CN116421556A - Budesonide suspension and preparation method thereof - Google Patents
Budesonide suspension and preparation method thereof Download PDFInfo
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- CN116421556A CN116421556A CN202310448930.2A CN202310448930A CN116421556A CN 116421556 A CN116421556 A CN 116421556A CN 202310448930 A CN202310448930 A CN 202310448930A CN 116421556 A CN116421556 A CN 116421556A
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- budesonide
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- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 title claims abstract description 88
- 229960004436 budesonide Drugs 0.000 title claims abstract description 88
- 239000000725 suspension Substances 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 239000002245 particle Substances 0.000 claims abstract description 41
- 239000002994 raw material Substances 0.000 claims abstract description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 39
- 239000003814 drug Substances 0.000 claims abstract description 37
- 230000001954 sterilising effect Effects 0.000 claims abstract description 37
- 239000007788 liquid Substances 0.000 claims abstract description 30
- 239000000463 material Substances 0.000 claims abstract description 26
- 238000004659 sterilization and disinfection Methods 0.000 claims abstract description 26
- 239000000243 solution Substances 0.000 claims abstract description 20
- 239000008213 purified water Substances 0.000 claims abstract description 19
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims abstract description 18
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims abstract description 18
- 229940068968 polysorbate 80 Drugs 0.000 claims abstract description 18
- 229920000053 polysorbate 80 Polymers 0.000 claims abstract description 18
- 238000010008 shearing Methods 0.000 claims abstract description 18
- 238000002156 mixing Methods 0.000 claims abstract description 15
- 239000004094 surface-active agent Substances 0.000 claims abstract description 15
- 238000003756 stirring Methods 0.000 claims abstract description 14
- 238000001914 filtration Methods 0.000 claims abstract description 7
- 239000011259 mixed solution Substances 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 30
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 22
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- 239000011780 sodium chloride Substances 0.000 claims description 11
- 239000001509 sodium citrate Substances 0.000 claims description 11
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 11
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 7
- 241000289690 Xenarthra Species 0.000 claims description 7
- 229960004543 anhydrous citric acid Drugs 0.000 claims description 7
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 4
- 229960002668 sodium chloride Drugs 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 229960001790 sodium citrate Drugs 0.000 claims 1
- 238000009826 distribution Methods 0.000 abstract description 10
- 238000000265 homogenisation Methods 0.000 abstract description 5
- 230000002159 abnormal effect Effects 0.000 abstract description 3
- 230000000052 comparative effect Effects 0.000 description 22
- 239000010419 fine particle Substances 0.000 description 19
- 239000000203 mixture Substances 0.000 description 13
- 238000005303 weighing Methods 0.000 description 9
- 238000007664 blowing Methods 0.000 description 6
- 238000011049 filling Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 238000005054 agglomeration Methods 0.000 description 5
- 230000002776 aggregation Effects 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 230000003321 amplification Effects 0.000 description 4
- 229940088679 drug related substance Drugs 0.000 description 4
- 238000003199 nucleic acid amplification method Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 3
- 238000000691 measurement method Methods 0.000 description 3
- 229940097496 nasal spray Drugs 0.000 description 3
- 239000007922 nasal spray Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 208000037883 airway inflammation Diseases 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003862 glucocorticoid Substances 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 229950008882 polysorbate Drugs 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000005429 filling process Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000007970 homogeneous dispersion Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010902 jet-milling Methods 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 210000002850 nasal mucosa Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Classifications
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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
- A61K9/0012—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
-
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
-
- 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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Pharmacology & Pharmacy (AREA)
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- Engineering & Computer Science (AREA)
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- Pulmonology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
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- Dispersion Chemistry (AREA)
- Otolaryngology (AREA)
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses budesonide suspension and a preparation method thereof, wherein the budesonide suspension comprises the following steps: dissolving a prescription amount of surfactant polysorbate 80 with partially purified water, adding a prescription amount of micronized budesonide, stirring and dispersing to obtain a raw material liquid medicine, and then carrying out damp-heat sterilization; sequentially adding other auxiliary materials with the prescription amount into the purified water, adding water to a preset value after dissolving to obtain an auxiliary material solution, and then sterilizing and filtering; uniformly stirring and mixing the sterilized and filtered auxiliary material solution and the raw material liquid medicine subjected to damp-heat sterilization to obtain a mixed solution; and (3) carrying out high-speed shearing and high-pressure homogenization on the mixed solution to obtain the budesonide suspension. The invention simplifies the operation steps and reduces the risk of abnormal increase of granularity. The particle size of the budesonide suspension prepared by the invention is basically consistent with the particle size and particle size distribution of the original developer.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to budesonide suspension and a preparation method thereof.
