CN107243080B - Inhalation type aerosol, raw material composition and preparation method thereof - Google Patents
Inhalation type aerosol, raw material composition and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a suction type aerosol, a raw material composition and a preparation method thereof. The invention discloses a raw material composition of an inhalation aerosol, which comprises a pharmaceutical active ingredient and a propellant, wherein the pharmaceutical active ingredient comprises a long-acting beta receptor agonist and glucocorticoid; the propellant comprises tetrafluoroethane. The invention discloses an inhalation aerosol, which comprises the raw material composition, a pressure-resistant container and a valve system. The inhalation aerosol adopts tetrafluoroethane as a propellant, and the pharmaceutical particles are prepared by adopting a supercritical method and a spray drying method during preparation, so that the inhalation aerosol with uniformly distributed particles can be obtained, and the loss in the preparation method is low; in addition, the inhalation aerosol provided by the invention adjusts the single dose spraying amount of the medicine, and effectively reduces the greenhouse effect gas dosage of the product.
Description
Technical Field
The invention relates to a suction type aerosol, a raw material composition and a preparation method thereof.
Background
Mometasone furoate and formoterol fumarate inhalation aerosol is a glucocorticoid and long-acting beta receptor stimulant compound medicine, and a product DULERA containing HFC227 is developed by Merck company. The medicine is used for treating asthma of 12 years old or more patients who cannot be controlled properly by inhaling corticoids at medium to high dose, and is not used as a treatment medicine for acute asthma patients. The medicine is provided with an electronic counting device, counting is carried out through a pressing touch sensor of a valve, and the product specification is 100mcg/5 mcg/press and 200mcg/5 mcg/press (mometasone furoate/formoterol fumarate dihydrate).
Clinical study results demonstrated that lung function (mean area under concentration-time curve measured at 0-12h corresponding to forced expiratory volume per second) in patients treated with mometasone furoate formoterol fumarate inhalation aerosol achieved a significantly greater improvement from baseline at 12wk compared to mometasone furoate and placebo alone. The asthma exacerbation rate of mometasone furoate formoterol fumarate inhalation aerosol is significantly lower than that of the formoterol fumarate dihydrate 5mcg group alone (P < 0.001).
In US patent (US7067502B2), a formulation and a process for the preparation of an inhalation aerosol of mometasone furoate and formoterol fumarate is disclosed. Wherein the drug particles are prepared by adopting a jet milling process, and heptafluoropropane (HFC-227ea) is used as a main propellant. However, this method has the disadvantages of large dispersion area of particle uniformity, severe process loss, etc., and in addition, heptafluoropropane has poor solubility for some active drugs in the formulation of a metered dose inhalation aerosol, or some commonly used surfactants or dispersants; inhalation of high concentration heptafluoropropane has certain harm and can cause death.
Therefore, there is a need in the art for a new mometasone furoate formoterol fumarate inhalation aerosol and a preparation method thereof, so as to overcome the problems of nonuniform particle distribution in the inhalation aerosol and serious loss in the preparation method in the prior art.
Disclosure of Invention
The invention aims to solve the technical problems that mometasone furoate and formoterol fumarate inhalation aerosol in the prior art has the defects of nonuniform particle distribution in the inhalation aerosol, serious loss in a preparation method and the like, and provides a inhalation aerosol, a raw material composition thereof and a preparation method thereof. The inhalation aerosol adopts tetrafluoroethane (HFC-134a) as a propellant, and the pharmaceutical particles are prepared by adopting a supercritical method and a spray drying method during preparation, so that the inhalation aerosol with uniformly distributed particles can be obtained, and the loss in the preparation method is low; in addition, the inhalation aerosol provided by the invention adjusts the single dose spraying amount of the medicine, and effectively reduces the greenhouse effect gas dosage of the product.
The invention mainly solves the technical problems through the following technical scheme.
The invention provides a raw material composition of an inhalation aerosol, which comprises a pharmaceutical active ingredient and a propellant, wherein the pharmaceutical active ingredient comprises a long-acting beta receptor agonist and glucocorticoid; the propellant comprises tetrafluoroethane (HFC-134 a).
The beta receptor agonist may be a beta receptor agonist conventional in the art, preferably mometasone furoate, indacaterol or salmeterol. The glucocorticoid may be a glucocorticoid conventional in the art, preferably formoterol fumarate, fluticasone propionate, budesonide or ciclesonide.
