WO2022116792A1

WO2022116792A1 - Isoniazid dry powder inhalant for treating pulmonary tuberculosis

Info

Publication number: WO2022116792A1
Application number: PCT/CN2021/130116
Authority: WO
Inventors: 张桐桐; 王实强; 曲伟; 张涛; 张国立; 颜携国; 李勇; 梁民彩
Original assignee: 深圳善康医疗健康产业有限公司
Priority date: 2020-12-04
Filing date: 2021-11-11
Publication date: 2022-06-09
Also published as: CN112336703B; CN112336703A

Abstract

An isoniazid dry powder inhalant for treating pulmonary tuberculosis, having high stability, containing an isoniazid micro-powder, and containing or not containing a carrier micro-powder. The particle size of the isoniazid micro-powder is processed to 0.1-10 μm by means of a fluidized bed supersonic jet milling method or a spray drying method. Preferably, an adjuvant such as leucine, mannitol, or phospholipid can be added into the dry powder inhalant to improve the granulation rate of the particles, and an adjuvant such as magnesium stearate, mannitol, leucine, and/or lactose are additionally added to improve the fluidity of the drug and reduce particle agglomeration. The dry powder inhalant is suitable for treating pulmonary tuberculosis patients with liver dysfunction.

Description

A kind of isoniazid dry powder inhaler for treating pulmonary tuberculosis

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of Chinese Application No. 2020114127893 filed on December 04, 2020. Said application number 2020114127893 is hereby incorporated by reference in its entirety.

technical field

The invention belongs to the field of pharmaceutical preparations, and in particular relates to an isoniazid dry powder inhaler for treating pulmonary tuberculosis, a preparation method thereof, and its use in preparing medicines for treating various types of pulmonary tuberculosis.

Background technique

Pulmonary tuberculosis is a highly contagious lung disease, which is highly destructive to the lungs and takes a long time to treat, usually more than half a year. The current clinical treatment of pulmonary tuberculosis often adopts oral administration of isoniazid, rifampicin, ethambutol and pyrazinamide. Among them, isoniazid has strong antibacterial activity against Mycobacterium tuberculosis, and is a very effective and rapid Mycobacterium tuberculosis fungicide. However, conventional oral preparations have strong hepatotoxicity, and it is difficult to achieve and maintain effective or high drug concentrations in the trachea, bronchi and alveolar secretions. During clinical use, it was found that isoniazid injection can assist in the treatment of pulmonary tuberculosis after inhalation by atomization.

Although many studies have been conducted, there is currently no isoniazid formulation specifically for clinical inhalation use. CN1102093A discloses an isoniazid aerosol, a spray and a preparation method thereof, wherein the content of the aerosol is composed of the drug isoniazid; diluent and specific gravity regulator anhydrous sodium sulfate or anhydrous lactose; Agent Span-85, ethyl oleate; latent solvent trichloromonofluoromethane; propellant dichlorodifluoromethane, dichlorotetrachloroethane, etc., wherein the content of the spray is the drug isoniazid; pH Regulator boric acid (salt), phosphate; osmotic pressure regulator sodium chloride, glucose, solvent water, etc. However, the defects of isoniazid aerosols and sprays are that the process is cumbersome and the delivery rate is very low, with only 2-5 mg of drug per swipe, while dry powder inhalers can deliver 10-50 mg of drug each time.

CN101684116A discloses an isoniazid lipid derivative and a composition thereof, characterized in that the structure of the isoniazid lipid derivative is: INH-THTT-R, wherein INH is isoniazid and THTT is thiadiazine thione , R is a long aliphatic chain with 6-20 carbon atoms. Tablets, capsules, injections, aerosols, dry powder inhalers and highly dispersible dosage forms can be prepared from isoniazid lipid derivatives. This application chemically synthesizes isoniazid and modifies it as a lipid derivative to improve the absorption of isoniazid in vivo, but this method has complicated preparation process, poor preparation stability, and difficulty in scaling up the process production.

