CN114129546A

CN114129546A - Medicinal composition for inhalation

Info

Publication number: CN114129546A
Application number: CN202111022261.XA
Authority: CN
Inventors: 袁建栋; 余佳琪; 李明; 孙娟; 刘承; 阮晓颖; 缪浩; 黄仰青
Original assignee: Brightgene Bio Medical Technology Co Ltd
Current assignee: Brightgene Bio Medical Technology Co Ltd
Priority date: 2020-09-03
Filing date: 2021-09-01
Publication date: 2022-03-04

Abstract

The invention belongs to the technical field of medicinal preparations, and relates to a medicinal composition for inhalation. Specifically, the pharmaceutical composition for inhalation comprises 1 wt% -70 wt% of pharmaceutical active ingredient and 30 wt% -99 wt% of pharmaceutically acceptable carrier, wherein the pharmaceutical active ingredient is Reidesciclovir or pharmaceutically acceptable salt thereof, and the carrier is selected from one or more of sugar and sugar alcohols, amino acids, lipids, inorganic salts and polymers. The pharmaceutical composition for inhalation has the characteristics of good particle stability, good powder fluidity, no agglomeration and the like, has remarkable advantages compared with the existing RudeSiwei preparation, and is suitable for clinical use.

Description

Medicinal composition for inhalation

Technical Field

The invention belongs to the technical field of medicinal preparations, relates to a medicinal composition for inhalation, and particularly relates to a medicinal composition for inhalation, which is used for treating infection of Marburg virus, Ebola virus, Nipah virus, respiratory syncytial virus, hepatitis C virus, human immunodeficiency virus, 2019 novel coronavirus and the like and contains Reidesvir serving as a medicinal active ingredient.

Background

Reidesvir (Remdesivir) is a nucleoside analog, has a broad-spectrum antiviral action mechanism, and has been reported to have certain efficacy against infections of Marburg Virus (MV), Ebola Virus (EV), Nipah Virus (NV), Respiratory Syncytial Virus (RSV), Hepatitis C Virus (HCV), Human Immunodeficiency Virus (HIV), novel coronavirus (SARS-CoV-2), and the like. However, in general, administration of the compound to a patient by intravenous injection is liable to cause adverse reactions (e.g., allergic reactions) and causes certain side effects; meanwhile, injection administration can cause local pain and cause rejection feeling of patients.

It has been reported that the intravenous dose of Reidesciclovir was 200mg on the first day, and then the daily dose was maintained at 100mg for 5-9 days. However, it is unlikely that administering reed-solomon alone using intravenous administration would result in good clinical results. Another study showed that systemic metabolic concentration of Reidesciclovir has no positive correlation with efficacy due to The virus being mainly present in The lung, but The local drug concentration in The lung is low (see Sun D., Remdesivier for Treatment of COVID-19: Combination of Pulmonary and IV Administration of May Administration of respiratory Benefit [ J ], The AAPS Journal,2020,22: 77).

In recent years, pulmonary inhalation provides a non-invasive administration method, namely, the medicine is delivered to the lung of a patient through a respiratory tract, the targeted administration can be effectively carried out on the lung, and the administration is rapid. Compared with intravenous injection, the inhalation preparation has less mechanical damage and convenient operation, and the compliance of patients is better; compared with oral preparation, the inhalation preparation has higher bioavailability, can directly act on lung, and avoids first pass effect of liver. Also, the dose of drug required for inhalation administration is generally less than for oral or injection administration. Thus, administration by inhalation may be used alone or in combination with oral or injection administration, with the aim of increasing the local drug concentration in the lung and reducing side effects.

Generally, inhalation administration requires the use of a combination of pharmaceutical devices, such as an atomizing spray device (nebulizer), a metered dose inhaler device (pMDI), a dry powder inhaler Device (DPI), a soft mist inhaler device (SMI), and the like. Nebulized spray devices can administer high doses of drugs, but are not portable and the treatment process is lengthy. Metered dose inhaler devices are portable and widely used, but require propellant and hand and mouth fit. Dry powder inhalation devices have high drug stability and do not require a cold chain, but the lung deposition rate is often not high. Soft mist inhalation devices have a high lung deposition rate but are also costly.

Generally, the administration of a drug (e.g., Reidesvir) by inhalation can be divided into the administration by nebulization and the administration by dry powder inhalation. For severe patients, the spontaneous respiratory pressure is not enough, and the aerosol inhalation administration is more suitable. But for patients with mild and moderate symptoms, the dry powder inhalation administration is more portable, the compliance is better, a cold chain is not needed, and the cost is lower. Thus, effective pulmonary delivery can be achieved by preparing the drug in dry powder form, mixing with carriers and/or excipients, and administering through a specific delivery device.

A research team of the United states university of Texas Austin (UT-Austin) developed a Reidsievir Dry Powder inhalant (see Sahakijpijar S., Development of Remdesive as a Dry Powder for Inhalation by Thin Film Freezing [ J ], pharmacy, 2020,12:1002), but the team prepared the Reidsievir Dry Powder inhalant by using a Thin Film freeze-drying Technology (TFF), the product stability was poor, the particle morphology uniformity was poor, the related items were only in the experimental stage, and the clinical requirements were difficult to satisfy.

Furthermore, the thin film lyophilization technique inevitably uses polar organic solvents to dissolve the ridciclovir, as the research team at the austin division of the university of texas uses acetonitrile/water solution or dioxane to dissolve the ridciclovir. In the pharmaceutical preparation, solvents such as acetonitrile and dioxane are generally avoided, and the pharmacopoeia has severe requirements on the solvent residues because of certain liver, kidney and nerve toxicity. The 2020 edition of pharmacopoeia defines acetonitrile and dioxyethane as a first class of solvent, with acetonitrile having a limited amount of solvent residue of 0.041% and dioxane having a limited amount of solvent residue of 0.038% (see the fourth part of the pharmacopoeia of the people's republic of china (2020 edition), page 0861); in addition, the film freeze-drying technology also needs harsh freeze-drying conditions at the temperature of-100 ℃, which is very unfavorable for pharmaceutical manufacturing enterprises, not only is the process difficult to realize, but also the production cost is increased. The technical defects all cause that the lyophilized powder of the Reidesciclovir prepared by the film freeze-drying technology is not suitable for being used as the Reidesciclovir inhalant prepared by pharmaceutical manufacturing enterprises. In addition, when the stability of the preparation is researched by the Austin university of Texas, only the stability of the Redesavir in the preparation is researched, the stability of the whole Redesavir dry powder preparation is not researched, and the stability of the whole preparation is very important for the pharmaceutical preparation.