The dosage of the beta receptor agonist and the glucocorticoid can be the dosage which is conventional in the field, and the mass ratio of the beta receptor agonist to the glucocorticoid is preferably 20:1-40: 1.
The content of the pharmaceutical active ingredient can be the content of the pharmaceutical active ingredient in the inhalation aerosol raw material prescription in the field, preferably 0.05-15%, more preferably 0.05-10%, and most preferably 0.05-1%, wherein the percentage refers to the mass percentage of the pharmaceutical active ingredient in the total mass of all the raw materials of the inhalation aerosol.
The content of the tetrafluoroethane can be the conventional content of the propellant in the inhalation aerosol raw material prescription in the field, preferably 85-99.95%, more preferably 90-99.95%, and most preferably 99-99.95%, wherein the percentage refers to the mass percentage of the propellant in the total mass of all the raw materials of the inhalation aerosol.
The inhalation aerosol raw material composition further comprises an additive. The additive is conventional in the art, and preferably one or more of cosolvent, suspending agent, cosolvent, wetting agent, emulsifier, stabilizer, flavoring agent and preservative. Wherein, the cosolvent, the suspending agent, the cosolvent, the wetting agent, the emulsifying agent, the stabilizing agent, the flavoring agent and the preservative are the cosolvents, the suspending agents, the cosolvents, the wetting agents, the emulsifying agents, the stabilizing agents, the flavoring agents and the preservatives which are conventional in the aerosol in the field of medicaments.
The additive is preferably a cosolvent, or a cosolvent and a suspending agent.
In a preferred embodiment of the present invention, the suspending agent may be one conventional in the art, preferably one or more of phospholipid, oleic acid, povidone K25, povidone K30 and povidone K40. The content of the suspending agent can be the content conventional in the field, and is preferably less than 0.5 percent of the total mass of the raw materials. The co-solvent may be one conventional in the art, preferably ethanol and/or dichloromethane. The amount of the cosolvent used may be an amount conventionally used in the art, and is preferably less than 3% of the total mass of the raw materials, and more preferably less than 1% of the total mass of the raw materials. Although the starting material of the inhalation aerosol of the present invention contains a cosolvent such as ethanol, methylene chloride, etc., it is removed by drying during the preparation of the inhalation aerosol. The inhalation aerosol finally produced is therefore (virtually) free of cosolvents.
In a preferred embodiment of the present invention, the raw material composition of the inhalation aerosol is composed of a pharmaceutically active ingredient and a propellant, wherein the pharmaceutically active ingredient is a long-acting beta receptor agonist and a glucocorticoid; the propellant is tetrafluoroethane.
In another preferred embodiment of the present invention, the inhalation aerosol raw material composition comprises a pharmaceutically active ingredient, a propellant and an additive, wherein the pharmaceutically active ingredient is a long-acting beta receptor agonist and a glucocorticoid; the propellant is tetrafluoroethane.
The invention also provides a preparation method of the inhalation aerosol raw material composition, which comprises the following steps:
(1) preparing the long-acting beta receptor agonist into medicine particles by adopting a supercritical solution rapid expansion method;
(2) preparing glucocorticoid into medicine particles by adopting a spray drying method;
(3) mixing the drug particles in the step (1) and the drug particles in the step (2), filtering and drying to obtain a drug particle wrap;
(4) and (4) mixing the medicament particle wrappage prepared in the step (3) with a propellant to obtain the inhalation aerosol raw material composition.
In the step (1), the long-acting beta receptor agonist can be directly placed in supercritical solution rapid expansion equipment, or can be mixed with an additive such as a cosolvent and then placed in supercritical solution rapid expansion equipment. When the long-acting beta receptor agonist and the cosolvent are mixed, the cosolvent can be used in an amount conventional in the art as long as the glucocorticoid can form a uniform solution in the cosolvent; and is not particularly limited. In the invention, the mass ratio of the long-acting beta receptor stimulant preparation to the cosolvent is generally 100:1-1000: 1.
In step (1), the conditions of the supercritical solution rapid expansion method can be conventional in the art, and the following conditions are preferred in the present invention: the active ingredients are saturated in an extraction kettle filled with carbon dioxide, and are sprayed out through a nozzle. In the invention, the temperature in the extraction kettle is preferably 80-250 ℃; the pressure in the extraction vessel is preferably from 10bar to 1000 bar.