CN103110633A relates to a dry powder inhaler that can prevent the respiratory tract transmission of Mycobacterium tuberculosis. 5%, firstly mix isoniazid sustained-release microspheres, rifampicin sustained-release microspheres, and glidant together, and put them in gelatin, plastic capsules or aluminum-plastic blister, or in the form of storage Packaged in a multi-dose dry powder inhaler device. In order to make the two drugs play a sustained-release role, this application uses a large amount of gelatin excipients. The gelatin is derived from animals and may have some immunogenicity when it enters the lung, so the safety cannot be guaranteed. In addition, the amount of added excipients is large, and the drug load will decrease.

It can be seen that the clinical demand for isoniazid inhalation dosage forms has not been met, and the currently known isoniazid inhalation dosage forms have different degrees of low delivery efficiency, poor formulation stability, unguaranteed safety, and low drug loading. question.

SUMMARY OF THE INVENTION

In order to solve the deficiencies of the prior art, the present inventor prepared an isoniazid dry powder inhaler with high stability and high drug loading by using modern formulation technology. Department to treat various types of tuberculosis. The isoniazid dry powder inhalation prepared by the method of the invention is especially suitable for treating pulmonary tuberculosis and bronchial tuberculosis in patients with impaired liver function.

In order to achieve the object of the present invention, the present invention has adopted the following technical solutions:

In a first aspect, the present invention relates to an isoniazid dry powder inhaler for treating pulmonary tuberculosis, characterized in that: the dry powder inhaler comprises isoniazid micropowder, and with or without carrier micropowder, by fluidizing The particle size of the isoniazid micropowder is processed to be d ₁₀ =0.1-3 μm, d ₅₀ =3-7 μm and d ₉₀ =7-10 μm by bed supersonic jet milling method or spray drying method. When the carrier micro-powder is included, the carrier The micropowder is prepared by adding excipients inside, and the excipients are amino acids, mannitol or phospholipids, and the dry powder inhaler also includes adjuvants selected from amino acids, phospholipids, sugars or magnesium stearate. one or more.

In one embodiment, the amino acid is selected from leucine, valine, glycine or isoleucine, preferably leucine.

In another embodiment, the saccharide is selected from mannitol, lactose, maltose, trehalose or sucrose, preferably lactose or mannitol.

In a more preferred embodiment, the type of lactose is one or more of Inhalac 120, Inhalac 140, Inhalac 230 or Inhalac 400.

In a further preferred embodiment, the internal adjuvant is leucine, and the added amount of the leucine accounts for 0-30%, preferably 2-10%, of the total weight of the dry powder inhaler.

In another further preferred embodiment, the adjuvant is leucine and/or lactose and/or magnesium stearate and/or mannitol, and the added amount of the leucine accounts for 5% of the total weight of the dry powder inhaler 0-30%, preferably 2-10%, the added amount of the lactose accounts for 0-50% of the total weight of the dry powder inhaler, preferably 10-30%. The addition amount of the magnesium stearate accounts for 0-10% of the total dry powder inhaler, preferably 1-5%, and the addition of the mannitol accounts for 0-50% of the total dry powder inhaler, preferably 10-30%. %. .

In a second aspect, the present invention relates to a method for preparing the above-mentioned isoniazid dry powder inhaler for treating pulmonary tuberculosis, the method comprising the steps of: passing the isoniazid through a fluidized bed supersonic jet pulverization method To prepare isoniazid micropowder, take isoniazid micropowder, mix lactose and isoniazid micropowder according to a certain proportion, add leucine after mixing, and then pack the mixed powder in a capsule or blister, or in the form of a reservoir Packaged in a multi-dose dry powder inhalation device, or the method includes the following steps: dissolving isoniazid in a certain amount of solvent, adding leucine to prepare a clear and transparent solution, spray-drying the above solution, collecting cyclone separation drying Continue to dry the micropowder in the container for a period of time, add lactose and/or magnesium stearate and continue to mix for a period of time, and then pack the mixed powder into a capsule or blister, or pack it in a multi-dose dry powder inhaler in the form of a reservoir inside the device.

In a preferred embodiment, the solvent is selected from purified water, propylene glycol or ethanol, preferably purified water.