Therefore, how to prepare a dry powder inhalant of the ridiflower with better stability is a problem to be solved at present. In addition, how to develop a dry powder inhalant of the ridciclovir, which has no toxic organic solvent residue and is beneficial to human body administration, is a technical problem to be solved in the field.

Disclosure of Invention

Problems to be solved by the invention

In view of the fact that when the novel coronavirus infection (COVID-2019) is treated by intravenous injection of reidoxir, the systemic metabolic concentration is not positively correlated with the curative effect, and the local drug concentration in the lung is too low, a safe and stable pharmaceutical composition suitable for inhalation needs to be prepared.

Means for solving the problems

In one aspect, the present invention provides a pharmaceutical composition for inhalation, characterized in that the pharmaceutical composition for inhalation comprises 1 wt% to 70 wt% of a pharmaceutically active ingredient, preferably 1 wt% to 50 wt% or 20 wt% to 70 wt% of a pharmaceutically active ingredient,

the active ingredient of the medicine is a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof.

Preferably, in the above pharmaceutical composition for inhalation, the particle size distribution characteristics of the pharmaceutically active ingredient are as follows: d₅₀Under 161 μm, and D₉₀Less than 361 μm, preferably D₅₀Below 5 μm, and D₉₀Less than 10 μm, more preferably D₁₀Below 0.5 μm.

Further, the particle size of the pharmaceutically active ingredient is determined using a particle size analysis-laser diffraction method.

In addition, the pharmaceutical composition for inhalation further comprises 30 wt% -99 wt% of a pharmaceutically acceptable carrier, preferably 50 wt% -99 wt% or 30 wt% -80 wt% of a pharmaceutically acceptable carrier.

Preferably, in the pharmaceutical composition for inhalation, the pharmaceutically acceptable carrier is one or more selected from the group consisting of sugars and sugar alcohols, amino acids, lipids, inorganic salts and polymers.

Further, in the pharmaceutical composition for inhalation, the sugar and sugar alcohol are selected from one or more of lactose, mannitol, maltose, sucrose, trehalose, glucose and hydrates thereof; the amino acids are selected from one or more of phenylalanine, leucine and glycine; the lipid is selected from one or more of stearic acid, magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate and lecithin; the inorganic salt is selected from one or more of sodium phosphate, sodium chloride, calcium phosphate and calcium hydrophosphate; the polymer is selected from one or two of polylactic acid and lactic acid-glycolic acid copolymer.

More preferably, in the pharmaceutical composition for inhalation described above, the pharmaceutically acceptable carrier is a sugar and a sugar alcohol, a lipid, or a combination thereof.

Further, in the pharmaceutical composition for inhalation, the sugar and the sugar alcohol are lactose monohydrate; the lipid is magnesium stearate.

Further preferably, in the pharmaceutical composition for inhalation, the pharmaceutically acceptable carrier is sugar and sugar alcohols, preferably lactose monohydrate.

Alternatively, it is further preferred that in the above pharmaceutical composition for inhalation, the pharmaceutically acceptable carrier is a combination of sugar and sugar alcohols and lipids, preferably a combination of lactose monohydrate and magnesium stearate.

Further, in the above pharmaceutical composition for inhalation, the lactose monohydrate is a combination of a first lactose monohydrate and a second lactose monohydrate, wherein: the particle size distribution characteristics of the first lactose monohydrate meet condition 1: d₁₀Between 10 and 50 μm, D₅₀Between 40 and 70 μm, and D₉₀60-120 μm; and the particle size distribution characteristics of the second lactose monohydrate meet condition 2: d₁₀Below 5 μm, D₅₀Below 30 μm, and D₉₀Below 70 μm.

Preferably, in the pharmaceutical composition for inhalation above, the lactose monohydrate is a combination of a first lactose monohydrate having a particle size distribution characteristic according to condition 1 and a second lactose monohydrate having a particle size distribution characteristic according to condition 2, wherein: the particle size distribution of the first lactose monohydrate is further characterized by condition 3: d₁₀Between 19 and 43 μm, D₅₀Between 53 and 66 μm and D₉₀Is between 75 and 106 μm.

Alternatively, preferably, in the pharmaceutical composition for inhalation above, the lactose monohydrate is a combination of a first lactose monohydrate having a particle size distribution characteristic according to condition 1 and a second lactose monohydrate having a particle size distribution characteristic according to condition 2, wherein: the particle size distribution of the second lactose monohydrate is further characterized by condition 4: d₁₀Between 1.4 and 3.3 μm, D₅₀Between 10.9 and 24.9 μm, and D₉₀Is between 32.6 and 60.4 μm.

More preferably, in the pharmaceutical composition for inhalation described above, the lactose monohydrate is a combination of a first lactose monohydrate having a particle size distribution characteristic in accordance with condition 3 and a second lactose monohydrate having a particle size distribution characteristic in accordance with condition 4.

Further, in the above pharmaceutical composition for inhalation, the particle size of the first lactose monohydrate is controlled by sieving, and the particle size of the second lactose monohydrate is controlled by pulverizing.

Further, in the above pharmaceutical composition for inhalation, the particle size of the lactose monohydrate is measured by particle size analysis-laser diffraction method.

