阅读说明：本技术 一类药用抗病毒药物吸入剂新型制剂及制备方法 (Novel medicinal antiviral drug inhalant preparation and preparation method thereof ) 是由 张哲峰 侯雯 赵海峰 于 2020-03-18 设计创作，主要内容包括：本发明公开了一类药用抗病毒药物吸入剂新型制剂及制备方法,本发明所述的新型制剂包括治疗剂、包覆剂、悬浮剂、包和剂、载体和助溶剂。本发明的剂型不但有改良二级颗粒表面性能、空气动力学优化的作用,还可以在达到提升肺泡内有效沉积率的效果后,促进对难溶性药物的溶解、吸收,加速起效。(The invention discloses a novel preparation of a medicinal antiviral drug inhalant and a preparation method thereof. The preparation of the invention not only has the functions of improving the surface performance of secondary particles and optimizing the aerodynamics, but also can promote the dissolution and absorption of insoluble drugs and accelerate the effect after achieving the effect of improving the effective deposition rate in alveolus.)

1. A medicinal antiviral drug inhalant is characterized in that: the components of the inhalant are as follows:

2. the inhalant as claimed in claim 1, wherein: the weight parts of the therapeutic agent, the coating agent, the suspending agent, the inclusion agent, the carrier and the cosolvent are 10-500 parts, 10-300 parts, 10-200 parts, 10-100 parts and 0-50 parts in sequence.

3. The inhalant as claimed in claim 2, wherein: the weight parts of the therapeutic agent, the coating agent, the suspending agent, the inclusion agent, the carrier and the cosolvent are 10-300 parts, 10-250 parts, 80-200 parts, 10-50 parts, 40-100 parts and 0-30 parts in sequence.

4. A pharmaceutical antiviral drug inhalant as claimed in any one of claims 1 to 3, wherein: the therapeutic agent is an antiviral drug, and the antiviral drug is a drug with the disease or potential drug effect of treating SARS, MERS and 2019 novel coronavirus (2019-nCoV);

preferably: the antiviral drug is at least one of mineral drug, botanical drug, chemical drug and biological drug;

further preferably: the antiviral drug is at least one of ribavirin, arbidol hydrochloride, chloroquine phosphate, ritonavir, ridciclovir, oseltamivir, lopinavir, SiRNA and alpha-interferon.

5. A pharmaceutical antiviral drug inhalant as claimed in any one of claims 1 to 3, wherein: the coating agent is phospholipid; preferably: the phospholipid is selected from one or more of egg yolk phospholipid, soybean phospholipid, hydrogenated soybean phospholipid, cephalin, cardiolipin, sphingomyelin or synthetic phospholipid; further preferred is: the phospholipid is soybean phospholipid, hydrogenated soybean phospholipid, or synthetic phospholipid.

6. A pharmaceutical antiviral drug inhalant as claimed in any one of claims 1 to 3, wherein: the suspending agent is ethyl acetate or ethanol with volume concentration of 60-90%.

7. A pharmaceutical antiviral drug inhalant as claimed in any one of claims 1 to 3, wherein: the inclusion agent is cyclodextrin and derivatives thereof; preferably: the inclusion agent is at least one of sulfobutyl-beta-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin and beta-cyclodextrin.

8. A pharmaceutical antiviral drug inhalant as claimed in any one of claims 1 to 3, wherein: the cosolvent is at least one of polyoxyethylene castor oil, poloxamer, tween, vitamin E, EDTA-2Na, disodium hydrogen phosphate, sodium dihydrogen phosphate and sucrose.

9. A pharmaceutical antiviral drug inhalant as claimed in any one of claims 1 to 3, wherein: the carrier is at least one of lactose, sucrose, trehalose and glucose.

10. A process for the preparation of an inhalant as claimed in any one of claims 1 to 3, characterized in that: the method comprises the following steps:

1) pulverizing the therapeutic agent with jet mill until D90 is 2-5 um.

2) Adding the coating agent and the cosolvent into the suspending agent, and stirring until the coating agent and the cosolvent are completely dissolved to obtain a mixed solution;

3) suspending the micronized therapeutic agent and the inclusion agent in the mixed solution, and performing spray drying to obtain drug particles;

4) micronizing the medicine particles to D90 of 2-5um by using a jet mill;

5) mixing the micronized particles obtained in the step 4) with a carrier to obtain a mixture; the mixture is encapsulated and remembered to the target product.

Technical Field

The invention belongs to the field of pharmaceutics, and particularly relates to a novel medicinal antiviral medicament inhalant preparation and a preparation method thereof.