In a preferred embodiment of the present invention, in the step (1), the pharmaceutically active ingredient is stabilized for 5 to 60 minutes, and more preferably for 10 to 20 minutes after reaching a saturation state in the carbon dioxide-filled extraction tank.
In step (1), the particle size (d90) of the drug particles is preferably less than 5 microns (e.g., 1.5-3 microns), more preferably less than 2 microns. By adopting a supercritical solution rapid expansion method, the loss of the drug particles is generally less than 5 percent, and the loss is low.
In step (2), the glucocorticoid may be mixed with an additive such as a cosolvent and then placed in a spray drying apparatus. The cosolvent can be used in an amount which is conventional in the art, as long as the glucocorticoid can form a uniform solution in the cosolvent, and the mass ratio of the cosolvent to the glucocorticoid is preferably 500:1-1000: 1. The conditions for the spray-drying method may be those conventional in the art. For example, the temperature of the spray drying apparatus is preferably 100 ℃ to 150 ℃. The particle size (d90) of the drug particles is preferably less than 5 microns, more preferably less than 2 microns.
In the step (2), the spray drying method can be replaced by a supercritical solution rapid expansion method.
In a preferred embodiment of the present invention, the order of step (1) and step (2) may be changed.
In the step (3), the mixing of the drug particles in the step (1) and the drug particles in the step (2) is preferably performed in the presence of one or more of a cosolvent, a suspending agent and a cosolvent. The operation of step (3) preferably comprises the steps of: mixing the suspending agent and the cosolvent to form a supersaturated solution, filtering 1, mixing the filtered supersaturated solution with the drug particles in the step (1) and the step (2), filtering, and drying to obtain the drug particle wrappage. Wherein, the mixing of the suspending agent and the cosolvent is preferably carried out at the temperature of 60-80 ℃. Preferably, the cosolvent is heated to 60-80 ℃, and then the suspending agent is added to form a supersaturated solution. After the cosolvent and the suspending agent form a supersaturated solution, the temperature is reduced to room temperature, and the solution is filtered 1 to remove the undissolved suspending agent. The operation of filtration 1 and filtration is preferably carried out using a filter having a pore size of 2 to 5 μm.
In step (3), the drying method may be a drying method conventional in the art, and preferably vacuum drying. The temperature of the vacuum drying is preferably 60-80 ℃, and the time of the vacuum drying is preferably more than 2 hours, such as 2-4 hours.
The invention also provides an inhalation aerosol comprising a starting composition of an inhalation aerosol as described above, a pressure-resistant container and a valve system.
In a preferred embodiment of the invention, the inhalation aerosol is composed of a pharmaceutically active ingredient, a propellant, a pressure-resistant container and a valve system.
In a preferred embodiment of the invention, the inhalation aerosol is composed of a pharmaceutically active ingredient, an additive, a propellant, a pressure-resistant container and a valve system.
It should be noted that when the additive is selected from the group consisting of co-solvents, suspending agents and latent solvents, the final inhalation aerosol is free of the additive if it can be removed by drying during the process for preparing the inhalation aerosol.
The invention also provides a preparation method of the inhalation aerosol, which comprises the following steps:
(1) preparing the long-acting beta receptor agonist into medicine particles by adopting a supercritical solution rapid expansion method;
(2) preparing glucocorticoid into medicine particles by adopting a spray drying method;
(3) mixing the drug particles in the step (1) and the drug particles in the step (2), filtering and drying to obtain a drug particle wrap;
(4) mixing the drug particle wrappage prepared in the step (3) with a propellant to obtain a suction type aerosol raw material composition;
(5) quantitatively subpackaging the inhalation type aerosol raw material composition into a pressure-resistant container of the aerosol, installing a valve system, and tightly rolling.
Wherein the conditions of steps (1) to (4) are the same as those of the method for preparing the inhalation type aerosol raw material composition of steps (1) to (4).
In step (5), the pressure-resistant container of the aerosol can be a pressure-resistant container of an aerosol conventional in the art, preferably a glass container or a metal container. The pressure vessel is preferably 14mL in size. The valve system may be conventional in the art. Among them, the size of the quantification cup (chamber) in the valve system of the present invention is preferably 30 to 45. mu.l, more preferably 40. mu.l.