Background
Budesonide is a high-efficiency local anti-inflammatory glucocorticoid, is one of the glucocorticoids commonly used in clinic, and can effectively control airway inflammation. The administration route of budesonide includes inhalation, oral administration, intravenous administration, etc. Wherein, inhalation administration is the preferred administration route, and the local anti-inflammatory effect of administration by the route is stronger, can effectively control airway inflammation, reduce the frequency of asthma attack and lighten the severity of the attack, and reduce the death rate.
There is a large difference between the inhaled budesonide suspension and budesonide nasal spray. The particle size requirements of the raw material medicines in the budesonide nasal spray are relatively loose, and the larger particle size is more beneficial to the adsorption of the raw material medicines on nasal mucosa, so that the treatment effect is improved. Compared with budesonide nasal spray, the particle size of the budesonide suspension (for atomization treatment) for inhalation is smaller and stricter, oversized particles are deposited in the oral cavity and the upper respiratory tract and can not be effectively deposited in the lung, and the particle size after sterilization is greatly increased, so that the particle size is difficult to recover to the state before sterilization through homogeneous dispersion. Especially, in mass production of budesonide suspension, the problem that the particle size is increased due to easy agglomeration and agglomeration of raw materials in the wet heat sterilization process is solved more difficultly than that of small-batch experiments.
The original grinding process of budesonide suspension for inhalation (patent CN 1173702C) comprises the following steps: and (3) after the micronized budesonide is subjected to dry heat sterilization, adding the micronized budesonide into the sterilized and filtered auxiliary material solution, mixing, and filling the mixture into a container through a blowing and filling system. The process has higher requirements on the sterilization process of the bulk drug and has higher risk in batch amplification.
The known preparation method of the budesonide suspension comprises the steps of mixing budesonide with part of surfactant and part of water to obtain raw material liquid medicine, and mixing the rest of auxiliary materials to obtain auxiliary material solution; the raw material liquid medicine is subjected to wet heat sterilization and then is uniformly mixed with the filtered and sterilized auxiliary material solution to obtain budesonide suspension. However, the surfactant is fed in two parts, and the operation is relatively complex.
Disclosure of Invention
The invention aims to solve the technical problems, overcome the defects and the shortcomings in the background art, provide the budesonide suspension for inhalation and the preparation method thereof, simplify the process and meet the requirement of the particle size of the budesonide suspension.
The research finds that: mixing budesonide with part of surfactant and part of water to obtain raw material liquid medicine, carrying out wet heat sterilization, and uniformly mixing the raw material liquid medicine with other filtered and sterilized auxiliary material solutions (comprising the rest surfactant and the rest water) to obtain budesonide suspension. In the process of production and amplification, if the concentration of the surfactant in the raw material liquid medicine is too low, too much water is added in the raw material liquid medicine, so that the granularity of the raw material liquid medicine is increased. And it was found that the process was not easily dispersible with budesonide and the Fine Particle Dose (FPD) was lower than the reference formulation during the operation.
In the research process of production amplification, the inventor tries to add the polysorbate 80 serving as a surfactant in one step so as to simplify the process, and researches find that if the polysorbate 80 is added at one time in the process of preparing the raw material liquid medicine, more water is needed, and the proportion of budesonide, polysorbate 80 and water in the raw material liquid medicine is ensured to be within a certain range, otherwise, agglomeration and agglomeration of the raw material medicine in the process of wet heat sterilization are inevitably caused, and the particle size is increased.
Therefore, the technical scheme provided by the invention is as follows:
a method of preparing a budesonide suspension comprising the steps of:
(1) Dissolving a prescription amount of surfactant polysorbate 80 with partially purified water, adding a prescription amount of micronized budesonide, stirring and dispersing to obtain a raw material liquid medicine, and then carrying out damp-heat sterilization;
the dosage of the partially purified water is 0.5-1% of the volume of the suspension, the mass ratio of budesonide to water in the raw material liquid medicine is 1 (10-15), and the mass ratio of polysorbate 80 to water is 1 (25-37.5);
the micronized budesonide particle size D90 is less than 5 μm and D50 is less than 2 μm;
(2) Sequentially adding other auxiliary materials with the prescription amount into the purified water, adding water to a preset value after dissolving to obtain an auxiliary material solution, and then sterilizing and filtering;
(3) Uniformly stirring and mixing the filtered and sterilized auxiliary material solution and the raw material liquid medicine subjected to damp-heat sterilization to obtain a mixed solution;
(4) The mixed solution is sheared at high speed and homogenized at high pressure to obtain the budesonide suspension;
the high-speed shearing rotating speed is 30-45 Hz, and the high-pressure homogenizing pressure is 250-350 bar.