Background

The diversity, variability, high transmission of viruses is a great challenge to public health safety. After viral infection, high fever, general pain and obvious hypodynamia are often caused, and pneumonia, respiratory failure and the like are caused in severe cases. Influenza is a respiratory infectious disease caused by influenza virus, is one of the main public health problems facing human beings, and has the epidemiology characteristic of sudden outbreak, rapid spread and wide spread. The influenza has high incidence rate and is generally susceptible. Influenza has severe clinical symptoms and high incidence of complications, particularly pneumonia, and can cause death. Anti-influenza virus therapy is one of means for controlling influenza epidemics, and anti-influenza drugs used in early onset of disease can relieve symptoms, shorten the course of disease and block transmission. Pneumonia caused by the novel coronavirus infection can occur in people with low immune function and normal immune function, and has a certain relation with the amount of the viruses. For people with poor immune function, such as the elderly, pregnant and lying-in women, or people with liver and kidney dysfunction or chronic diseases, the disease condition after infection is worse. The new coronary epidemic situation in winter brings up the call of 'urgent need for better anti-influenza treatment medicine' again.

This time, the pneumonia caused by 2019 new coronavirus (hereinafter referred to as "new coronavirus") infection, the international committee for virus classification (ICTV) formally named the new coronavirus as SARS coronavirus-2 (SARS-CoV-2) from the academic paper and the substitution of WHO official message "2019-nCoV", which together with SARS outbreak in 2003 and MERS outbreak later in the middle east region, seriously threaten human health and have a potential global epidemic crisis. Therefore, the development of a novel inhalant with high drug loading, quick response, clear action target organs and small systemic toxic and side effects is urgently needed, and the novel inhalant has more urgent clinical requirements.

Disclosure of Invention

The invention provides a novel medicinal antiviral medicament inhalant preparation aiming at the technical problems.

The invention also aims to provide a preparation method of the novel medicinal antiviral medicament inhalant.

The purpose of the invention can be realized by the following technical scheme:

a medicinal antiviral drug inhalant comprises the following components:

in some preferred embodiments: the weight parts of the therapeutic agent, the coating agent, the suspending agent, the inclusion agent, the carrier and the cosolvent are 10-500 parts, 10-300 parts, 10-200 parts, 10-100 parts and 0-50 parts in sequence.

In some more preferred embodiments: the weight parts of the therapeutic agent, the coating agent, the suspending agent, the inclusion agent, the carrier and the cosolvent are 10-300 parts, 10-250 parts, 80-200 parts, 10-50 parts, 40-100 parts and 0-30 parts in sequence.

In the example case: the above-mentioned parts by weight may be, but not limited to, mg.

The technical scheme of the invention is as follows: the therapeutic agent is an antiviral drug, and the antiviral drug is a drug with the disease or potential drug effect of treating SARS, MERS and 2019 novel coronavirus (2019-nCoV).

In some specific embodiments: the antiviral drug is at least one of mineral drug, botanical drug, chemical drug and biological drug.

In some more specific embodiments: the antiviral drug is at least one of ribavirin, arbidol hydrochloride, chloroquine phosphate, ritonavir, ridciclovir, oseltamivir, lopinavir, SiRNA and alpha-interferon.

The technical scheme of the invention is as follows: the coating agent is phospholipid; preferably: the phospholipid is selected from one or more of egg yolk phospholipid, soybean phospholipid, hydrogenated soybean phospholipid, cephalin, cardiolipin, sphingomyelin or synthetic phospholipid.

Further preferred is: the phospholipid is one or more of soybean phospholipid, hydrogenated soybean phospholipid and synthetic phospholipid.

The technical scheme of the invention is as follows: the suspending agent is ethyl acetate or ethanol with volume concentration of 60-90%.

The technical scheme of the invention is as follows: the inclusion agent is cyclodextrin and its derivative.

The technical scheme of the invention is as follows: the inclusion agent is at least one of sulfobutyl-beta-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin and beta-cyclodextrin.

The technical scheme of the invention is as follows: the cosolvent is at least one of polyoxyethylene castor oil, poloxamer, tween, vitamin E, EDTA-2Na, disodium hydrogen phosphate, sodium dihydrogen phosphate and sucrose.

The technical scheme of the invention is as follows: the carrier is at least one of lactose, sucrose, trehalose and glucose.