In a preferred embodiment of the present invention, the operations of steps (4) and (5) preferably comprise the steps of: and (4) quantitatively adding the medicament particle wrappage prepared in the step (3) into a (split charging) aerosol container, installing a valve system, tightly rolling, and filling a propellant.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
(1) according to the preparation method, tetrafluoroethane is used as a propellant, and the supercritical solution rapid expansion method and the spray drying method are adopted to prepare the medicine particles, so that the inhalation type aerosol with uniformly distributed particles can be obtained, and the loss in the preparation method is low; in addition, the inhalation aerosol provided by the invention adjusts the single dose spraying amount of the medicine, and effectively reduces the pollution of the medicine to the environment.
(2) The inhalation aerosol of the present invention is removed by drying in step (3), although a cosolvent such as ethanol, methylene chloride or the like is used in the production process. The inhalation aerosol thus finally produced is (almost) free of cosolvents and therefore has certain advantages for patients who are intolerant to ethanol or dichloromethane compared to inhalation aerosols which contain cosolvents, such as ethanol or dichloromethane.
(3) The total dose of the 3-F grade active pharmaceutical ingredient fine particles is 60 percent higher than the standard dose, and the dose is obviously improved.
Drawings
FIG. 1 is a graph showing a simulated distribution profile of a pharmaceutical active ingredient after the detection of inhalation aerosol sample 1 prepared by the method of example 1.
FIG. 2 is a graph showing a simulated distribution profile of the pharmaceutical active ingredient after the detection of inhalation aerosol-like 2 prepared by the method of example 1.
FIG. 3 is a graph showing a simulated distribution profile of the pharmaceutical active ingredient after the detection of inhalation aerosol-like 3 prepared by the method of example 1.
In FIGS. 1-3, A denotes a drive + adapter; t represents a throat; f represents a filter membrane. A. T, 0, 1, 2, 3, 4, 5, 6, 7 and F represent ACI hierarchy. The ordinate is the distribution of the particles of the pharmaceutically active ingredient in%.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
Production on 10000 bottles scale
(1) Preparation of mometasone furoate medicine particles
Adding 240 g of mometasone furoate into a solvent (such as ethanol and/or dichloromethane) for dissolving, wherein the dosage of the solvent is not particularly limited as long as a uniform solution can be obtained; then adding the mixture into an extraction kettle; or directly adding mometasone furoate into the extraction kettle; filling a certain amount of carbon dioxide into the extraction kettle, controlling the temperature of the extraction kettle at 150 ℃, and controlling the pressure of the extraction kettle at 500 bar; mometasone furoate is saturated in supercritical fluid and stable for 15min, and the mometasone furoate is sprayed out through a nozzle to form spherical particles, wherein the particle size (d90) of the particles is less than 5 microns (for example, less than 2 microns) (the loss of the drug particles by adopting the method is generally less than 5 percent, and the loss of the drug particles by adopting the methods such as jet milling and the like is generally more than 10 percent);
(2) preparation of formoterol fumarate medicinal granules
6 g of formoterol fumarate is dissolved in a solvent (such as ethanol), and spray drying equipment is used, wherein the spray speed is 20 ml/min; spray drying at 120 deg.C to collect formoterol fumarate particles having a particle size (d90) of less than 5 microns (e.g. less than 2 microns);
(3) adding about 2L of ethanol into a dispensing device, heating to 80 deg.C, adding 25400 g of polyvidone K (or other suspending agent) to form a supersaturated solution, cooling to room temperature, and filtering undissolved polyvidone K (or other suspending agent); adding the drug particles obtained in the steps (1) and (2) into the supersaturated solution, stirring, filtering the suspension, filtering by adopting a filter ball with a pore size of 4 microns to obtain a drug particle wrap, and drying in vacuum;
(4) and (4) directly adding the medicament particle wrappage prepared in the step (3) into filling equipment of a one-step method, and adding a propellant HFC-134a (about 80000 g) for dispensing to obtain the raw material of the inhalation aerosol prescription.