As a further improvement, the micronized budesonide particle size D90 is less than 4 μm, D50 is less than 1.5 μm, and span is no greater than 2.5.
As a further improvement, the budesonide content in the budesonide suspension prescription is 0.25-0.5 g/L, and the polysorbate 80 content is 0.15-0.25 g/L.
As a further improvement, the other auxiliary materials comprise disodium edentate, sodium chloride, citric acid anhydrous and sodium citrate.
As a further improvement, the budesonide suspension is formulated with the following contents of disodium edetate, sodium chloride, citric acid anhydrous and sodium citrate:
as a further improvement, the wet heat sterilization temperature is above 121 ℃ and the time is not less than 12min.
As a further improvement, the high-speed shearing time is not less than 30min.
As a further improvement, the budesonide suspension is prepared in an amount of 15 to 30L at one time.
The invention also provides a budesonide suspension, which is prepared by adopting the method.
Compared with the prior art, the invention has the beneficial effects that:
the invention aims at simplifying the operation steps and reducing the risk of abnormal increase of granularity in the production and amplification process (reaching 20 kg) of the budesonide suspension for inhalation. Factors influencing the particle size and particle size distribution of the budesonide suspension are: the preparation method comprises the steps of preparing parameters such as granularity of a budesonide raw material, types of surfactants, dosage proportion of budesonide, surfactants and water in raw material liquid medicine, mixing shearing parameters, homogenizing parameters and the like, wherein all the factors are mutually influenced. The invention simplifies the process operation by adding the surfactant at one time in the process of preparing the raw material liquid medicine, but the invention brings difficulty in controlling the particle size. The invention adopts the specific surfactant polysorbate 80, strictly controls the ratio of the polysorbate 80 content to water in the raw material liquid medicine, simultaneously controls the shearing rotating speed and the homogenizing pressure within the range of the invention, and jointly controls a plurality of process parameters, so that the problem of abnormal increase of granularity in the mass production process of the invention is avoided, and the content uniformity in the tank and the blowing and filling process is improved.
Secondly, the invention increases the control range of the granularity D50 value of the bulk drug, so that the granularity distribution span is smaller, thereby ensuring the narrow granularity distribution of the bulk drug in the budesonide suspension and further improving the quality control of the granularity of the product; meanwhile, during the storage and use processes, the budesonide suspension is ensured to be easy to mix evenly, and the administration dosage is accurate.
The particle size of the budesonide suspension prepared by the invention is basically consistent with the particle size and particle size distribution of the original developer. Aerodynamic particle size distribution results showed that the fine particle dose (Fine Particle Dose, FPD) and fine particle fraction (Fine Particle Fraction, FPF) values were consistent with the original ground product and that the Population Bioequivalence (PBE) analysis results showed "PASS". The preparation provided by the invention is highly consistent with the original research result in vitro, so that a determination basis is provided for in vivo bioequivalence.
Detailed Description
The present invention will be described more fully hereinafter with reference to the preferred embodiments for the purpose of facilitating understanding of the present invention, but the scope of the present invention is not limited to the following specific embodiments.
Unless defined otherwise, all technical and scientific terms used hereinafter have the same meaning as commonly understood by one of ordinary skill in the art. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the scope of the present invention.
Unless otherwise specifically indicated, the various raw materials, reagents, instruments, equipment and the like used in the present invention are commercially available or may be prepared by existing methods.
The budesonide suspension for inhalation according to some embodiments of the present invention comprises the following components:
the preparation method of the budesonide suspension for inhalation in some embodiments of the present invention comprises the following steps:
(1) Raw material liquid medicine preparation and sterilization
In some embodiments, the budesonide drug substance is first micronized, for example, by jet milling. Preferably, the particle size of the budesonide drug substance after micronization requires a D90 of less than 5 μm, a D50 of less than 2 μm, and a span (span value) of no more than 2.5. More preferably, the particle size D90 is less than 4 μm, D50 is less than 1.5 μm and D10 is less than 1 μm.