In some embodiments, the invention provides a pharmaceutical antiviral inhalant, which comprises the following components:

optionally: the weight parts of the therapeutic agent, the coating agent, the suspending agent, the inclusion agent, the carrier and the cosolvent are 10-500 parts, 10-300 parts, 10-200 parts, 10-100 parts and 0-50 parts in sequence; alternatively, the first and second electrodes may be,

the weight parts of the therapeutic agent, the coating agent, the suspending agent, the inclusion agent, the carrier and the cosolvent are 10-300 parts, 10-250 parts, 80-200 parts, 10-50 parts, 40-100 parts and 0-30 parts in sequence;

optionally, the therapeutic agent is at least one of ribavirin, arbidol hydrochloride, chloroquine phosphate, ritonavir, ridciclovir, oseltamivir, lopinavir, SiRNA, and interferon-alpha;

optionally, the coating agent is a phospholipid; wherein the phospholipid is one or more of soybean phospholipid, hydrogenated soybean phospholipid and synthetic phospholipid;

optionally, the suspending agent is ethyl acetate or ethanol with volume concentration of 60-90%;

optionally, the inclusion agent is at least one of sulfobutyl-beta-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin and beta-cyclodextrin;

optionally, the cosolvent is at least one of polyoxyethylene castor oil, poloxamer, tween, vitamin E, EDTA-2Na, disodium hydrogen phosphate, sodium dihydrogen phosphate and sucrose;

optionally, the carrier is at least one of lactose, sucrose, trehalose, and glucose.

A preparation method of a medicinal antiviral drug inhalant comprises the following steps:

1) pulverizing the therapeutic agent with jet mill until D90 is 2-5 um.

2) Adding the coating agent and the cosolvent into the suspending agent, and stirring until the coating agent and the cosolvent are completely dissolved to obtain a mixed solution;

3) suspending the micronized therapeutic agent and the inclusion agent in the mixed solution, and performing spray drying to obtain drug particles;

4) micronizing the medicine particles to D90 of 2-5um by using a jet mill;

5) mixing the micronized particles obtained in the step 4) with a carrier to obtain a mixture; the mixture is encapsulated and remembered to the target product.

The inhalant in the technical scheme of the invention is powder inhalant.

The invention has the beneficial effects that:

according to the technical scheme, a mode that phospholipid and other auxiliary agents are coated on the surface of the therapeutic agent for surface modification is successful through specific comparative experiments, the combined component of the phospholipid and the auxiliary agents can improve the powder performance of the therapeutic agent in a dry powder form, the aerodynamic characteristics are optimized, more medicaments are effectively delivered to lower respiratory tract and deep alveolar tissues, the deposition rate of the effective part of the therapeutic agent medicament in some embodiments is as high as 45-60%, and compared with the deposition rate of the effective part of 10-30% of a conventional DPI preparation, the therapeutic agent has remarkable advantages;

meanwhile, in experiments, it is unexpectedly found that the coating composed of phospholipid and an auxiliary agent can also effectively reduce the loss caused by the adsorption of the solution-state medicament and materials at the valve, silica gel, sealing ring and the like to the medicament, and for the active substances of the conventional solution dosage form or the MDI dosage form without the particle protective coating, the loss of the effective dose caused by the adsorption is common, which is another great advantage of the invention.

In addition, the composition of the coating layer group of the phospholipid and the auxiliary agent composition reduces the agglomeration of dry powder in the DPI dosage form by improving the surface of secondary particles, and avoids the condition that the dry powder cannot be effectively redispersed after being stored for a certain time; meanwhile, the flocculation degree of suspension particles in the P-MDI dosage form can be reduced, so that the redispersion of the secondary particles after sedimentation is easier to realize, and certain improvement is achieved.

In addition, the phospholipid and the auxiliary agent not only have the functions of improving the surface performance of secondary particles and optimizing the aerodynamics, but also can promote the dissolution and absorption of insoluble drugs and accelerate the effect after achieving the effect of improving the effective deposition rate in alveolus.

Detailed Description

The present invention will be further described with reference to the following examples, which are intended to illustrate the present invention and not to limit the scope of the present invention, and all simple modifications of the preparation method of the present invention based on the idea of the present invention are within the scope of the present invention. The following examples are experimental methods without specifying specific conditions, and generally follow the methods known in the art. The test materials used in the following examples were purchased from a conventional biochemical reagent store unless otherwise specified.

The preparation equipment, detection equipment and the like used by the invention comprise:

(1) the switzerland BUCHI191 mini spray dryer, used and set up the parameters: inlet temperature: 90-140 ℃; outlet temperature: 60-105 ℃; flow rate of fluidizing air: 200-800L/h (pressure: 0.15-0.4bar)

(2) Nuoze jet mill: jetmil pilot type, the usual pressure is 5-8bar, the sealing pressure: 6.5-10bar.

(3) Malvern laser particle size detector: the particle size distribution D90:1-1000um can be detected.

(4) Shenzhen Xinyite XYT G6 high-speed shearing mixing granulator can mix 0.5L-6L material.