Further preferably, in the pharmaceutical composition for inhalation above, the weight ratio of the second lactose monohydrate to the first lactose monohydrate is from 50:50 to 100:0, preferably from 40:40 to 60:20 or from 60:20 to 80:0, more preferably from 70:10 to 75: 5.

Or, further, in the above pharmaceutical composition for inhalation, the lactose monohydrate is a combination of a second lactose monohydrate and a third lactose monohydrate, wherein: the second lactose monohydrateThe particle size distribution characteristics of the compound meet condition 2: d₁₀Below 5 μm, D₅₀Below 30 μm, and D₉₀Below 70 μm; and the particle size distribution characteristics of the third lactose monohydrate meet condition 5: d₅₀Below 5 μm, and D₉₀Below 10 μm.

Preferably, in the pharmaceutical composition for inhalation above, the lactose monohydrate is a combination of a second lactose monohydrate having a particle size distribution characteristic according to condition 2 and a third lactose monohydrate having a particle size distribution characteristic according to condition 5, wherein: the particle size distribution of the second lactose monohydrate is further characterized by condition 4: d₁₀Between 1.4 and 3.3 μm, D₅₀Between 10.9 and 24.9 μm, and D₉₀Is between 32.6 and 60.4 μm.

Further, in the above pharmaceutical composition for inhalation, the particle diameters of the second lactose monohydrate and the third lactose monohydrate are controlled by pulverization.

Further preferably, in the pharmaceutical composition for inhalation above, the weight ratio of the second lactose monohydrate to the third lactose monohydrate is from 50:50 to 100:0, preferably from 40:40 to 60:20 or from 60:20 to 80:0, more preferably from 70:10 to 75: 5.

Further, in the above pharmaceutical composition for inhalation, the particle size distribution characteristics of magnesium stearate are as follows: d₁₀Between 1 and 3 μm, D₅₀Between 5 and 25 μm, and D₉₀Is between 50 and 100 μm.

Further, in the pharmaceutical composition for inhalation described above, the particle size of the magnesium stearate is measured by a particle size analysis-laser diffraction method.

Preferably, in the pharmaceutical composition for inhalation above, the pharmaceutically acceptable carrier is a combination of lactose monohydrate and magnesium stearate, the weight ratio of magnesium stearate to lactose monohydrate being 0.05:100 to 5:100, preferably 0.05:100 to 1:100, more preferably 1: 100.

In another aspect, the present invention provides a use of the above pharmaceutical composition for inhalation in the preparation of a medicament for preventing and/or treating a disease caused by a viral infection.

Preferably, in the above uses, the virus is selected from one or more of marburg virus, ebola virus, nipah virus, respiratory syncytial virus, hepatitis c virus, human immunodeficiency virus and novel coronaviruses, preferably novel coronaviruses.

ADVANTAGEOUS EFFECTS OF INVENTION

The pharmaceutical composition for inhalation (the RudeSewei dry powder inhalant) has the characteristics of good particle stability, good powder fluidity, no agglomeration and the like, has remarkable advantages compared with the UT-Austin RudeSewei preparation, and is suitable for clinical use. The invention avoids the difficult problem of solvent residue control of the film freeze-drying Rudexiwei preparation in Austin university of Texas, and the ultra-low temperature harsh conditions are not needed in the process.

During the development process, the inventor of the invention surprisingly found that magnesium stearate is necessary for maintaining good stability of the dry powder inhalation preparation of the ridiflower, and the stability of the preparation of the ridiflower without adding magnesium stearate or replacing the magnesium stearate with other lipid is obviously inferior to that of the preparation of the ridiflower by adopting a mixed carrier of lactose monohydrate and magnesium stearate.

The inventors of the present invention have also found that the pharmaceutical composition for inhalation of the present invention can be efficiently delivered to the respiratory system of a subject and has excellent flowability, fillability, dispersibility.

Drawings

FIG. 1 shows an SEM (x2k) of the Reidesciclovir/magnesium stearate micropowder of example 1 on a 20 μm scale;

FIG. 2 shows an SEM (x5k) of the Reidesciclovir/magnesium stearate micropowder of example 1 on a 10 μm scale bar;

FIG. 3 shows an SEM (x25k) of the Reidesciclovir/magnesium stearate micropowder of example 1 on a 2 μm scale;

FIG. 4 shows an SEM (x100) of the pharmaceutical composition for inhalation of example 1 at a scale bar of 500 μm;

FIG. 5 shows an SEM (x1k) of the pharmaceutical composition for inhalation of example 1 at a scale bar of 50 μm;

FIG. 6 shows an SEM (x4k) of the pharmaceutical composition for inhalation of example 1 at a scale of 10 μm;

FIG. 7 shows an SEM (x2k) of the Reidesciclovir/magnesium stearate micropowder of example 2 on a 20 μm gauge scale;

FIG. 8 shows an SEM (x5k) of the Reidesciclovir/magnesium stearate micropowder of example 2 at a 10 μm scale bar;

fig. 9 shows an SEM (x25k) of the fine reed-seivir/magnesium stearate powder of example 2 on a 2 μm scale.

Detailed Description

First, the present invention provides a pharmaceutical composition suitable for inhalation administration, which may comprise redciclovir or a pharmaceutically acceptable salt thereof as a pharmaceutically active ingredient.

The term "Reidesciclovir" as used herein, unless otherwise indicated, refers to a compound of formula (I) having the English name Remdesivir and the chemical name (S) -2-ethylbutyl 2- ((S) - ((2R,3S,4R,5R) -5- (4-aminopyrrolo [1, 2-f)][1,2,4]Triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphorylamino) propionate having CAS registry number 1809249-37-3, formula C₂₇H₃₅N₆O₈P, molecular weight 602.58.

