CN106551919B

CN106551919B - Novel inhalation formulations

Info

Publication number: CN106551919B
Application number: CN201510634476.5A
Authority: CN
Inventors: 姜庆伟; 张强; 梁希; 颜琨; 杨文斌; 衣伟锋; 吴黄焱; 刘飞; 滕丽佳; 郑阳; 陈丹
Original assignee: BEIJING TIANHENG DRUG RESEARCH INSTITUTE
Current assignee: BEIJING TIANHENG DRUG RESEARCH INSTITUTE
Priority date: 2015-09-30
Filing date: 2015-09-30
Publication date: 2020-12-18
Anticipated expiration: 2035-09-30
Also published as: CN106551919A

Abstract

The invention relates to a novel inhalation preparation, in particular to a preparation suitable for inhalation administration of children of 0-12 years old. Mixing the insoluble drug and the auxiliary material, and then crushing by a wet grinding method to obtain a suspension containing particles with a proper particle size, wherein the particle size is 0.1-7 mu m, and preferably 0.1-5 mu m; further preferably 0.1 to 3 μm. Then obtaining solid powder by a freeze-drying method, and sealing to obtain the product; mixing with liquid suitable for atomization before use, and dispersing again to obtain suspension for children to inhale. The preparation is stored and transported in the form of solid powder, so that the problems of poor physical stability and chemical stability caused by adopting a suspension form are solved, the particle size of the medicine is basically unchanged, the impurity increase is small, and the content is basically unchanged. Compared with inhalation powder inhalation, the aerosol is especially suitable for children to carry out aerosol administration, can adopt medicines with smaller particle size, and can also play an ideal drug effect even under the conditions that infants breathe shallowly and the deposition rate of effective parts is low.

Description

Novel inhalation formulations

Technical Field

The invention relates to a novel inhalation preparation, in particular to a preparation suitable for inhalation administration of children of 0-12 years old, belonging to the field of pharmaceutical preparations.

Background

Asthma is one of the most common chronic diseases of respiratory tract in childhood, and the prevalence rate of asthma in 0-14 year old urban children in China is 0.5-3.4% in 2000. The most common method for the clinical treatment of childhood asthma is by local administration by inhalation, which on the one hand acts directly on the target organ and on the other hand avoids systemic side effects. If the insoluble medicine such as the potent corticoid needs to be inhaled and administered, the insoluble medicine is usually prepared into an inhalation powder spray for active inhalation, and has the advantages of convenient carrying, quick administration and quick response. However, children are difficult to actively inhale the powder inhalation because of insufficient lung capacity due to their young and weak respiratory capacity due to their illness, and therefore, children generally inhale the powder inhalation in the form of a suspension, atomize the suspension by an atomizing pump, and inhale the atomized liquid medicine into the respiratory tract by breathing, such as the budesonide suspension for inhalation by the company asikang. However, this suspension is a heterogeneous system, and the drug has a very small particle size and a large surface area, resulting in poor stability, which is manifested by large surface energy, easy aggregation and precipitation of drug particles during storage and transportation, resulting in large particle size and poor physical stability of the drug, and poor chemical stability due to the large surface area being prone to degradation reactions such as hydrolysis and oxidation.

Disclosure of Invention

In order to overcome the defects of the existing inhalation preparation for children, applicants invent a novel inhalation preparation, the inhalation preparation is prepared by mixing insoluble drugs and auxiliary materials, then grinding by a wet grinding method to obtain a suspension containing particles with proper particle size, then obtaining solid powder by a freeze-drying method, and sealing and storing; before use, the solid powder is mixed with a liquid suitable for aerosolization and redispersed to provide a suspension for aerosolization by a child.

The novel inhalation preparation comprises medicine particles with proper particle size and auxiliary materials. The drug particles with the proper particle size range from 0.1 to 7 microns, and the preferable particle size range from 0.1 to 5 microns; more preferably 0.1 to 3 μm. The auxiliary materials comprise a freeze-drying protective agent and a suspending agent, wherein the freeze-drying protective agent is selected from saccharides and comprises one or more of lactose, sucrose and the like, and the suspending agent is selected from a surfactant, preferably Tween, and further preferably Tween-80.