In a more preferred embodiment, the spray drying air inlet temperature is 100°C-180°C, preferably 120°C-150°C; the fan frequency is 30Hz-40Hz, preferably 34Hz-38Hz; the rotational speed is 5rpm-40rpm, preferably 8rpm-20rpm ; Atomization pressure 0.20MPa-0.30MPa, preferably 0.24MPa-0.28MPa; orifice size 0.5mm-1.2mm, preferably 0.8mm-1mm.

In another more preferred embodiment, the drying time is 5h-48h; the mixing time is 0.5h-1h.

In a third aspect, the present invention relates to the use of the above-mentioned dry powder inhaler or the dry powder inhaler prepared by the above-mentioned preparation method in the preparation of a medicine for treating pulmonary tuberculosis.

In a preferred embodiment, the pulmonary tuberculosis is pulmonary tuberculosis in a patient with poor liver function, or the pulmonary tuberculosis is bronchial tuberculosis.

Compared with the prior art, the present invention has the following beneficial effects:

(1) The present invention adopts a dry powder inhalation dosage form, which has a high drug delivery rate, and can deliver a dose of 10-50 mg each time. The dry powder inhaler of the present invention has a relatively high drug load, and more than 50% or even more than 75% of the pharmaceutical preparation is the active ingredient isoniazid.

(2) the dry powder inhaler of the present invention has higher formulation stability, and the preparation process is simple, can quickly prepare the isoniazid dry powder inhaler, and can meet the requirements of scale-up production.

(3) The isoniazid dry powder inhaler prepared by the method of the present invention is especially suitable for treating pulmonary tuberculosis and bronchial tuberculosis in patients with impaired liver function.

Description of drawings

Figure 1: shows the scanning electron microscope results of the isoniazid dry powder inhaler of Example 6. The large block in the picture is lactose, on which the isoniazid active pharmaceutical ingredient (API) raw material is adsorbed.

Figure 2: shows the scanning electron microscope results of the isoniazid dry powder inhaler of Example 8. The figure shows that after adding magnesium stearate, the particles are more dispersed and the agglomeration is reduced.

Detailed ways

The preferred embodiments of the present invention will be described below, and it should be understood that the preferred embodiments described herein are only used to illustrate and explain the present invention, but not to limit the present invention. If no specific technique or condition is indicated in the examples, the technique or condition described in the literature in the field or the product specification is used. The reagents or instruments used without the manufacturer's indication are conventional products that can be purchased through formal channels.

The present invention will be further described below with reference to specific embodiments. It should be understood that the specific embodiments described herein are only used to illustrate the present invention, but not to limit the scope of the present invention.

The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the following examples are all commercially available products unless otherwise specified.

1. Preparation Examples

The application has prepared the following isoniazid dry powder inhalers, and used them in various effect experiments described below.

Example 1: Pulverize 10.0 g of isoniazid through a fluidized bed supersonic jet pulverization method to make the particle size reach d ₁₀ =0.5-2.0 μm, d ₅₀ =2.0-5.0 μm, d ₉₀ =5.0-9.5 μm, Take the above-mentioned isoniazid micropowder, mix Inhalac 140 type lactose and isoniazid micropowder, and the mixing weight ratio is 1:1; after mixing, add the adjuvant leucine, and the leucine accounts for 5% of the total weight of the preparation.

Example 2: 10.0 g of isoniazid was crushed by fluidized bed supersonic jet to make the particle size reach d ₁₀ =0.5-2.0 μm, d ₅₀ =2.0-5.0 μm, d ₉₀ =5.0-9.5 μm, Take the above-mentioned isoniazid micropowder, mix Inhalac 230 type lactose and isoniazid micropowder, and the mixing weight ratio is 1:1; after mixing, add the adjuvant leucine, and the leucine accounts for 5% of the total weight of the preparation.

Example 3: Pulverize 10.0 g of isoniazid by a fluidized bed supersonic jet pulverization method to make the particle size reach d ₁₀ =0.5-2.0 μm, d ₅₀ =2.0-5.0 μm, d ₉₀ =5.0-9.5 μm, Take the above isoniazid micropowder, mix Inhalac 230 type lactose and isoniazid micropowder in a weight ratio of 2:1; after mixing, add adjuvant leucine, and leucine accounts for 5% of the total weight of the preparation.