Examples of the term "pharmaceutically acceptable salt" used in the present invention include the following, unless otherwise specified: hydrohalic acid salts (or halides), such as hydrofluoride (or fluoride), hydrochloride (or chloride), hydrobromide (or bromide), and hydroiodide (or iodide); oxygen-containing inorganic acid salts such as nitrates, perchlorates, sulfates and phosphates; alkyl sulfonates such as methanesulfonate, ethanesulfonate and trifluoromethanesulfonate; arylsulfonates such as benzenesulfonate and p-toluenesulfonate; organic acid salts such as acetate, trifluoroacetate, citrate, tartrate, oxalate and maleate; amino acid salts such as glycinate, lysinate, arginate, ornithine, glutamate and aspartate; alkali metal salts such as lithium salts, sodium salts and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; other metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts and cobalt salts; organic amine salts or organic ammonium salts such as ammonium salts, tert-octylamine salts, dibenzylamine salts, morpholine salts, glucamine salts, ethylenediamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, procaine salts, ethanolamine salts, diethanolamine salts, piperazine salts and tetramethylammonium salts. Preferably, in the present invention, the pharmaceutically acceptable salt is an alkali metal salt, such as a lithium salt, a sodium salt or a potassium salt; organic acid salts such as acetate or trifluoroacetate; or inorganic acid salts such as hydrochloride or sulfate.

In one embodiment of the present invention, the content of the pharmaceutically active ingredient in the pharmaceutical composition may be 1 wt% to 70 wt% in terms of weight percentage (wt%). For example, the content of the pharmaceutically active ingredient may be 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, or 70 wt%.

In a preferred embodiment of the present invention, the content of the pharmaceutically active ingredient in the pharmaceutical composition may be 1 wt% to 50 wt%, on a wt% basis. For example, the content of the pharmaceutically active ingredient may be 1 wt%, 5 wt%, 10 wt%, 15 wt%, 20 wt%, 30 wt%, 40 wt%, or 50 wt%.

In another preferred embodiment of the present invention, the content of the pharmaceutically active ingredient in the pharmaceutical composition may be 20 wt% to 70 wt%, on a wt% basis. For example, the content of the pharmaceutically active ingredient may be 20 wt%, 30 wt%, 40 wt%, 50 wt%, 60 wt%, or 70 wt%.

The pharmaceutically active ingredient in the pharmaceutical composition of the present invention may have a specific particle size.

The term "D" as used herein, unless otherwise indicated₁₀”、“D₅₀"and" D₉₀"indicates the particle diameters at 10%, 50% and 90%, respectively, in the cumulative particle size distribution curve.

In one embodiment of the present invention, the particle size distribution characteristics of the pharmaceutically active ingredient may be as follows: d₅₀Under 161 μm, and D₉₀Is less than 361 μm.

In a preferred embodiment of the present invention, the particle size distribution characteristics of the pharmaceutically active ingredient may be as follows: d₅₀Below 5 μm, and D₉₀Below 10 μm.

In a more preferred embodiment of the invention, the particle size distribution of the pharmaceutically active ingredient may also be characterized as follows: d₁₀Below 0.5 μm.

The particle size can be measured by a particle size analysis-laser diffraction method.

The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier in addition to the pharmaceutically active ingredient.

In one embodiment of the present invention, the carrier may be present in the pharmaceutical composition in an amount of 30 to 99% by weight. For example, the content of the carrier may be 99 wt%, 98 wt%, 97 wt%, 96 wt%, 95 wt%, 94 wt%, 93 wt%, 92 wt%, 91 wt%, 90 wt%, 89 wt%, 88 wt%, 87 wt%, 86 wt%, 85 wt%, 84 wt%, 83 wt%, 82 wt%, 81 wt%, 80 wt%, 79 wt%, 78 wt%, 77 wt%, 76 wt%, 75 wt%, 74 wt%, 73 wt%, 72 wt%, 71 wt%, 70 wt%, 69 wt%, 68 wt%, 67 wt%, 66 wt%, 65 wt%, 64 wt%, 63 wt%, 62 wt%, 61 wt%, 60 wt%, 55 wt%, 50 wt%, 45 wt%, 40 wt%, 35 wt%, or 30 wt%.

In one embodiment of the present invention, the carrier may be present in the pharmaceutical composition in an amount of 50 to 99% by weight. For example, the carrier may be present in an amount of 99 wt%, 95 wt%, 90 wt%, 85 wt%, 80 wt%, 70 wt%, 60 wt%, or 50 wt%.

In another preferred embodiment of the present invention, the carrier may be present in the pharmaceutical composition in an amount of 30 to 80% by weight. For example, the carrier may be present in an amount of 80 wt%, 70 wt%, 60 wt%, 50 wt%, 40 wt%, or 30 wt%.

In one embodiment of the present invention, the carrier in the pharmaceutical composition can be selected from various kinds, such as one or more selected from sugars and sugar alcohols, amino acids, lipids (also called lipid), inorganic salts and polymers.

When the carrier is a sugar or sugar alcohol, the sugar or sugar alcohol may be a sugar, a sugar alcohol, or a combination of a sugar and a sugar alcohol, for example, one or more selected from lactose, mannitol, maltose, sucrose, trehalose, glucose, and hydrates thereof.

When the carrier is an amino acid, the amino acid may be either an L-amino acid or a D-amino acid, or a combination of an L-amino acid and a D-amino acid, for example, one or more selected from phenylalanine (especially in the L form), leucine (especially in the L form), and glycine (especially in the L form).

When the carrier is a lipid, the lipid may be either a fatty acid, a fatty acid salt (e.g. an alkali metal salt or an alkaline earth metal salt), a fatty acid ester (e.g. a glyceride or sugar ester), or any combination of the above, e.g. one or more selected from stearic acid, magnesium stearate, calcium stearate, sucrose fatty acid esters, sodium stearyl fumarate and lecithin.

When the carrier is an inorganic salt, the inorganic salt may be an inorganic oxygen-free acid salt (e.g., hydrochloride), an inorganic oxygen-containing acid salt (e.g., phosphate or acid phosphate), or a combination of an inorganic oxygen-free acid salt and an inorganic oxygen-containing acid salt, such as one or more selected from sodium phosphate, sodium chloride, calcium phosphate, and calcium hydrogen phosphate.