The particle size of the medicine generally used for inhalation is 0.5-7 μm, so that the medicine can reach the lung to exert the drug effect, therefore, the particle size of the medicine inhaled into the powder inhalation is controlled to be below 10 μm, most of the medicine is below 5 μm, and even if the medicine is, only a small amount of the medicine can be deposited on the effective part to take effect. However, the inhalation suspension is different from the inhalation powder, the inhalation powder inhales the drug particles, the inhalation suspension inhales the atomized droplets, the drug particles are wrapped in the droplets, the relationship between the distribution of the droplets (deposition rate of the effective part) and the particle size of the drug particles is not large, but the particle size of the atomized droplets is related, and the deposition rate of the effective part can meet the requirement as long as the particle size of the atomized droplets still meets the requirement of the particle size. On the other hand, in the case of an inhalation suspension, the relationship between the droplet distribution (corresponding to the deposition rate of the effective site) and the particle size of the drug particles itself is not large, but the efficacy or bioavailability of a poorly soluble drug is related to the particle size of the drug particles themselves, and the smaller the particle size, the larger the contact area with the site of action, and the shorter the time for the drug to take effect, the higher the efficacy or bioavailability, and therefore, the efficacy or bioavailability of the finer particle is relatively high at the same deposition rate of the effective site, in other words, the fine particle can exhibit an ideal efficacy even at a low deposition rate of the effective site due to shallow breathing of infants and young children. Therefore, the novel inhalation preparation of the present invention has a particle size of the drug in the range of 0.1 μm to 7 μm, preferably in the range of 0.1 μm to 5 μm; more preferably 0.1 to 3 μm.

The liquid suitable for atomization in the invention includes but is not limited to one or more of pure water, normal saline and glucose solution for injection.

The preparation method of the novel inhalation preparation comprises the following steps:

1. mixing the insoluble drug and the auxiliary material, and then crushing by a wet grinding method to obtain a suspension containing particles with proper particle size, wherein the range of the particle size is 0.1-7 mu m, and the preferable range of the particle size is 0.1-5 mu m; more preferably 0.1 to 3 μm;

2. subpackaging, and vacuum freeze-drying to obtain solid powder;

3. and sealing to obtain the product.

Before use, the novel inhalation preparation provided by the invention is prepared by mixing solid powder and liquid suitable for atomization, and redispersing to obtain suspension for children to inhale. The liquid suitable for atomization includes, but is not limited to, pure water, physiological saline, glucose solution for injection, and the like.

The novel inhalation preparation is stored and transported in a solid powder form, and is prepared into suspension before use, compared with the common inhalation suspension, the aerosol distribution (deposition rate of effective parts) is not obviously different, and compared with a preparation with smaller medicine particle size and larger particle size, the aerosol distribution (deposition rate of the effective parts) is larger, and meanwhile, the problems of poor physical stability and chemical stability caused by storage and transportation in a suspension form are solved, the medicine particle size is basically unchanged, the impurity is increased slightly, the content is basically unchanged, and the novel inhalation preparation has good stability. Compared with inhalation powder inhalation, the aerosol is particularly suitable for aerosol administration of children of 0-12 years old, the particle size of the medicament is basically irrelevant to the particle size of inhaled liquid drops, the medicament with smaller particle size can be adopted to obtain higher drug effect or bioavailability, and ideal drug effect can be exerted even under the condition that the effective part deposition rate is lower due to shallower breath of the young infants.

Detailed Description

The embodiments of the present invention will be described below by taking budesonide suspensions for inhalation as examples, but the scope of the present invention should not be limited thereto, and other ranges of budesonide or other drug embodiments can be implemented by referring to the principles of the present invention and the operation of the following examples, and still fall within the scope of the present invention.