Example 4: Dissolve 10.0 g of isoniazid in 200 mL of purified water, add leucine with a concentration of 5% (w/v, g/mL) to prepare a clear and transparent solution, spray-dry the above solution, and prepare the solution. The air temperature was set to 150°C, the rotational speed was 15rpm, the fan frequency was 35Hz, and the outlet air temperature was 135°C, and the particles in the cyclone were collected. Continue to dry for 5h, add Inhalac 120 lactose and mix for 30min, and lactose accounts for 30% of the total preparation weight.

Example 5: Dissolve 10.0 g of isoniazid in 200 mL of purified water, add leucine with a concentration of 10% (w/v, g/mL) to prepare a clear and transparent solution, spray-dry the above solution, and prepare the solution. The air temperature was set to 150°C, the rotational speed was 10rpm, the fan frequency was 35Hz, and the outlet air temperature was 135°C, and the particles in the cyclone were collected. Continue to dry for 5h, add Inhalac 120 lactose and mix for 30min, lactose accounts for 30% of the total weight of the preparation.

Example 6: Dissolve 10.0 g of isoniazid in 200 mL of purified water, add leucine at a concentration of 8% (w/v, g/mL) to prepare a clear and transparent solution, spray-dry the above solution, and prepare the solution. The air temperature was set to 150°C, the rotational speed was 10rpm, the fan frequency was 35Hz, and the outlet air temperature was 130°C, and the particles in the cyclone were collected. Continue to dry for 15h, add Inhalac 140 lactose and mix for 30min, lactose accounts for 30% of the total weight of the preparation.

Example 7: Dissolve 10.0 g of isoniazid in 300 mL of purified water, add leucine at a concentration of 8% (w/v, g/mL) to prepare a clear and transparent solution, spray-dry the above solution, and prepare the solution. The air temperature was set to 150°C, the rotational speed was 10rpm, the fan frequency was 35Hz, and the outlet air temperature was 130°C, and the particles in the cyclone were collected. Continue to dry for 15h, add Inhalac 140 lactose and mix for 30min, lactose accounts for 30% of the total weight of the preparation.

Example 8: Dissolve 10.0 g of isoniazid in 300 mL of purified water, add leucine at a concentration of 8% (w/v, g/mL) to prepare a clear and transparent solution, spray-dry the above solution, and prepare the solution. The air temperature was set to 150°C, the rotational speed was 10rpm, the fan frequency was 35Hz, and the outlet air temperature was 130°C, and the particles in the cyclone were collected. Continue to dry for 15h, add magnesium stearate and mix for 30min, and the magnesium stearate accounts for 2.5% of the total weight of the preparation.

Example 9: Dissolve 10.0 g of isoniazid in 200 mL of purified water, add leucine at a concentration of 8% (w/v, g/mL) to prepare a clear and transparent solution, spray-dry the above solution, and prepare the solution. The air temperature was set to 150°C, the rotational speed was 25rpm, the fan frequency was 35Hz, and the outlet air temperature was 130°C, and the particles in the cyclone were collected. Continue to dry for 5h, add Inhalac 140 lactose and mix for 30min, lactose accounts for 30% of the total weight of the preparation.

Example 10: Dissolve 10.0 g of isoniazid in 200 mL of purified water, add leucine with a concentration of 10% (w/v, g/mL) to prepare a clear and transparent solution, spray-dry the above solution, and prepare the solution. The air temperature was set to 150°C, the rotational speed was 25rpm, the fan frequency was 45Hz, and the outlet air temperature was 130°C, and the particles in the cyclone were collected. Continue to dry for 5h, add Inhalac 140 lactose and mix for 30min, lactose accounts for 30% of the total weight of the preparation.

Example 11: Dissolve 10.0 g of isoniazid in 200 mL of purified water, add leucine at a concentration of 8% (w/v, g/mL) to prepare a clear and transparent solution, spray-dry the above solution, and prepare the solution. The air temperature was set to 120°C, the rotational speed was 10rpm, the fan frequency was 45Hz, and the outlet air temperature was 130°C, and the particles in the cyclone were collected. Continue to dry for 5h.