(5) Filling process: the inhalation aerosol formulation raw materials were dosed into the container closure system (pressure resistant container and valve system). The specification of a quantitative cup (chamber) of the selected valve system is 40 microliter; the selected pressure vessel had a size of 14 mL. Every press of specification: mometasone furoate in an amount of about 200 micrograms and formoterol fumarate in an amount of about 5 micrograms. The amount of propellant HFC-134a per bottle of 120 puffs was about 8 grams and the amount of povidone K25 per bottle was about 40 micrograms.
Example 2
The rest of the same procedure as in example 1, wherein the operation of step (2) is as follows:
6 g of formoterol fumarate is dissolved in a solvent (such as methanol), and spray drying equipment is used, wherein the spray speed is 2 ml/min; spray drying is carried out at the temperature of 90 ℃, and formoterol fumarate medicine particles are collected, and the particle size d50 of the particles is 4 microns.
Example 3
The rest of the same procedure as in example 1, wherein the operation of step (2) is as follows:
6 g of formoterol fumarate is dissolved in a solvent (such as methanol), and spray drying equipment is used, wherein the spray speed is 4 ml/min; spray drying at 120 deg.c to collect formoterol fumarate medicine granule with d50 as 4 microns size.
Example 4
The rest of the same procedure as in example 1, wherein the operation of step (2) is as follows:
6 g of formoterol fumarate is dissolved in a solvent (such as acetone), and spray drying equipment is used, wherein the spray speed is 0.5 ml/min; spray drying is carried out at the temperature of 90 ℃, and formoterol fumarate medicine particles are collected, and the particle size d50 of the particles is 2 microns.
Example 5
The rest of the same procedure as in example 1, wherein the operation of step (2) is as follows:
6 g of formoterol fumarate is dissolved in a solvent (such as acetone), and spray drying equipment is used, wherein the spray speed is 1 ml/min; spray drying at 120 deg.c to collect formoterol fumarate medicine granule with d50 as 3 microns size.
Example 6
The rest of the same example 1, wherein the operation of step (3) is as follows:
(3) adding about 2L of ethanol into a dispensing device, heating to 80 deg.C, adding 25200 g of polyvidone K (or other suspending agent) to form a supersaturated solution, cooling to room temperature, and filtering undissolved polyvidone (or other suspending agent); and (3) adding the drug particles obtained in the steps (1) and (2) into the supersaturated solution, stirring, filtering the suspension, filtering by adopting a filter ball with a pore size of 4 microns to obtain a drug particle wrap, and drying in vacuum.
Every press of specification: mometasone furoate in an amount of about 200 micrograms and formoterol fumarate in an amount of about 5 micrograms. The amount of propellant HFC-134a per bottle was about 8g per bottle of 120 puffs and the amount of povidone K25 per bottle was about 20 micrograms per bottle.
Example 7
(1) Preparation of mometasone furoate medicine particles
Adding 240 g of mometasone furoate into a solvent (such as ethanol and/or dichloromethane) for dissolving, wherein the dosage of the solvent is not particularly limited as long as a uniform solution can be obtained; then adding the mixture into an extraction kettle; or directly adding mometasone furoate into the extraction kettle; filling a certain amount of carbon dioxide into the extraction kettle, controlling the temperature of the extraction kettle to be 250 ℃, and controlling the pressure of the extraction kettle to be 1000 bar; the mometasone furoate is in a saturated state in the supercritical fluid and is stable for 20min, the mometasone furoate is sprayed out through a nozzle to form spherical particles, and the particle size (d90) of the particles is less than 2 microns (the loss of the drug particles is generally less than 5 percent by adopting the method);
(2) preparation of formoterol fumarate medicinal granules
Formoterol fumarate 6 g was dissolved in a solvent (e.g. methanol). Spraying drying equipment is used, and the spraying speed is 25 ml/min; spray drying at 150 deg.C, and collecting formoterol fumarate granule with particle diameter (d90) less than 2 μm;
(3) adding about 2L of ethanol into a dispensing device, heating to 100 ℃, adding 100 g of phospholipid to form a supersaturated solution, and cooling to room temperature; adding the drug particles obtained in the steps (1) and (2) into the supersaturated solution, stirring, filtering the suspension, filtering by adopting a filter ball with a pore size of 5 microns to obtain a drug particle wrap, and drying in vacuum;
(4) and (4) directly adding the medicament particle wrappage prepared in the step (3) into filling equipment of a one-step method, and adding a propellant HFC-134a (about 80000 g) for dispensing to obtain the raw material of the inhalation aerosol prescription.