EXAMPLE 1 novel inhalation formulations containing budesonide

The preparation process comprises the following steps:

1. the wet grinding method is adopted, the equipment is a DYNO-MILL RESEARCH LAB bead mill, the diameter of grinding beads is 0.1mm, budesonide, auxiliary materials and pure water are uniformly mixed and then added into a hopper, the machine is started, the rotating speed is 1500 rpm, and the grinding is carried out twice by a pass-through mode.

2. The ground suspension was dispensed into glass injection vials, 2ml each, and lyophilized under vacuum to give a solid powder.

3. And (4) covering and sealing.

EXAMPLE 2 novel inhalation formulations containing budesonide

Prescription: same as example 1

The preparation process comprises the following steps: the same procedure as in example 1 was repeated except that the grinding beads were changed to those having a diameter of 0.5 mm.

Example 3

Prescription: same as example 1

The preparation process comprises the following steps: the same procedure as in example 1 was repeated except that the grinding beads were changed to those having a diameter of 2.0 mm.

EXAMPLE 4 novel inhalation formulations containing budesonide

Prescription: same as example 1

The preparation process comprises the following steps: the same procedure as in example 1 was repeated except that the grinding beads were changed to grinding beads having a diameter of 4.0 mm.

Example 5 particle size and droplet distribution stability Studies of novel budesonide-containing inhalation formulations

Particle size inspection of budesonide particles

Taking the novel budesonide-containing inhalation preparations prepared by the methods described in examples 1 to 4 of the present invention, the particle size changes of the budesonide microparticles before and after lyophilization were examined, respectively, and the results are shown in table 2 below,

before freeze-drying: and taking the suspension, and placing the suspension into a Malvern laser particle size analyzer to measure the particle size.

After freeze-drying: taking the product, adding 2ml of physiological saline into each 1 bottle, fully shaking to uniformly disperse to obtain suspension, and measuring the particle size by the same method.

TABLE 1 drug particle size (unit μm) before and after lyophilization

The results show that the drug particle size in the suspension of the product is essentially unchanged before and after lyophilization.

Second, investigation of droplet size

The test method comprises the following steps:

the apparatus used is shown in Table 2.

The specific operation is as follows:

1. assembling HELOS-INHALER, selecting neb mode, connecting the suction nozzle of the atomizer with the simulated throat of the INHALER, and checking airtightness;

2. starting a vacuum pump, and adjusting the vacuum degree to be 5mbar (which is about equivalent to the gas flow rate of 15L/min) until the vacuum degree is stable;

3. unscrewing the atomizing cup cover, pouring the liquid medicine into the atomizing cup, and screwing the atomizing cup cover;

4. after the test background is deducted, the atomizer is started to start the measurement, the atomization time lasts for 10s, data are collected, and the atomizer is closed. The same method is used for measuring three times continuously, processing data and reporting results. The results are given in Table 3 below.

The original product on the market as a reference is budesonide suspension for inhalation (pramipexole) produced by the company of astrazen, and the specification is 2 ml: 1 mg.

TABLE 2 Instrument for particle size determination

Name of instrument	Instrument type	Manufacturer of the product
			Laser particle size analyzer	HELOS-INHALER	Germany New Partack Ltd
Compressed air type atomizer	403C	JIANGSU YUYUE MEDICAL EQUIPMENT& SUPPLY Co.,Ltd.

TABLE 3 investigation of droplet size (in μm)

Batch number	d10	d50	d90
				Example 1	0.78	2.96	6.85
Example 2	0.79	2.80	6.83
				Example 3	0.81	2.92	6.87
Example 4	0.82	2.88	6.93
				Originally ground and marketed product	0.81	2.91	6.84

The results show that the droplets obtained by the compressed air type nebulizer were almost the same in particle size as those of examples 1 to 4 and the commercial products originally developed, and the particle size of the droplets was not related to the particle size of the budesonide drug particles, but was determined by the nebulization effect of the nebulizer.