When the carrier is a polymer, the polymer may be a homopolymer obtained from the same monomer, a copolymer obtained from different monomers, or a combination of a homopolymer and a copolymer, such as one or two selected from polylactic acid and lactic acid-glycolic acid copolymer.

In a preferred embodiment of the present invention, the carrier in the pharmaceutical composition may be a sugar and a sugar alcohol, a lipid or a combination thereof.

When the carrier is a sugar or sugar alcohol, the sugar or sugar alcohol may be a lactose hydrate, such as lactose monohydrate (or lactose monohydrate).

When the carrier is a lipid, the lipid may be magnesium stearate.

In a more preferred embodiment of the invention, the carrier in the pharmaceutical composition may be sugars and sugar alcohols, preferably lactose monohydrate.

In another more preferred embodiment of the invention, the carrier in the pharmaceutical composition may be a combination of sugars and sugar alcohols and lipids, preferably a combination of lactose monohydrate and magnesium stearate.

When the carrier in the pharmaceutical composition of the present invention comprises lactose monohydrate, the lactose monohydrate may consist of two parts, i.e. a first lactose monohydrate and a second lactose monohydrate.

In one embodiment of the invention, the particle size distribution of the first lactose monohydrate of the lactose monohydrate may be characterized by the following condition 1: d₁₀Between 10 and 50 μm, D₅₀Between 40 and 70 μm, and D₉₀60-120 μm; and, the particle size distribution characteristics of the second lactose monohydrate may meet condition 2: d₁₀Below 5 μm, D₅₀Below 30 μm, and D₉₀Below 70 μm.

In a preferred embodiment of the present invention, the lactose monohydrate may consist of a first lactose monohydrate according to condition 1 and a second lactose monohydrate according to condition 2, wherein: the particle size distribution characteristics of the first lactose monohydrate may also meet condition 3: d₁₀Between 19 and 43 μm, D₅₀Between 53 and 66 μm and D₉₀Is between 75 and 106 μm.

In another preferred embodiment of the present invention, the lactose monohydrate may consist of a first lactose monohydrate according to condition 1 and a second lactose monohydrate according to condition 2, wherein: the particle size distribution characteristics of the second lactose monohydrate may also meet condition 4: d₁₀Between 1.4 and 3.3 μm, D₅₀Between 10.9 and 24.9 μm, and D₉₀Is between 32.6 and 60.4 μm.

In a more preferred embodiment of the present invention, the lactose monohydrate can consist of a first lactose monohydrate according to condition 3 and a second lactose monohydrate according to condition 4.

In addition, the particle size of the first lactose monohydrate can be controlled by sieving and the particle size of the second lactose monohydrate can be controlled by pulverizing. The particle sizes of both can be measured by a particle size analysis-laser diffraction method.

When the carrier in the pharmaceutical composition of the present invention comprises lactose monohydrate, the first lactose monohydrate and the second lactose monohydrate in the lactose monohydrate can have a specific dosage ratio.

In one embodiment of the invention, the weight ratio of the second lactose monohydrate to the first lactose monohydrate may be 50:50 to 100:0, based on 100 parts by weight. For example, the weight ratio may be 50:50, 55:45, 60:40, 65:35, 70:30, 71:29, 72:28, 73:27, 74:26, 75:25, 76:24, 77:23, 78:22, 79:21, 80:20, 85:15, 90:10, 95:5, or 100: 0.

In a preferred embodiment of the invention, the weight ratio of the second lactose monohydrate and the first lactose monohydrate may be 40:40 to 60:20, based on 80 parts by weight.

In another preferred embodiment of the present invention, the weight ratio of the second lactose monohydrate to the first lactose monohydrate may be 60:20 to 80:0, based on 80 parts by weight.

In a more preferred embodiment of the present invention, the weight ratio of the second lactose monohydrate and the first lactose monohydrate may be 70:10 to 75:5, based on 80 parts by weight.

When the carrier in the pharmaceutical composition of the present invention comprises lactose monohydrate, this lactose monohydrate may also consist of a second lactose monohydrate and a third lactose monohydrate.

In one embodiment of the invention, the particle size distribution of the second lactose monohydrate of the lactose monohydrate may be characterized according to condition 2: d₁₀Below 5 μm, D₅₀Below 30 μm, and D₉₀Below 70 μm; and, the particle size distribution characteristics of the third lactose monohydrate may meet condition 5: d₅₀Below 5 μm, and D₉₀Below 10 μm.

In a preferred embodiment of the present invention, the lactose monohydrate can consist of a second lactose monohydrate according to condition 2 and a third lactose monohydrate according to condition 5, wherein: the particle size distribution characteristics of the second lactose monohydrate may also meet condition 4: d₁₀Between 1.4 and 3.3 μm, D₅₀Between 10.9 and 24.9 μm, and D₉₀Is between 32.6 and 60.4 μm.

In addition, the particle size of the second lactose monohydrate and the third lactose monohydrate can be controlled by pulverization. The particle sizes of both can be measured by a particle size analysis-laser diffraction method.

When the carrier in the pharmaceutical composition of the present invention comprises lactose monohydrate, the second lactose monohydrate and the third lactose monohydrate in the lactose monohydrate can have a specific dosage ratio.

In one embodiment of the invention, the weight ratio of the second lactose monohydrate and the third lactose monohydrate is from 50:50 to 100:0, based on 100 parts by weight. For example, the weight ratio may be 50:50, 55:45, 60:40, 65:35, 70:30, 71:29, 72:28, 73:27, 74:26, 75:25, 76:24, 77:23, 78:22, 79:21, 80:20, 85:15, 90:10, 95:5, or 100: 0.

In a preferred embodiment of the invention, the weight ratio of the second lactose monohydrate and the third lactose monohydrate may be 40:40 to 60:20, based on 80 parts by weight.

In another preferred embodiment of the present invention, the weight ratio of the second lactose monohydrate and the third lactose monohydrate may be 60:20 to 80:0, based on 80 parts by weight.