(5) Filling process: the inhalation aerosol formulation raw materials were dosed into the container closure system (pressure resistant container and valve system). The specification of a quantitative cup (chamber) of the selected valve system is 45 microliters; the selected pressure vessel had a size of 14 mL. Every press of specification: mometasone furoate in an amount of about 200 micrograms and formoterol fumarate in an amount of about 5 micrograms. The total 120 puffs per bottle, the amount of propellant HFC134a was approximately 8g per bottle.
Example 8
Production was carried out on a 5000-bottle scale
(1) Preparation of mometasone furoate medicine particles
Adding 120 g of mometasone furoate into a solvent (such as ethanol and/or dichloromethane) for dissolving, wherein the dosage of the solvent is not particularly limited as long as a uniform solution can be obtained; then adding the mixture into an extraction kettle; or directly adding mometasone furoate into the extraction kettle; filling a certain amount of carbon dioxide into the extraction kettle, controlling the temperature of the extraction kettle at 80 ℃, and controlling the pressure of the extraction kettle at 10 bar; the mometasone furoate is saturated in the supercritical fluid and is stable for 10min, the mometasone furoate is sprayed out through a nozzle to form spherical particles, and the particle size (d90) of the particles is less than 5 microns (for example, less than 2 microns) (the loss of the drug particles by adopting the method is generally less than 5 percent, and the loss of the drug particles by adopting the methods such as jet milling and the like is generally more than 10 percent);
(2) preparation of formoterol fumarate medicinal granules
Dissolving 3 g formoterol fumarate in a solvent (such as ethanol), and spraying with a spray drying device at a speed of 15 ml/min; spray drying at 100 deg.C to collect formoterol fumarate particles having a particle size (d90) of less than 5 microns (e.g. less than 2 microns);
(3) adding about 1L of ethanol into a blending device, heating to 60 ℃, adding 80 g of oleic acid to form a supersaturated solution, and cooling to room temperature; adding the drug particles obtained in the steps (1) and (2) into the supersaturated solution, stirring, filtering the suspension, filtering by adopting a filter ball with the pore size of 2 microns to obtain a drug particle wrap, and drying in vacuum;
(4) and (4) directly adding the medicament particle wrappage prepared in the step (3) into filling equipment of a one-step method, and adding a propellant HFC-134a (about 45000 g) for dispensing to obtain the raw material of the inhalation aerosol prescription.
(5) Filling process: the inhalation aerosol formulation raw materials were dosed into the container closure system (pressure resistant container and valve system). The specification of a quantitative cup (chamber) of the selected valve system is 30 microliter; the selected pressure vessel had a size of 14 mL. Every press of specification: mometasone furoate in an amount of about 100 micrograms and formoterol fumarate in an amount of about 2.5 micrograms. The amount of HFC-134a per bottle was about 9g per bottle of 120 puffs.
Example 9
The rest of the steps are the same as the example 1, wherein the raw materials and the dosage in the steps are as follows:
in the step (1), 240 g of mometasone furoate;
in the step (2), formoterol fumarate 12 g;
in the step (3), 25300 g of povidone K;
in the step (4), 90000 g of propellant HFC-134 a;
every press of specification: mometasone furoate in an amount of about 200 micrograms and formoterol fumarate in an amount of about 10 micrograms. The amount of HFC-134a per bottle was about 9g per bottle of 120 puffs.
Example 10
The rest of the steps are the same as the example 1, wherein the raw materials and the dosage in the steps are as follows:
in the step (1), 270 g of mometasone furoate;
in the step (2), formoterol fumarate 9 g;
in the step (3), povidone K25200 g;
in the step (4), 85000 g of propellant HFC-134 a;
every press of specification: mometasone furoate in an amount of about 220 micrograms and formoterol fumarate in an amount of about 7.5 micrograms. The amount of propellant HFC-134a per bottle was about 8.5g per bottle at 120 puffs per bottle.