MDI aerosol inhaler tests used:

westech Anderson eight-stage impact aerosol particle samplers (meeting the standards USP Chapter <601> and EP Chapter 29.9.18). After the sample to be detected detects the aerodynamic particle size distribution data, the average speed of the device is set as: 0.20 ml/min. The NGI apparatus was pre-cooled for 3 hours at 4 ℃ before measurement, and then at room temperature: the gas flow rate was set at 28. + -. 1.0L/min, measured at 22 ℃. Particles were deposited at each collection site of the instrument: after the medicines are collected in the guiding device, the collecting discs at all levels and the micropore collector, the content is measured by an HPLC method, and the medicine interception amount and the proportion of each part can be obtained. By analyzing the deposition locations of the particulate matter, information on the fine particle fraction, the fine particle dose, the mass median diameter (MMAD), and the geometric mean diameter (GSD) can be obtained to evaluate the particle properties of the aerosol. At the same time, the appearance and the like of the film are observed and photographed by a biological microscope.

Examples 1-36 and formulation processes of comparative examples 1-8: (the dosage of the formulation components is shown in the following table) 1) crushing the therapeutic agent by adopting a jet mill of a Nuozez jet mill, wherein the feeding speed is 15-20g/min, and the jet milling crushing pressure is 5.5-7.0 bar; the particle size distribution is detected as follows: d90: 2-5 um.

2) Adding the coating agent and the cosolvent into the suspending agent, and stirring until the coating agent and the cosolvent are completely dissolved to obtain a mixed solution;

3) suspending the micronized therapeutic agent and the inclusion agent in the mixed solution, and performing spray drying; BUCHI191 spray dryer set-up parameters were:

i. the inlet air temperature is 130 +/-5 DEG C

ii, outlet temperature of 75 + -5 deg.C

Air compressor pressure is: 8.0-8.5bar

The pressure is: 0.15-0.2bar

v. air flow rate: 800-1500L/h;

the pumping speed is: 6-10ml/min

4) Micronizing the medicine particles by a Nuozejilm pilot jet mill, wherein the pressure of the jet milling is as follows: 6.5-7.5 kg, and the particle size detection of the treated particles by the Malvern laser is as follows: d90: 2-5 um;

5) step 4), mixing the crushed particles with a prescription amount of inhalation carrier-free carrier in a trusted and trusted special high shear mixer granulator XYT-G6 (with a temperature control module) to obtain a mixture; the capsule packing (loading: 260-400 mg/capsule) is carried out by an inhalant capsule filling machine, and 60 inhalations are used as a commercial packing unit and are packaged by double aluminum.

Examples 1 to 6: ribavirin dry powder inhaler formulation:

TABLE 1-1 compositions and amounts of examples 1-6, specification 10-300mg (1 inhale)

TABLE 1-2 compositions and amounts thereof, specification: 20-100mg (1 st)

Tables 1-3 Performance testing of examples 1-6

Tables 1-4 Performance testing of comparative examples 1-6

Tables 1-5 compositions of examples 7-9 and comparative examples 7-8 and amounts thereof (1 bar)

Tables 1-6 Performance testing of examples 7-9 and comparative examples 7-8

Examples 10 to 18:

TABLE 2-1 compositions and amounts of examples 10-15, specification 10-300mg (1 inhale)

TABLE 2-2 Performance testing of examples 10-15

TABLE 2-3 Components and amounts of examples 16-18 (1 bar)

Tables 2-4 Performance testing of examples 16-18

Examples 19 to 21:

TABLE 3-1 Components and amounts of examples 19-21 (1 bar)

TABLE 3-2 Performance tests 19-21

Examples 22 to 24:

TABLE 4-1 Components and amounts of examples 22-24 (1 bar)

TABLE 4-2 Performance tests 22-24

Examples 25 to 27:

TABLE 4-1 Components and amounts of examples 25-27 (1 bar)

TABLE 4-2 Performance tests 25-27

Inspection item	Example 25	Example 26	Example 27
				Properties (Secondary particle)	Granule and powder	Granule and powder	Granule and powder
Average aerodynamic particle size (MMAD)	5.51um	5.57um	5.49um
				Geometric Standard Deviation (GSD)	1.09	1.89	1.82
Deposition rate of effective part of Fine Particle (FPF)	65.0％	63.3％	67.3％

Examples 28 to 30:

TABLE 5-1 Components and amounts of examples 28-30 (1 bar)

TABLE 5-2 Performance tests 28-30

Examples 31 to 33:

TABLE 6-1 Components and amounts thereof of examples 31-33 (1 bar)

TABLE 6-2 Performance tests 28-30

Examples 34 to 37:

TABLE 7-1 Components and amounts thereof for examples 34-36 (1 bar)

TABLE 7-2 Performance testing of examples 34-36

Inspection item	Example 34	Example 35	Example 36	Example 36
					Properties (Secondary particle)	Granule and powder	Granule and powder	Granule and powder	Granule and powder
Average aerodynamic particle size (MMAD)	5.88um	5.92um	6.02um	5.73um
					Geometric Standard Deviation (GSD)	1.92	1.75	1.36	1.60
Deposition rate of effective part of Fine Particle (FPF)	60.1％	59.2％	66.6％	67.2％