CN111939143A - Budesonide solution type aerosol and preparation method thereof - Google Patents
Budesonide solution type aerosol and preparation method thereof Download PDFInfo
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- CN111939143A CN111939143A CN201910404405.4A CN201910404405A CN111939143A CN 111939143 A CN111939143 A CN 111939143A CN 201910404405 A CN201910404405 A CN 201910404405A CN 111939143 A CN111939143 A CN 111939143A
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- budesonide
- aerosol
- solution
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
- A61K9/124—Aerosols; Foams characterised by the propellant
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
Abstract
The invention belongs to the field of chemical pharmaceutical preparations, and particularly relates to a budesonide solution type aerosol and a preparation method thereof. The budesonide solution type aerosol disclosed by the invention is composed of budesonide, a propellant, a cosolvent, a stabilizer and a pH buffer solution, breaks through the limitation of the particle size of a raw material and the size of an inhalation particle in the traditional budesonide suspension type aerosol, and has the advantages of uniform distribution, good absorption effect, more stable quality, safety, reliability, suitability for industrial production and the like.
Description
Technical Field
The invention belongs to the field of chemical pharmaceutical preparations, and particularly relates to a budesonide solution type aerosol and a preparation method thereof.
Background
Aerosol is a preparation which contains medicine, emulsion or suspension and proper propellant, and is packaged in a pressure-resistant container with a special valve system, and when in use, the content is sprayed out in the form of mist under the pressure of the propellant, and the aerosol is used for lung inhalation or directly sprayed to mucosa, skin and space of cavity and tract for disinfection. The aerosol is packaged in a closed pressure-resistant container of a specific valve system together with a proper propellant, and sprays the content drug by means of the pressure of the propellant, and the aerosol is widely used for local skin drug delivery or respiratory tract inhalation drug delivery in the field of medicine due to continuous perfection and increased application range of the dosage form, and is approved by patients and manufacturers.
Budesonide is a glucocorticoid medicine, has high-efficiency local anti-inflammatory effect, and is suitable for treating bronchial asthma. By enhancing the stability of endothelial cells, smooth muscle cells and lysosome membranes, the immune response is inhibited and the synthesis of antibodies is reduced, thereby reducing the release of allergic active media such as histamine and the like, relieving the enzymatic process excited during antigen-antibody binding and inhibiting the synthesis and release of bronchoconstrictor substances.
Currently marketed budesonide products are budesonide inhalation aerosols (budesonide aerosols containing hydrofluoroalkane propellant were first marketed in finland in formerly known as astrazen, first in 1998), budesonide inhalation powder aerosols (originally known as astrazen, first in the us in 2 months in 1998), budesonide aerosol inhalation suspensions (primekins, formerly known as astrazen, first in the us in 2 months in 2001). In addition, there are some compound preparations, such as budesonide formoterol inhalation aerosol and powder inhalation aerosol.
Most of the budesonide aerosols in the prior art are prepared by dispersing budesonide particles in a propellant, which may result in poor dispersibility of the budesonide particles in the propellant and/or easy aggregation and even irreversible aggregation of the particulate matter, and thus may form non-uniform dispersions, resulting in non-constant administration dosage.
The liquid preparation is atomized and inhaled, and the patient can realize the delivery of the medicine under the normal breathing condition without the synchronous coordination of the atomization starting and the inhalation action (required for inhaling the aerosol) of the patient and depending on the larger inspiratory airflow of the patient (required for inhaling the powder aerosol), so the liquid preparation is particularly suitable for children, the old and other patients who cannot better use the inhalation aerosol and the inhalation powder aerosol.
In addition, in the preparation of budesonide aerosol, the dissolution stability of budesonide is a very critical issue, and therefore how to make the dissolved budesonide have high dissolution stability is a technical problem which needs to be solved in the field.
Disclosure of Invention
The invention aims to overcome the technical problems in the prior art, and provides a budesonide solution type aerosol for the first time, wherein the budesonide solution type aerosol solves the problem of solubility of the budesonide in the solution type aerosol and ensures the stability of physical properties and chemical properties of the budesonide solution type aerosol by adjusting the using amounts of a propellant and a cosolvent, optimizing the selection and using amount of a stabilizer and adjusting the pH of the solution.
The second object of the present invention is to provide a method for producing the budesonide solution type aerosol.
