content comprises the following components in parts by weight:

ma Xiteng ultrafine powder 1 part and lactose 1-30 parts;

the average D90 particle size of the Ma Xiteng ultrafine powder is 2-5 mu m.

2. The Ma Xiteng tam capsule type inhalation powder spray of claim 1, wherein the Ma Xiteng tam superfine powder is 1 part by weight and the lactose is 6-21 parts by weight;

the average D90 particle size of the Ma Xiteng ultrafine powder is 2.5-4 mu m.

3. The Ma Xiteng tam capsule type inhalation powder spray according to claim 1 or 2, wherein the weight of the capsule content is from 5 to 25mg.

4. The Ma Xiteng tam capsule type inhalation powder spray according to claim 1 or 2, wherein the lactose is one or more of crystalline lactose, spray-dried lactose and commercially inhaled lactose.

5. The Ma Xiteng tam capsule type inhalation powder spray according to claim 1 or 2, wherein the lactose has a D90 average particle size of 30 to 200 μm.

6. Ma Xiteng-tan capsule type inhalation powder according to claim 1 or 2, characterized in that the D90 average particle size of the capsule content is 100-200 μm.

7. The method for preparing Ma Xiteng tam capsule type inhalation powder spray according to any one of claims 1 to 6, which is characterized by comprising the following steps: pulverizing Ma Xiteng to superfine powder, and mixing with lactose to obtain total mixed powder of moxidectanum; and filling the Ma Xiteng tam total mixed powder into capsules.

8. The method of claim 7, wherein the capsule is a hypromellose empty capsule.

9. The process of claim 7, wherein the method of crushing Ma Xiteng is jet milling.

10. The use of Ma Xiteng tan capsule type inhalation powder spray as claimed in any of claims 1 to 6 for the preparation of a medicament for treating pulmonary hypertension.