Example 12: Dissolve 10.0 g of isoniazid in 200 mL of purified water, add leucine at a concentration of 8% (w/v, g/mL) to prepare a clear and transparent solution, spray-dry the above solution, and prepare the solution. The air temperature was set to 120°C, the rotational speed was 10rpm, the fan frequency was 45Hz, and the outlet air temperature was 130°C, and the particles in the cyclone were collected. Continue to dry for 5h, add magnesium stearate and Inhalac 140 lactose and mix for 30min, magnesium stearate accounts for 2.5% of the total preparation weight and lactose accounts for 30% of the total preparation weight

2. Characterization of isoniazid micropowder particles in isoniazid dry powder inhaler

The shape of the isoniazid micropowder particles was observed by scanning electron microscope, the particle size of the powder was determined by the dry method, and the fine particle dose of the isoniazid micropowder particles was determined by the NGI method. The SEM results of Example 6 and Example 8 are shown in Figure 1 and Figure 2, respectively. The results are shown in Table 1.

Table 1: Characterization of Isoniazid Micropowder Particles in Isoniazid Dry Powder Inhaler

The above results show that the fine particle dosage (FPD) values of the above batches all reach the value specified in the Chinese Pharmacopoeia (>10%), and the micronization and spray drying technologies can meet the requirements, but the addition of different lactose may cause changes in fine particles. Example 3 shows that adding a certain amount of fine-grained lactose has a certain advantage over adding large-grained lactose, but when the amount of lactose is excessive, the FPD value will drop significantly, which may be due to the fact that when the amount of lactose is too large, a large amount of fine-grained raw materials are sucked into the surface, causing Fine particles are deposited in the throat along with lactose, reducing FPD. In addition, the change of spray drying process parameters can cause the change of particle size. When the rotation speed is selected lower, the FPD value of the particles increases. When the concentration of API is low, the FPD value of the particles increases. The addition of magnesium stearate can The significant increase in the FPD value of the particles may be related to their good lubrication and flow-assisting effects, and the interaction between particles decreases. However, as shown in Example 9 and Example 10, when the rotation speed is too high, adjusting other parameters has little effect on the FPD effect of the particles, and the rotation speed is closely related to the size of the particles obtained by the pursuit.

3. Stability study of isoniazid dry powder absorbent

The powders collected in Example 11 and Example 12 were placed in a stability test chamber, under the conditions of 40°C ± 2°C 5%, and the particle size of the powder was measured by dry method in 0, January, February, and March, respectively. NGI measures the particle size of fine particles, and measures the moisture content of the powder by the loss-on-drying method. The results are shown in Table 2 and Table 3, respectively.

Table 2: Stability results of the isoniazid dry powder inhaler prepared in Example 11

Table 3: Stability results of the isoniazid dry powder inhaler prepared in Example 12

The results show that when the spray drying technology is selected, the particles prepared by this method are more uniform than those prepared by the fluidized bed supersonic jet pulverization method. The addition of an antistatic agent can enhance the spheroidization of the raw material, reduce the particle size of the drug, and make the distribution of the drug and the excipients uniform. , while adding glidant magnesium stearate or lactose to further optimize the fluidity and dispersibility of the powder, the prepared powder is more stable and easy to fill.

4. The plasma concentration of isoniazid dry powder inhaler in rats and the distribution in rat tissues

Twelve SD rats (200g±20g) were taken, 6 rats in the isoniazid tablet group; 6 rats in the isoniazid inhalation powder aerosol group (Example 6). The two groups were given the same amount of isoniazid, 5.4mg/only. 10min, 30min, 1h, 2h, 4h, 6h, 8h, 12h respectively. Plasma drug concentrations were determined using LC-MS.

Another 64 SD rats (200g±20g) were taken, 32 rats in the isoniazid tablet group; 32 rats in the isoniazid inhalation powder aerosol group (Example 6). Both groups were given the same amount of isoniazid, 5.4mg/only. 10min, 30min, 1h, 2h, 4h, 6h, 8h, 12h respectively. Four animals in each group were dissected, and the drug concentration in liver and lung tissue was determined by LC-MS. The results are shown in Table 4, Table 5 and Table 6, respectively.