In order to realize the first object, the invention is realized according to the following technical scheme:
a budesonide solution type aerosol takes budesonide as a main drug, accounts for 0.28-0.30% of the aerosol, takes tetrafluoroethane (HFA134a) or heptafluoropropane (HFA227) as a propellant, takes ethanol, polyethylene glycol and propylene glycol as cosolvent, takes one or a combination of oleic acid, citric acid, glacial acetic acid, glycerol, vitamin C and edetate disodium as a stabilizer, and adopts citric acid-sodium citrate buffer solution and acetic acid-sodium acetate buffer solution as pH buffer solution.
The propellant is preferably tetrafluoroethane, and accounts for 83% -90%, preferably 88.6% of the aerosol.
The cosolvent is preferably ethanol, and accounts for 8% -16%, preferably 11% of the aerosol.
The stabilizer is preferably a combination of oleic acid, vitamin C and edetate disodium, and accounts for 0.023% -1.17% of the aerosol, and is preferably 0.039%.
The pH buffer solution is preferably citric acid-sodium citrate, and the pH of the solution is adjusted to 3.0-6.0, preferably 4.0-5.0, and more preferably 4.5.
In order to achieve the second purpose, the invention is realized according to the following technical scheme:
the first preparation method of the budesonide solution type aerosol comprises the following steps:
adding stabilizer into cosolvent to dissolve, adding budesonide to dissolve, adding pH buffer solution, pressurizing, charging propellant, stirring, pressurizing, filling the solution into aerosol bottle.
Further, the preparation method comprises the following steps:
adding oleic acid, vitamin C and edetate disodium into polyethylene glycol for dissolving, adding budesonide for dissolving, adding citric acid-sodium citrate buffer solution for adjusting pH to 4.5, pressurizing, charging propellant tetrafluoroethane, stirring uniformly, pressurizing, filling the solution, and filling into an aerosol bottle.
Compared with the prior art, the invention has the beneficial effects that:
according to the budesonide solution type aerosol, the content of the main drug budesonide, the cosolvent, the stabilizer and other components is set, the pH buffer solution is added to adjust the pH of the solution, the components are mutually cooperated, a stable dissolving and storing environment is provided for the main drug budesonide, the limitation of the traditional budesonide suspension type aerosol caused by the particle size of the raw material and the size of the inhalation particle is broken through, the budesonide solution type aerosol has the advantages of uniform distribution and good absorption effect, the prepared product has extremely high stability, and the budesonide solution type aerosol is safe and reliable and is suitable for industrial production.
The specific implementation mode is as follows:
the invention is further described by the following examples, which are intended for illustrative purposes only and are not intended to limit the scope of the invention.
Example 1:
adding oleic acid, vitamin C and edetate disodium into ethanol for dissolving, adding budesonide for dissolving, adding citric acid-sodium citrate buffer solution for adjusting the pH value of the solution to be 4.5, pressurizing, filling propellant tetrafluoroethane, stirring uniformly, filling the solution into an aerosol bottle by pressurizing and filling.
Example 2:
adding citric acid, glacial acetic acid and edetate disodium into polyethylene glycol for dissolving, adding budesonide for dissolving, adding acetic acid-sodium acetate buffer solution for adjusting pH to 4, pressurizing, charging propellant heptafluoropropane, stirring, pressurizing, filling, and filling into aerosol bottle.
Example 3:
dissolving glacial acetic acid, vitamin C and glycerol in propanol, adding budesonide, dissolving, adding citric acid-sodium citrate buffer solution to regulate pH to 5, pressurizing, charging propellant tetrafluoroethane, stirring, pressurizing, filling, and filling into aerosol bottle.
Example 4:
adding citric acid, glycerol and edetate disodium into ethanol for dissolving, adding budesonide for dissolving, adding citric acid-sodium citrate buffer solution for adjusting pH to 3, pressurizing, charging propellant heptafluoropropane, stirring uniformly, pressurizing, filling the solution, and filling into an aerosol bottle.
Example 5:
adding citric acid, glycerol and edetate disodium into ethanol for dissolving, adding budesonide for dissolving, adding citric acid-sodium citrate buffer solution for adjusting pH to 5, pressurizing, charging propellant tetrafluoroethane, stirring uniformly, pressurizing, filling the solution, and filling into an aerosol bottle.
Example 6:
dissolving glycerol and edetate disodium in ethanol, adding budesonide, dissolving, adding citric acid-sodium citrate buffer solution to adjust pH to 4, pressurizing, charging propellant tetrafluoroethane, stirring, pressurizing, filling into aerosol bottle.