In a more preferred embodiment of the present invention, the weight ratio of the second lactose monohydrate and the third lactose monohydrate may be 70:10 based on 80 parts by weight.

When the carrier in the pharmaceutical composition of the present invention comprises magnesium stearate, the magnesium stearate may have a specific particle size.

In one embodiment of the invention, the particle size distribution characteristics of the magnesium stearate may be as follows: d₁₀Between 1 and 3 μm, D₅₀Between 5 and 25 μm, and D₉₀Is between 50 and 100 μm.

When the carrier in the pharmaceutical composition of the present invention is a combination of lactose monohydrate and magnesium stearate, the magnesium stearate and the lactose monohydrate can have a specific dosage ratio.

In one embodiment of the invention, the weight ratio of the magnesium stearate and the lactose monohydrate may be from 0.05:100 to 5: 100. For example, the weight ratio may be 0.05:100, 0.1:100, 0.2:100, 0.5:100, 1:100, 1.5:100, 2:100, 2.5:100, 3:100, 3.5:100, 4:100, 4.5:100, or 5: 100.

In a preferred embodiment of the invention, the weight ratio of the magnesium stearate and the lactose monohydrate may be from 0.05:100 to 1: 100. For example, the weight ratio may be 0.05:100, 0.1:100, 0.2:100, 0.5:100, or 1: 100.

In a more preferred embodiment of the invention, the weight ratio of the magnesium stearate and the lactose monohydrate may be 1: 100.

Secondly, the invention provides the pharmaceutical application of the pharmaceutical composition. The medicine can be used for preventing and/or treating diseases caused by virus infection, wherein the virus causing the infection can be Filoviridae (Filoviridae) virus, Paramyxoviridae (Paramyxoviridae) virus, Flaviviridae (Flaviviridae) virus, Retroviridae (Retroviridae) virus, Coronaviridae (Coronaviridae) virus.

In one embodiment of the invention, the virus is selected from one or more of marburg virus, ebola virus, nipah virus, respiratory syncytial virus, hepatitis c virus, human immunodeficiency virus and novel coronaviruses.

In a preferred embodiment of the invention, the virus is a novel coronavirus.

The invention will be further described with reference to the drawings and specific examples, which should not be construed as limiting the scope of the invention.

Experimental Material

Materials such as lactose monohydrate and magnesium stearate used in the following examples are listed in table 1, and particle sizes of the materials were measured by particle size analysis-laser diffraction method. Of these, the three commercial lactose monohydrate are referred to as lactose 1, lactose 2 and lactose 3, respectively.

TABLE 1 particle size distribution of lactose monohydrate and magnesium stearate used as carriers

Examples 1 to 16: and (3) preparing a Rudesivir dry powder inhalant.

Firstly, weighing the materials according to the prescription in the table 3; secondly, adding magnesium stearate, calcium stearate or stearic acid into the ridciclovir, mixing, and performing jet milling (for example, the shearing air flow is nitrogen or air with the RH percent lower than 20%, the central ring pressure is 0.5-12 bar, the Venturi pressure is 1-14 bar, and the feeding speed is 0.1-3 g/min) to obtain medicine-containing micro powder with different particle sizes (the components such as magnesium stearate serving as a glidant have almost no influence on the particle size measurement result of the ridciclovir), so the particle size measurement result of the medicine-containing micro powder can still reflect the particle size condition of the medicine-effective component ridciclovir to a certain extent) (preferably, the micro powder is subjected to aging treatment, for example, exposed in an environment with the temperature of 5-88 ℃ and the RH percent of 10-95% for at least 60 minutes), wherein the SEM of the medicine-containing micro powder of the examples 1 and 2 are respectively shown in figures 1-3 and 7-9; finally, the lactose and the fine powder containing the drug, which were sieved in advance, were physically mixed in a solid mixing device (for example, Turbula mixer (Willy a. bachofen AG)) to obtain the pharmaceutical compositions for inhalation of examples 1 to 16, and SEM of the pharmaceutical composition for inhalation of example 1 is shown in fig. 4 to 6. The preparation process is carried out in an environment with the temperature of 19-27 ℃ and the RH percent of 30-65 percent.

Table 2 shows the D of the fine powder containing the drug of each example measured by particle size analysis-laser diffraction method₁₀、D₅₀And D₉₀Particle size, the prescription composition of the pharmaceutical compositions of the examples is listed in table 3.

TABLE 2 particle size distribution of the active ingredients of examples 1,2 and 9 to 16

TABLE 3 prescription composition of the pharmaceutical compositions of examples 1 to 16

1 represents the content of the active ingredient in the pharmaceutical composition (wt%, in terms of anhydrate); taking example 1 as an example, the content of the active ingredient in the pharmaceutical composition is 20 wt%, and correspondingly, the content of the carrier consisting of lactose 1, lactose 2 and magnesium stearate is 80 wt%.

2 denotes the relative amount of carrier in parts by weight; taking example 1 as an example, the parts by weight of lactose 1, lactose 2 and magnesium stearate as carriers are 70 parts, 10 parts and 0.8 part, respectively, and the content of the carrier in the pharmaceutical composition is 80 wt%.

Examples 17 to 20: and (3) preparing a Rudesivir dry powder inhalant.

Firstly, weighing the materials according to the prescription in the table 5; secondly, referring to the process conditions in examples 1-16, adding magnesium stearate into the Rudexilvir, mixing, and performing jet milling to obtain drug-containing micro powder with different particle sizes; finally, the lactose sieved in advance and the drug-containing fine powder were put into a solid mixing device to be physically mixed, to obtain the pharmaceutical compositions for inhalation of examples 17 to 20.

Table 4 shows the D of the fine powder containing the drug of each example measured by particle size analysis-laser diffraction method₁₀、D₅₀And D₉₀Particle size, the prescription composition of the pharmaceutical compositions of the examples is listed in table 5.