Example 11
The rest of the steps are the same as the example 1, wherein the raw materials and the dosage in the steps are as follows:
in the step (1), 240 g of mometasone furoate;
in the step (2), 6 g of formoterol fumarate;
in the step (3), povidone K25100 g;
in the step (4), propellant HFC-134a 75000 g;
every press of specification: mometasone furoate in an amount of about 200 micrograms and formoterol fumarate in an amount of about 5 micrograms. 120 puffs per bottle, the amount of propellant per bottle is about 7.5 g.
Example 12
The rest of the steps are the same as the example 1, wherein the raw materials and the dosage in the steps are as follows:
in the step (1), 240 g of mometasone furoate;
in the step (2), 6 g of formoterol fumarate;
in the step (3), povidone K25200 g;
in the step (4), the propellant HFC-134a 70000 g;
every press of specification: mometasone furoate in an amount of about 200 micrograms and formoterol fumarate in an amount of about 5 micrograms. The amount of propellant HFC-134a per bottle was about 7.0g per bottle at 120 puffs per bottle.
Effect examples inhalation aerosol test results
An Anderson multistage impact sampling collector (Anderson Cascade Impactor, ACI) is selected to examine the fine particle dose of the prepared inhalation aerosol (Chinese pharmacopoeia inhalation preparation general rule stipulates equipment). The results are shown in fig. 1-3 and table 1, and are examined mainly for the sum of the drug particle contents from grade 3 to grade F of ACI. Experimental results show that by adopting the process, the fine particle dose of the product is remarkably improved, the total dose of the 3-F grade mometasone furoate and formoterol fumarate fine particles can reach 60% of the standard amount, and the process is remarkably improved compared with the DULERA original research.
Three batches of samples, sample 1, sample 2 and sample 3, were prepared using the preparation method of example 1.
TABLE 1 ACI data sheet for testing content of active ingredients in medicine
___________________________
| | Sample | 1% by | Sample | 2% by | Sample | 3% by weight |
| Driver + |
10 | 9 | 10 | |||
| |
25 | 24 | 23 | |||
| |
1 | 1 | 1 | |||
| |
0 | 0 | 0 | |||
| |
14 | 15 | 13 | |||
| |
27 | 26 | 27 | |||
| 4 |
15 | 16 | 14 | |||
| |
11 | 10 | 11 | |||
| |
7 | 6 | 7 | |||
| |
3 | 3 | 3 | |||
| |
1 | 1 | 1 | |||
| Σ3-F | 64 | 62 | 63 |
Claims (10)
1. An inhalable aerosol comprising a starting composition for an inhalable aerosol, a pressure-resistant vessel and a valve system;
the raw material composition of the inhalation aerosol comprises a pharmaceutical active ingredient and a propellant, wherein the pharmaceutical active ingredient consists of a long-acting beta receptor agonist and glucocorticoid; the propellant comprises tetrafluoroethane;
the mass ratio of the beta receptor stimulant to the glucocorticoid is 40: 1;
the content of the active pharmaceutical ingredients is 0.05-1%, and the percentage refers to the mass percentage of the active pharmaceutical ingredients in the total mass of the inhalation aerosol raw materials;
the content of the tetrafluoroethane is 99-99.95%, and the percentage refers to the mass percentage of the propellant in the total mass of all the raw materials of the inhalation aerosol;
the beta receptor stimulant is mometasone furoate;
the glucocorticoid is formoterol fumarate;
the preparation method of the raw material composition of the inhalation aerosol comprises the following steps:
(1) preparing the long-acting beta receptor agonist into medicine particles by adopting a supercritical solution rapid expansion method;
(2) preparing glucocorticoid into medicine particles by adopting a spray drying method; the temperature of spray drying equipment in the spray drying method is 100-150 ℃;
(3) mixing the drug particles in the step (1) and the drug particles in the step (2), filtering and drying to obtain a drug particle wrap;
(4) mixing the drug particle wrappage prepared in the step (3) with a propellant to obtain a raw material composition of the inhalation aerosol;
the specification of the pressure-resistant container is 14 mL;
the size of the quantitative cup in the valve system is 30-45 microliter.
2. The inhalable aerosol of claim 1, wherein the starting composition of the inhalable aerosol further comprises an additive.
3. The inhalable aerosol of claim 2, wherein the additive is one or more of a cosolvent, a suspending agent, a cosolvent, a wetting agent, an emulsifier, a stabilizer, a flavoring agent, and a preservative.