In some embodiments, a prescribed amount of polysorbate 80 (surfactant) is dissolved with partially purified water, and then the prescribed amount of budesonide is added and stirred until completely dispersed without significant agglomeration to provide a raw medicinal solution. In some specific embodiments, the amount of the partially purified water is 0.5-1% of the volume of the suspension, the mass ratio of the budesonide to the water in the raw material liquid medicine is 1 (10-15), and the mass ratio of the polysorbate 80 to the water is 1 (25-37.5). Outside the above range, the particle size of the drug substance increases, which affects the Fine Particle Dose (FPD) and the Fine Particle Fraction (FPF). The values in the above range are also closely related to the choice of polysorbate 80 as the surfactant.
In some embodiments, the raw medical fluid is subjected to damp heat sterilization. Since budesonide is poorly soluble in water, filtration sterilization is not possible. In some embodiments, the materials are placed in a sterilization tank, and subjected to damp heat sterilization at a temperature above 121 ℃ for no less than 12min.
(2) Preparing auxiliary material solution and sterilizing
In some specific embodiments, the prescription amount of disodium edentate, sodium chloride, anhydrous citric acid and sodium citrate are sequentially added into the purified water, the weight of the purified water is fixed to a preset value after the purified water is completely dissolved, an auxiliary material solution is obtained, and then filtering and sterilizing are carried out.
(3) Mixing
In some embodiments, the auxiliary material solution and the raw material liquid medicine cooled to room temperature are stirred and mixed uniformly to obtain a mixed solution.
(4) Shearing and homogenizing
In some embodiments, the mixture is subjected to high speed shearing and high pressure homogenization to provide a suspension. In some embodiments, the shear rate is 3000 to 4500rpm (30 to 45 Hz). In some embodiments, the homogenization pressure is 250-350 bar. The particle size is too large if the high shear rate and high pressure homogenization pressure are too low, and too small if too high. Meanwhile, the shearing rotating speed and the homogenizing pressure are matched with the content of budesonide and polysorbate 80 in the prescription in the range, so that the granularity and granularity distribution of the final suspension are in proper ranges.
In some embodiments, the homogenized product is filled by a blow-fill-seal system.
Example 1
The present example provides a method for preparing budesonide suspension, wherein the various raw materials and auxiliary materials have the compositions shown in table 1 (wherein, the granularity and the granularity distribution of budesonide raw materials are d10=0.573 μm, d50=1.473 μm, d90= 4.641 μm, span value=2.21):
TABLE 1
Preparing and sterilizing raw material liquid medicine: weighing the prescription amount of polysorbate in a clean container, adding 100g of purified water into the clean container, and stirring for dissolution; weighing the prescription amount of budesonide, adding the budesonide, and stirring and dispersing the budesonide evenly; sealing the container, placing in a high pressure steam sterilizing pot, sterilizing at 121deg.C for at least 12min.
Preparing auxiliary material solution, filtering and sterilizing: adding 19.24kg of purified water into a clean stainless steel barrel, sequentially weighing sodium chloride, disodium edentate, anhydrous citric acid and sodium citrate according to a weighing table, and stirring until the sodium chloride, the disodium edentate, the anhydrous citric acid and the sodium citrate are completely dissolved; weighing to 19.90kg; the adjuvant solution was filtered through a 0.22 μm sterilizing filter.
Mixing: mixing the filtrate after filtration and sterilization with the raw material liquid medicine after damp-heat sterilization, and stirring and uniformly mixing for not less than 30min;
shearing: the suspension is sheared into a buffer tank 1 at an online high speed, the rotating speed of a high-speed shearing machine is 30Hz, and the shearing time is not less than 30min;
homogenizing: homogenizing the suspension after shearing treatment under high pressure, wherein the homogenizing pressure is 300bar;
blowing and filling and sealing: the homogenized suspension is transferred into a storage tank 2, and then is pressed into a blowing and filling system by sterile air plug, and is filled and molded.