TABLE 4 particle size distribution of the active ingredients of examples 17 to 20

TABLE 5 prescription composition of the pharmaceutical compositions of examples 17 to 20

Examples 21 to 22: and (3) preparing a Rudesivir dry powder inhalant.

Firstly, weighing the materials according to the prescription in the table 7; secondly, referring to the process conditions in examples 1-16, adding magnesium stearate into the Rudexilvir, mixing, and performing jet milling to obtain drug-containing micro powder with different particle sizes; finally, the lactose sieved in advance and the drug-containing fine powder were put into a solid mixing device to be physically mixed, to obtain the pharmaceutical compositions for inhalation of examples 21 to 22.

Table 6 shows the D of the fine powder containing the drug of each example measured by particle size analysis and laser diffraction method₁₀、D₅₀And D₉₀Particle size, the prescription composition of the pharmaceutical compositions of the examples is listed in table 7.

TABLE 6 particle size distribution of the active ingredients of examples 21 to 22

TABLE 7 prescription composition of pharmaceutical compositions of examples 21 to 22

Examples 23 to 26: and (3) preparing a Rudesivir dry powder inhalant.

Firstly, weighing the materials according to the prescription in the table 9; secondly, referring to the process conditions in examples 1 to 16, airflow crushing the ridciclovir (examples 23 and 24), or adding magnesium stearate into the ridciclovir, mixing and then airflow crushing (examples 25 and 26) to obtain medicine-containing micro powder with different particle sizes; finally, the lactose sieved in advance and the drug-containing fine powder were put into a solid mixing device to be physically mixed, to obtain the pharmaceutical compositions for inhalation of examples 23 to 26.

Table 8 shows the D of the fine powder containing the drug of each example measured by particle size analysis and laser diffraction₁₀、D₅₀And D₉₀Particle size, the prescription composition of the pharmaceutical compositions of the examples is listed in table 9.

TABLE 8 particle size distribution of the active ingredients of examples 23 to 26

TABLE 9 prescription composition of the pharmaceutical compositions of examples 23 to 26

Examples 27 to 28: and (3) preparing a Rudesivir dry powder inhalant.

Firstly, weighing the materials according to the prescription in the table 11; secondly, with reference to the process conditions in examples 1 to 16, carrying out jet milling on the Rudexilawir to obtain drug-containing micro powder with different particle sizes; finally, the lactose sieved in advance and the fine powder containing the drug were put in a solid mixing device to be physically mixed, to obtain the pharmaceutical compositions for inhalation of examples 27 to 28.

Table 10 shows the D of the fine powder containing the drug of each example measured by particle size analysis and laser diffraction method₁₀、D₅₀And D₉₀Particle size, the prescription composition of the pharmaceutical compositions of the examples is listed in table 11.

TABLE 10 particle size distribution of the active ingredients of examples 27 to 28

TABLE 11 prescription composition of pharmaceutical compositions of examples 27 to 28

Examples 29 to 40: and (3) preparing a Rudesivir dry powder inhalant.

Firstly, weighing the materials according to the prescription in the table 13; secondly, adding magnesium stearate into the Ruidexilvir, mixing, and performing jet milling to obtain medicine-containing micro powder with different particle sizes; finally, the lactose sieved in advance and the fine powder containing the drug were put into a solid mixing device (for example, Turbula mixer (Willy a. bachofen AG)) to be physically mixed, to obtain pharmaceutical compositions for inhalation of examples 29 to 40. The preparation process is carried out in an environment with the temperature of 19-27 ℃ and the RH percent of 30-65 percent.

Table 12 shows the D of the fine powder containing the drug of each example measured by particle size analysis and laser diffraction method₁₀、D₅₀And D₉₀Particle size, the prescription composition of the pharmaceutical compositions of the examples is listed in table 13.

TABLE 12 particle size distribution of the active ingredients of examples 29 to 40

TABLE 13 formulation of the pharmaceutical compositions of examples 29 to 40

Example of effects: the fine particle percentage (FPF) and Fine Particle Dose (FPD) of the reed siewe dry powder inhaler were examined.

When the ability of a drug in an inhalation formulation to reach the respiratory system is evaluated by in vitro testing (examining the link between primary drug particle size and FPF), a multistage impactor is typically used to determine the amount of fine particles (see, for example, USP31, <601> aerosol/physical test, and european pharmacopoeia inhalation formulation: aerodynamic evaluation of fine particles).

In this method, a device for classifying drug particles is used, in which the drug particles are introduced from an inhaler by inhalation with a pump to a multistage impactor. The introduced drug particles reach any of the 12 sections of the multistage impactor (spigot, preseparator, aspiration, stages 0-7 and filter) depending on particle size. Large particles (e.g., diluent particles, particles of drug not released from the diluent, and aggregates) are collected at the cannula fitting, preseparator, suction port. Drug particles released from the diluent may reach any of stages 0 to 7 in the filter, with smaller sized particles reaching the higher numbered stages, where the drug particles passing through stage 7 are collected.

It is known that in clinical use, the amount of drug reaching a particular fraction, or the ratio of that amount in a labeled amount, correlates with the ability of the drug to reach the respiratory system (see, e.g., USP31, <601> aerosol/physical test). The former is called fine particle dose (hereinafter referred to as FPD) and the latter is called fine particle percentage (hereinafter referred to as FPF). Regarding the labeled amount in the pharmaceutical composition of the present invention, FPD is defined as the amount of the drug reaching from grade 3 to the filter, and FPF is defined as the ratio of FPD in the labeled amount. These parameters are used to assess the ability to reach the respiratory system.

Table 14 lists the FPF results for the pharmaceutical compositions of the present invention. Table 15 lists the FPD results for the pharmaceutical compositions of the present invention.