Example 7:
dissolving glycerol and edetate disodium in ethanol, adding budesonide, dissolving, adding citric acid-sodium citrate buffer solution to adjust pH to 3, pressurizing, charging propellant tetrafluoroethane, stirring, pressurizing, filling into aerosol bottle.
Example 8:
adding citric acid, glacial acetic acid and edetate disodium into polyethylene glycol for dissolving, adding budesonide for dissolving, adding acetic acid-sodium acetate buffer solution for adjusting pH to 6, pressurizing, charging propellant heptafluoropropane, stirring, pressurizing, filling, and filling into aerosol bottle.
Comparative example 1:
dissolving glycerol, vitamin C and glacial acetic acid in ethanol, adding budesonide, dissolving, adding citric acid-sodium citrate buffer solution to adjust pH to 4, pressurizing, charging propellant tetrafluoroethane, stirring, pressurizing, filling, and filling into aerosol bottle.
Comparative example 2:
dissolving oleic acid in ethanol, adding budesonide for dissolving, adding citric acid-sodium citrate buffer solution for adjusting the pH value of the solution to be 5, pressurizing, filling propellant tetrafluoroethane, stirring uniformly, pressurizing, filling the solution, and filling into an aerosol bottle.
Comparative example 3:
dissolving vitamin C in ethanol, adding budesonide, dissolving, adding citric acid-sodium citrate buffer solution to adjust pH to 5, pressurizing, charging propellant tetrafluoroethane, stirring, pressurizing, filling into aerosol bottle.
Comparative example 4:
dissolving oleic acid, vitamin C, edetate disodium and budesonide in ethanol, adding citric acid-sodium citrate buffer solution to adjust pH to 5, pressurizing, charging propellant tetrafluoroethane, stirring, pressurizing, filling the solution, and filling into an aerosol bottle.
Comparative example 5:
dissolving glacial acetic acid, vitamin C and edetate disodium in ethanol, adding budesonide, dissolving, adding citric acid-sodium citrate buffer solution to adjust pH to 2, pressurizing, charging propellant tetrafluoroethane, stirring, pressurizing, filling, and filling into aerosol bottle.
Comparative example 6:
adding citric acid, glacial acetic acid and edetate disodium into polyethylene glycol for dissolving, adding budesonide for dissolving, adding acetic acid-sodium acetate buffer solution for adjusting pH to 6.5, pressurizing, charging propellant heptafluoropropane, stirring, pressurizing, filling, and filling into aerosol bottle.
Stability study:
and (3) accelerated test:
the prepared budesonide solution type aerosol formulations of examples 1 to 8 and comparative examples 1 to 6 were allowed to stand at a temperature of 40 ℃. + -. 2 ℃ and a relative humidity of 75%. + -. 5% for 6 months, and were sampled and analyzed at 0, 1, 2, 3, and 6 months, respectively, and the results are shown in the following table.
TABLE 1 accelerated test results
The accelerated test result shows that the budesonide solution type aerosol prepared by the method in the embodiment 1-8 is placed for 6 months under the conditions that the temperature is 40 ℃ plus or minus 2 ℃ and the relative humidity is 75% + orminus 5%, the content of the main drug per press is more than 99% and can reach 99.8% at most, the fog drops are distributed over 30%, the maximum single impurity content is less than 0.45%, and the total amount of impurities is 0.82% -1.01%.
The budesonide solution type aerosol prepared by the method in comparative examples 1 to 6 was allowed to stand for 6 months under the same conditions as in examples 1 to 8, and the content of the main drug per unit weight was 85.7% at the maximum, the distribution of the droplets was 26% at the maximum, the content of the single impurity was 5.4% at the minimum, and the total amount of the impurities was 13.36% or more.
The comparison of the data shows that the budesonide solution type aerosol prepared by the method in the examples 1 to 8 has high content of main drugs per press, small change of droplet distribution, and lower maximum single impurity content and total impurity content in related substance determination, which indicates that the product prepared by the examples has extremely high stability and uniform distribution.
And (3) long-term test:
the prepared budesonide solution type aerosols of examples 1 to 8 and comparative examples 1 to 5 were allowed to stand at 25 ℃ C. + -. 2 ℃ and 60%. + -. 10% relative humidity for 12 months, and were sampled and analyzed at 0, 3, 6, 9 and 12 months, respectively, and the results are shown in the following table.