Distribution of fog drops (particles)

The instrument comprises the following steps: NGI (Copley corporation), seven grades, referred to the pharmaceutical multistage impactor method (NGI) described in the united states pharmacopeia USP35, flow rate: 30L/min, detecting the amount of the drug deposited in grades 1, 2, 3, 4, 5, 6 and 7, and the result is shown in table 4, wherein the liquid medicine is atomized by the compressed air atomizer shown in table 2. The content was measured according to the method described in BP2010 inhalation budesonide suspension standard.

TABLE 4 fogdrop (particle) distribution results

And (4) conclusion: the fog drop (particle) distribution of the products of examples 1 to 4 and the products on the market in the original research are not significantly different, and the SUM value of the fog drop (particle) distribution is slightly larger in example 1 with smaller drug particle size than in example 4 with larger particle size.

Example 6 stability Studies of novel inhalation formulations containing budesonide

The sample of example 3, which has a similar particle size to that of a commercially available budesonide suspension for inhalation (pramipexole), and the commercially available budesonide suspension and the sample of example 3 are placed in a constant temperature and humidity chamber with a temperature of 40 ℃/RH 75% and a constant humidity chamber with a temperature of 25 ℃/RH 65% respectively, and the stability of the samples under accelerated conditions and long-term conditions is examined, and the results are shown in tables 5 and 6 below.

TABLE 540 deg.C/RH 75% accelerated stability data

Note: the related substances and content measuring conditions are the same as the British pharmacopoeia BP2010 inhalation budesonide suspension standard.

The product is prepared by adding 2ml of physiological saline into each bottle, sufficiently shaking to uniformly disperse to obtain a suspension, and preparing a test solution according to the method of the standard of budesonide suspension for BP2010 inhalation.

The results show that after being stored for 6 months under the accelerated condition of 40 ℃/RH 75%, the novel inhalation preparation containing budesonide prepared in the embodiment 3 of the invention has basically no change of the granularity, no obvious increase of related substances and basically no change of the content compared with the commercially available sumikegsu, and the commercially available sumikegsu has slightly increased granularity, relatively larger increase of related substances and slightly reduced content.

TABLE 625 deg.C/RH 65% stability data under Long term conditions

The result shows that after the novel inhalation preparation containing budesonide prepared in the embodiment 3 of the invention is stored for 24 months under the accelerated condition of 25 ℃/RH 65%, compared with the commercially available sumikeshu, the particle size of the medicament is not obviously changed, the related substances are not obviously increased, the content is basically unchanged, the particle size of the commercially available sumikeshu is slightly increased, the related substances are relatively greatly increased, and the content is slightly reduced.

Claims

1. A preparation method of suspension for children to atomize and inhale is characterized in that after insoluble drugs and auxiliary materials are mixed, the mixture is ground by a wet grinding method to obtain suspension containing particles with proper particle size, then the suspension is freeze-dried to obtain solid powder, the solid powder is sealed and stored, and the solid powder and liquid suitable for atomization are mixed and re-dispersed before use to obtain suspension for children to atomize and inhale; the indissolvable drug is budesonide, and the auxiliary materials are lactose serving as a freeze-drying protective agent and Tween-80 serving as a suspending agent.

2. The process for preparing a suspension for children's aerosol inhalation according to claim 1, wherein the particle size of the poorly soluble drug is in the range of 0.1 μm to 7 μm when the poorly soluble drug is pulverized by wet milling to obtain a suspension containing particles having an appropriate particle size.

3. The process for preparing a suspension for children's aerosol inhalation according to claim 1, wherein the particle size of the poorly soluble drug is in the range of 0.1 to 5 μm when the poorly soluble drug is pulverized by wet milling to obtain a suspension containing particles having an appropriate particle size.

4. The process for preparing a suspension for children's aerosol inhalation according to claim 1, wherein the particle size of the poorly soluble drug is in the range of 0.1 to 3 μm when the poorly soluble drug is pulverized by wet milling to obtain a suspension containing particles having an appropriate particle size.

5. The method of claim 1, wherein the liquid suitable for nebulization comprises one or more of pure water, physiological saline, and glucose solution for injection.