Table 4: Plasma Drug Concentrations of Isoniazid in Rats in Isoniazid Dry Powder Inhaler and Isoniazid Tablets

Table 5: Drug concentrations of isoniazid in isoniazid dry powder inhaler and isoniazid tablet in rat lung tissue

Table 6: Drug concentration of isoniazid in isoniazid dry powder inhaler and isoniazid tablet in rat liver tissue

As shown in Table 4, the results of drug concentration in plasma show that the change of drug concentration in plasma of inhaled powder is similar to that of injection, and it is quickly absorbed into the blood, and the _Cmax is higher than the _Cmax of the gavage group, and it has a fast blood entry. Advantage. As shown in Table 5, the results of drug concentration in lung tissue show that the change of drug concentration in lung tissue of inhaled powder is also similar to that of injection, but _Cmax can reach about 3 times of _Cmax of gavage group, indicating that isoniazid powder After the aerosol is inhaled, it can quickly reach a higher concentration in the lung tissue and kill the Mycobacterium tuberculosis in the lungs. As shown in Table 6, the results of drug concentration in liver tissue showed that the drug concentration of inhaled powder in liver tissue did not change much compared with the gavage group, but the retention time in liver tissue of gavage group was relatively long, >1 μg /mL group, the gavage group lasted from 10min to 6h, while the inhalation group only lasted from 10min to 2h. Isoniazid has the potential advantage of reducing liver toxicity after inhalation.

5. Pharmacodynamic test results of isoniazid dry powder inhaler in mice

Aerosol infection of acute mouse tuberculosis model, diluted with PBS+0.04% Tween 80 cryopreserved Mycobacterium tuberculosis H37Rv (storage concentration should be > 10 ⁸ cfu/mL), diluted cryopreserved Mycobacterium tuberculosis H37Rv to a concentration of 5 ×10 ⁶ cfu/mL. The 24 BALB/C mice (18-20 g) to be infected were loaded into the nebulizer chamber, the chamber was closed, and the bacterial liquid was sucked into the nebulizer. According to preheating for 15 minutes, atomization for 30 minutes, smoke decay for 30 minutes, and purification for 15 minutes, atomization infection and sterilization were carried out. After the infection, the mice were kept in separate cages in the negative pressure infection animal room. On the 3rd day after the infection, 3 mice were dissected, and the viable bacteria were counted to determine whether the infection was successful. Three mice were dissected on day 10 post-infection to provide basal values for lung viable counts at the start of treatment.

The treatment was started on the 10th day after infection. The blank control group (6 animals): 0.5% hydroxymethyl cellulose (CMC), the positive control group (6 animals): isoniazid tablets (5.4 mg/nose, concentration 54mg/gavage) mL, 0.1 mL per gavage), positive treatment group (6 rats): isoniazid dry powder inhalation group (preparation of Example 7, the dose of each drug powder is 10 mg, the isoniazid content is about 60%, which is equivalent to about 60% of isoniazid) drug 6mg), using a miniature lung dust atomizer, each mouse tracheal intubation nebulized 5.4mL. The mice were administered once a day for 4 consecutive weeks, and the next day after 28 doses, the mice in each group were sacrificed, the mice were weighed, and the viable lung bacteria were counted. The results are shown in Table 7.

Table 7: Viable counts (log10cfu) in different treatment groups

The results showed that a large number of tuberculosis bacteria still grew in the lungs on the third day, and the number of tuberculosis bacteria increased on the tenth day. After four weeks of treatment, the bacterial count in the lung tissue showed that the number of bacteria in the treatment group was significantly lower than that in the control group. It can significantly reduce tuberculosis bacteria in tissues, which proves that inhalation has better local bactericidal effect than gavage treatment. And the trend of body weight change has a certain correlation with the number of bacteria in the lungs. The higher the number of bacteria, the lighter the weight of mice, which may be related to the growth of bacteria in the lungs affecting the growth state of mice. It is speculated that isoniazid powder aerosol may have potential clinical advantages in improving the living conditions of pulmonary tuberculosis patients.

To sum up, the dry powder inhaler of the present invention has a relatively high drug load, and 80% or even more than 95% of the pharmaceutical preparation is the active ingredient isoniazid. The dry powder inhalant of the invention has high formulation stability and simple preparation process, can rapidly prepare the isoniazid dry powder inhalant, and can meet the requirements of scaled production. The isoniazid dry powder inhaler prepared by the method of the invention is especially suitable for treating pulmonary tuberculosis and bronchial tuberculosis in patients with impaired liver function, and has important clinical significance.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit and scope of the invention. Thus, provided that these modifications and variations of the present invention fall within the scope of the claims of the present invention and technical equivalents thereof, the present invention is also intended to include these modifications and variations.