TABLE 2 Long-term test results
Long-term test results show that the budesonide solution type aerosol prepared by the method in the embodiment 1-8 is placed for 12 months under the conditions of 25 ℃ plus or minus 2 ℃ and relative humidity of 60 percent plus or minus 10 percent, the content of the main drug per press is more than 99 percent and reaches 99.7 percent at most, the fog drops are distributed about 30 percent, the maximum single impurity content is less than 0.27 percent, and the total amount of impurities is 0.82-0.92 percent.
The budesonide solution type aerosol prepared by the method in comparative examples 1 to 6 was allowed to stand for 12 months under the same conditions as in examples 1 to 8, and the content of the main drug per actuation was 85.3% at the maximum, the droplet distribution was 26% at the maximum, the content of the single impurity was 5.62% at the minimum, and the total amount of the impurity was 8.52% or more.
The comparison of the data shows that the budesonide inhalation solution type aerosol provided by the invention is placed for 12 months for a long time, the content of the main drug, the droplet distribution and related substances do not change obviously every second stroke, and the budesonide inhalation solution type aerosol provided by the invention has good stability.
Claims (10)
1. The budesonide solution type aerosol is characterized by comprising budesonide, a propellant, a cosolvent, a stabilizer and a pH buffer solution, wherein the propellant accounts for 83-90 percent, the cosolvent accounts for 8-16 percent and the stabilizer accounts for 0.023-1.17 percent in percentage by weight.
2. The aerosol formulation of claim 1 wherein the propellant is tetrafluoroethane or heptafluoropropane; the cosolvent is one or more of ethanol, polyethylene glycol and propylene glycol.
3. The aerosol formulation of claim 1, wherein the propellant is present in an amount of 88.6%.
4. The aerosol formulation of claim 1, wherein the cosolvent is present at 11.0%.
5. The aerosol formulation of claim 1, wherein the stabilizer is one or a combination of oleic acid, citric acid, glacial acetic acid, glycerol, vitamin C, and edetate disodium; preferably oleic acid, vitamin C, and edetate disodium.
6. The aerosol formulation of claim 1, wherein the stabilizer is present at 0.039%.
7. The aerosol of claim 1, wherein the pH buffer is one of citric acid-sodium citrate buffer and acetic acid-sodium acetate buffer, preferably citric acid-sodium citrate buffer.
8. The aerosol formulation of claim 1, wherein the pH buffer adjusts the solution pH to 3.0 to 6.0, preferably to 4.0 to 5.0, more preferably to 4.5.
9. A method of preparing an aerosol formulation as claimed in any one of claims 1 to 8, comprising the steps of:
adding stabilizer into cosolvent to dissolve, adding budesonide to dissolve, adding pH buffer solution, pressurizing, charging propellant, stirring, pressurizing, filling the solution into aerosol bottle.
10. The method of claim 9, comprising the steps of:
adding oleic acid, vitamin C and edetate disodium into ethanol for dissolving, adding budesonide for dissolving, adding citric acid-sodium citrate buffer solution for adjusting the pH value of the solution to be 4.5, pressurizing, filling tetrafluoroethane, stirring uniformly, pressurizing, filling the solution, and filling into an aerosol bottle.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910404405.4A CN111939143A (en) | 2019-05-16 | 2019-05-16 | Budesonide solution type aerosol and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201910404405.4A CN111939143A (en) | 2019-05-16 | 2019-05-16 | Budesonide solution type aerosol and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1189096A (en) * | 1995-06-27 | 1998-07-29 | 贝林格尔·英格海姆公司 | New stable medicinal compositions for generating propellant-free aerosols |
| WO2000078286A1 (en) * | 1999-06-18 | 2000-12-28 | 3M Innovative Properties Company | Steroid solution aerosol products with enhanced chemical stability |
| US20050095206A1 (en) * | 2003-10-30 | 2005-05-05 | Laboratorio Pablo Cassara S.R.L. | Aerosol pharmaceutical solution formulation containing glucocorticoids stable to the storage; method for stabilizing formulations and use of a stabilizer |
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- 2019-05-16 CN CN201910404405.4A patent/CN111939143A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1189096A (en) * | 1995-06-27 | 1998-07-29 | 贝林格尔·英格海姆公司 | New stable medicinal compositions for generating propellant-free aerosols |
| WO2000078286A1 (en) * | 1999-06-18 | 2000-12-28 | 3M Innovative Properties Company | Steroid solution aerosol products with enhanced chemical stability |
| US20050095206A1 (en) * | 2003-10-30 | 2005-05-05 | Laboratorio Pablo Cassara S.R.L. | Aerosol pharmaceutical solution formulation containing glucocorticoids stable to the storage; method for stabilizing formulations and use of a stabilizer |
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