4. The inhalable aerosol of claim 2, wherein the starting composition of the inhalable aerosol further comprises a co-solvent, or a co-solvent and a suspending agent; the suspending agent is one or more of phospholipid, oleic acid, povidone K25, povidone K30 and povidone K40; the cosolvent is ethanol and/or dichloromethane.
5. The inhalable aerosol of claim 1, wherein the dosing cup in the valve system is 40 μ l in size.
6. The inhalable aerosol of claim 1, wherein in the method of preparing a starting composition for the inhalable aerosol,
in the step (1), the conditions of the supercritical solution rapid expansion method are as follows: the active ingredients of the medicine are saturated in an extraction kettle filled with carbon dioxide and are sprayed out through a nozzle;
and/or, changing the order of step (1) and step (2);
and/or, in the step (3), mixing the drug particles in the step (1) and the drug particles in the step (2) in the presence of one or more of a cosolvent, a suspending agent and a cosolvent;
and/or, in the step (3), the drying method is vacuum drying.
7. The inhalation aerosol of claim 6, wherein in step (1), the temperature in the extraction vessel is from 80 ℃ to 250 ℃;
and/or, in the step (1), the pressure in the extraction kettle is 10bar-1000 bar;
and/or, in the step (1), stabilizing the active ingredients of the medicines for 5-60 minutes after the active ingredients of the medicines reach a saturated state in an extraction kettle filled with carbon dioxide;
and/or, the operation of step (3) comprises the following steps: mixing a suspending agent and a cosolvent to form a supersaturated solution, filtering, mixing the filtered supersaturated solution with the drug particles in the step (1) and the step (2), filtering, and drying to obtain a drug particle wrap;
and/or, in the step (3), the temperature of the vacuum drying is 60-80 ℃, and the time of the vacuum drying is more than 2 hours.
8. The inhalable aerosol of claim 7, wherein in step (1), the pharmaceutically active ingredient is stabilized for 10-20 minutes after reaching saturation in an extraction vessel filled with carbon dioxide.
9. A process for the preparation of an inhalable aerosol according to any of the claims 1 to 8, characterized in that it comprises the following steps:
(1) preparing the long-acting beta receptor agonist into medicine particles by adopting a supercritical solution rapid expansion method;
(2) preparing glucocorticoid into medicine particles by adopting a spray drying method;
(3) mixing the drug particles in the step (1) and the drug particles in the step (2), filtering and drying to obtain a drug particle wrap;
(4) mixing the drug particle wrappage prepared in the step (3) with a propellant to obtain a suction type aerosol raw material prescription;
(5) quantitatively packaging the inhalation type aerosol raw material prescription into a pressure-resistant container of the aerosol, installing a valve system, and tightly rolling.
10. The process for the preparation of an inhalable aerosol according to claim 9,
the conditions of steps (1) to (4) are as defined in claim 6 or 7;
and/or, in the step (5), the pressure-resistant container of the aerosol is a glass container or a metal container;
and/or, the operations of steps (4) and (5) comprise the following steps: and (4) quantitatively subpackaging the medicament particle wrappage prepared in the step (3) into an aerosol container, installing a valve system, tightly rolling and filling a propellant.
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| CN102753152A (en) * | 2009-05-29 | 2012-10-24 | 珍珠治疗公司 | Respiratory Delivery of Active Agents |
| CN103930095A (en) * | 2011-08-08 | 2014-07-16 | 普罗索尼克斯有限公司 | Eutectic mixture for pulmonary administration |
| CN104208688A (en) * | 2013-05-29 | 2014-12-17 | 天津金耀集团有限公司 | Pharmaceutical composition containing individually-packaged mometasone furoate and epinephrine beta2-acceptor stimulant placed in inhalation device for synchronous application |
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| CN102753152A (en) * | 2009-05-29 | 2012-10-24 | 珍珠治疗公司 | Respiratory Delivery of Active Agents |
| CN103930095A (en) * | 2011-08-08 | 2014-07-16 | 普罗索尼克斯有限公司 | Eutectic mixture for pulmonary administration |
| CN104208688A (en) * | 2013-05-29 | 2014-12-17 | 天津金耀集团有限公司 | Pharmaceutical composition containing individually-packaged mometasone furoate and epinephrine beta2-acceptor stimulant placed in inhalation device for synchronous application |
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