Claims

An isoniazid dry powder inhaler for treating pulmonary tuberculosis, characterized in that: the dry powder inhaler contains isoniazid micropowder, and contains or does not contain carrier micropowder, and is subjected to a fluidized bed supersonic jet pulverization method or a spray drying method. The particle size of the isoniazid micro-powder is processed to be d 10 =0.1-3 μm, d 50 =3-7 μm and d 90 =7-10 μm, when the carrier micro-powder is included, the carrier micro-powder is made by adding auxiliary materials, the The internal adjuvant is amino acid, mannitol or phospholipid, and the dry powder inhaler further comprises external adjuvant, and the external adjuvant is selected from one or more of amino acids, phospholipids, carbohydrates or magnesium stearate.
The dry powder inhaler according to claim 1, wherein the amino acid is selected from leucine, valine, glycine or isoleucine, preferably leucine, and the saccharide is selected from mannitol, Lactose, maltose, trehalose or sucrose, preferably lactose or mannitol.
dry powder inhaler according to claim 2, is characterized in that: the model of described lactose is one or more of Inhalac 120, Inhalac 140, Inhalac 230 or Inhalac 400.
The dry powder inhaler according to any one of claims 1 to 3, wherein the added auxiliary material is leucine, and the addition of the leucine accounts for 0-30% of the total weight of the dry powder inhaler , preferably 2-10%, the adjuvant is leucine and/or lactose and/or magnesium stearate and/or mannitol, the addition of the leucine accounts for 0-30% of the total weight of the dry powder inhaler %, preferably 2-10%, the addition of the lactose accounts for 0-50% of the total weight of the dry powder inhaler, preferably 10-30%, the addition of the magnesium stearate accounts for 0-50% of the total weight of the dry powder inhaler 10%, preferably 1-5%, the added amount of the mannitol accounts for 0-50% of the total dry powder inhaler, preferably 10-30%.
The preparation method of the dry powder inhaler according to any one of claims 1 to 4, the method comprising the steps of: preparing the isoniazid micropowder by a fluidized bed supersonic jet pulverization method, and taking the isoniazid micropowder , mix lactose and isoniazid micropowder in a certain proportion, add leucine after mixing, and then pack the mixed powder in a capsule or blister, or pack it in a multi-dose dry powder inhalation device in the form of a reservoir, or The method includes the following steps: dissolving isoniazid in a certain amount of solvent, adding leucine to prepare a clear and transparent solution, spray-drying the solution, collecting the fine powder in the cyclone dryer, and continuing to dry for a period of time, Lactose and/or magnesium stearate are added and mixing is continued for a period of time before the mixed powder is packaged in capsules or blister packs, or in a depot in a multi-dose dry powder inhaler device.
The preparation method according to claim 5, wherein the solvent is selected from purified water, propylene glycol or ethanol, preferably purified water.
The preparation method according to claim 5 or 6, characterized in that: the spray drying air inlet temperature is 100°C-180°C, preferably 120°C-150°C; the fan frequency is 30Hz-40Hz, preferably 34Hz-38Hz; the rotational speed is 5rpm -40rpm, preferably 8rpm-20rpm; atomization pressure 0.20MPa-0.30MPa, preferably 0.24MPa-0.28MPa; orifice size 0.5mm-1.2mm, preferably 0.8mm-1mm.
The preparation method according to any one of claims 5 to 7, characterized in that: the drying time is 5h-48h; the mixing time is 0.5h-1h.
Use of the dry powder inhaler according to any one of claims 1 to 4 or the dry powder inhaler prepared by the preparation method according to any one of claims 5 to 8 in the preparation of a medicine for treating pulmonary tuberculosis.
The use according to claim 9, wherein the pulmonary tuberculosis is pulmonary tuberculosis in patients with poor liver function, or the pulmonary tuberculosis is bronchial tuberculosis.