TABLE 14 FPF of the pharmaceutical compositions of examples 1,2 and 9 to 40

TABLE 15 FPD of the pharmaceutical compositions of examples 1,2 and 9 to 40

During the course of the study, it has surprisingly been found that by selecting lactose 1, lactose 2 (or lactose 3 as a substitute) and magnesium stearate as carriers, the resulting Reidesciclovir inhalant has a higher FPF value, whereas the use of stearic acid and/or calcium stearate in place of or without magnesium stearate results in an FPF value that is either too low (too low to allow the inhalant to settle sufficiently in the user's respiratory tract) or too high (too high to allow the inhalant that has been inhaled into the user's respiratory tract to be expelled from the body by breathing), indicating that the combination of lactose 1, lactose 2 (or lactose 3 as a substitute) and magnesium stearate as carriers achieves unexpected technical effects.

The samples of examples 39 and 40, which gave relatively ideal FPF and FPD results, were selected as the preferred pharmaceutical compositions and were placed under accelerated stability test conditions (75% RH + -5%, 40 ℃) for one month and the respective FPFs and FPDs were determined, the results of which are shown in tables 16 and 17.

TABLE 16 FPF of the pharmaceutical compositions of examples 39 and 40 after stability testing

Example numbering	FPF(％)
		39	58.55
40	59.40

TABLE 17 FPD of the pharmaceutical compositions of examples 39 and 40 after stability testing

Example numbering	FPD
		39	8.97
40	8.85

When lactose 1, lactose 2 and magnesium stearate were selected as carriers, 70 wt% Reidesciclovir inhalant was prepared with a higher FPF value and a slightly decreased FPF value after one month of storage under accelerated test conditions (75% RH + -5%, 40 ℃), indicating a better stability of the formulation.

Claims

1. A pharmaceutical composition for inhalation comprising 1 to 70 wt% of a pharmaceutically active ingredient, preferably 1 to 50 wt% or 20 to 70 wt% of a pharmaceutically active ingredient,

2. The pharmaceutical composition for inhalation according to claim 1,

the particle size distribution characteristics of the pharmaceutical active ingredient are as follows: d₅₀Under 161 μm, and D₉₀Less than 361 μm, preferably D₅₀Below 5 μm, and D₉₀Below 10 μm.

3. The pharmaceutical composition for inhalation according to claim 1 or 2,

the pharmaceutical composition for inhalation further comprises 30 wt% -99 wt% of a pharmaceutically acceptable carrier, preferably 50 wt% -99 wt% or 30 wt% -80 wt% of a pharmaceutically acceptable carrier.

4. The pharmaceutical composition for inhalation according to claim 3,

the pharmaceutically acceptable carrier is selected from one or more of sugar and sugar alcohol, amino acid, lipid, inorganic salt and polymer, preferably sugar and sugar alcohol, lipid or their combination.

5. The pharmaceutical composition for inhalation according to claim 4,

the sugar and sugar alcohols are lactose monohydrate;

the lipid is magnesium stearate.

6. The pharmaceutical composition for inhalation according to claim 5,

the lactose monohydrate is a combination of a first lactose monohydrate and a second lactose monohydrate, wherein:

the particle size distribution characteristics of the first lactose monohydrate meet condition 1: d₁₀Between 10 and 50 μm, D₅₀Between 40 and 70 μm, and D₉₀60-120 μm; and the particle size distribution characteristics of the second lactose monohydrate meet condition 2: d₁₀Below 5 μm, D₅₀Below 30 μm, and D₉₀Below 70 μm;

preferably, the particle size distribution of the first lactose monohydrate is further characterized by condition 3: d₁₀Between 19 and 43 μm, D₅₀Between 53 and 66 μm and D₉₀75-106 μm; alternatively, the particle size distribution of the second lactose monohydrate is further characterized by condition 4: d₁₀Between 1.4 and 3.3 μm, D₅₀Between 10.9 and 24.9 μm, and D₉₀Is between 32.6 and 60.4 mu m;

more preferably, the particle size distribution characteristics of the first lactose monohydrate meet condition 3 and the particle size distribution characteristics of the second lactose monohydrate meet condition 4.

7. The pharmaceutical composition for inhalation according to claim 6,

the weight ratio of the second lactose monohydrate to the first lactose monohydrate is from 50:50 to 100:0, preferably from 40:40 to 60:20 or from 60:20 to 80:0, more preferably from 70:10 to 75: 5.

8. The pharmaceutical composition for inhalation according to claim 5,

the lactose monohydrate is a combination of a second lactose monohydrate and a third lactose monohydrate, wherein:

the particle size distribution characteristics of the second lactose monohydrate meet condition 2: d₁₀Below 5 μm, D₅₀Below 30 μm, and D₉₀Below 70 μm; and the particle size distribution characteristics of the third lactose monohydrate meet condition 5: d₅₀Below 5 μm, and D₉₀Below 10 μm;

preferably, the particle size distribution of the second lactose monohydrate is further characterized by condition 4: d₁₀Between 1.4 and 3.3 μm, D₅₀Between 10.9 and 24.9 μm, and D₉₀Is between 32.6 and 60.4 μm.

9. The pharmaceutical composition for inhalation according to claim 8,

the weight ratio of the second lactose monohydrate to the third lactose monohydrate is from 50:50 to 100:0, preferably from 40:40 to 60:20 or from 60:20 to 80:0, more preferably from 70:10 to 75: 5.

10. The pharmaceutical composition for inhalation according to claim 5,

the particle size distribution characteristics of the magnesium stearate are as follows: d₁₀Between 1 and 3 μm, D₅₀Between 5 and 25 μm, and D₉₀Is between 50 and 100 μm.

11. The pharmaceutical composition for inhalation according to claim 5,

the weight ratio of magnesium stearate to lactose monohydrate is from 0.05:100 to 5:100, preferably from 0.05:100 to 1:100, more preferably 1: 100.

12. Use of a pharmaceutical composition for inhalation according to any one of claims 1 to 11 in the manufacture of a medicament for the prevention and/or treatment of a disease caused by a viral infection;

preferably, the virus is selected from one or more of marburg virus, ebola virus, nipah virus, respiratory syncytial virus, hepatitis c virus, human immunodeficiency virus and novel coronaviruses;

more preferably, the virus is a novel coronavirus.