Other examples and comparative examples
The prescription composition is the same as in example 1, the granularity of the budesonide raw material and the preparation process parameters are shown in table 2 (other parameters are the same as in example 1):
TABLE 2
Comparative example 4
The comparative example provides a preparation method of budesonide suspension, which adopts a mode of mixing an auxiliary material solution with budesonide raw material liquid medicine and then carrying out damp-heat sterilization. The particle size of the budesonide used is the same as that of example 1, and the composition of the various raw materials and auxiliary materials is shown in Table 3:
TABLE 3 Table 3
| Name of the name | Prescription of prescriptionComposition (g) |
| Budesonide | 10.0 |
| Polysorbate 80 | 4.0 |
| Edetic acid disodium salt | 2.0 |
| Sodium chloride | 170.0 |
| Citric acid anhydrous | 5.6 |
| Sodium citrate | 10.0 |
| Purified water | To 20L |
Preparing a suspension: adding 19.24kg of purified water into a clean stainless steel barrel, sequentially weighing sodium chloride, disodium edentate, anhydrous citric acid and sodium citrate according to a weighing table, and stirring until the sodium chloride, the disodium edentate, the anhydrous citric acid and the sodium citrate are completely dissolved; weighing the prescription amount of polysorbate in a clean container, adding 100g of purified water into the clean container, stirring for dissolution, weighing the prescription amount of budesonide, adding the budesonide into the clean container, stirring for uniform dispersion, transferring the mixture into an auxiliary material solution, and stirring for uniform mixing.
And (3) sterilization: sterilizing at 121 deg.c for 12min or more.
Shearing: the suspension is sheared into a buffer tank 1 at an online high speed, the rotating speed of a high-speed shearing machine is between 30Hz, and the shearing time is not less than 30min;
homogenizing: homogenizing the suspension after shearing treatment under high pressure, wherein the homogenizing pressure is 350bar;
blowing and filling and sealing: the homogenized suspension is transferred into a storage tank 2, and then is pressed into a blowing and filling system by sterile air plug, and is filled and molded.
Comparative example 5
The comparative example is to reduce the batch to 2L based on comparative example 1, and the prescription composition of each raw and auxiliary material is shown in Table 4:
TABLE 4 Table 4
| Name of the name | Prescription composition (g) |
| Budesonide | 1.0 |
| Polysorbate 80 | 0.4 |
| Edetic acid disodium salt | 0.2 |
| Sodium chloride | 17.0 |
| Citric acid anhydrous | 0.56 |
| Sodium citrate | 1.0 |
| Purified water | To 2L |
The liquid preparation process and the technological parameters are the same as those of comparative example 1.
Test experiment:
the particle sizes of examples 1 to 4 and comparative examples 1 to 5 were measured, and the results are shown in Table 5.
The particle size measurement method comprises the following steps: the particle size and particle size distribution measurement method (Chinese pharmacopoeia 2020 edition, fourth edition, general rule 0982 third method light scattering method) is adopted for wet detection.
TABLE 5
It can be seen that examples 1 to 4, having particle sizes and particle size distributions comparable to the reference formulation, have D90 even smaller, avoiding the problem of particle size increase. By comparing example 2 with example 4, it can be seen that the drug substance D90 and D50 become smaller and the suspension particle size D90 becomes significantly smaller. Comparative examples 1 to 4 have a problem of an increase in particle size. As can be seen from examples 1 and comparative examples 1 to 2, the mass ratio of budesonide to water in the raw material liquid medicine is out of the range of the present invention, and the particle size of the suspension is significantly increased. From example 1 and comparative example 3, it can be seen that the particle size decreases significantly as the shear rate and the homogenization pressure increase. From comparative examples 1 and 5, it can be seen that the particle size of the suspension increases significantly after the formulation is scaled up from 2L to 20L, indicating that the particle size control is more difficult after scale up and that the condition parameters required for scale up production and small lot experiments are different.
The Fine Particle Dose (FPD) and the Fine Particle Fraction (FPF) of examples 1 to 4 and comparative examples 1 to 5 were measured, and the results are shown in Table 6.
The fine particle dose was measured by the apparatus 3 according to the inhalation fine particle aerodynamic characteristics measurement method (the fourth edition of Chinese pharmacopoeia 2020 edition, general rule 0951).
TABLE 6
| Examples | FPD(μg) | FPF(％) |
| Example 1 | 159.190 | 37.394 |
| Example 2 | 164.653 | 35.319 |
| Comparative example 1 | 120.955 | 34.145 |
| Comparative example 2 | 144.014 | 34.745 |
| Comparative example 3 | 147.903 | 35.184 |
| Example 3 | 164.759 | 35.972 |
| Example 4 | 170.218 | 36.680 |
| Comparative example 4 | 120.955 | 34.145 |
| Comparative example 5 | 157.105 | 35.184 |
| Reference formulation | 166.007 | 36.695 |
The results of the embodiment 1-4 show that the ratio of budesonide to water in the raw material liquid medicine is in the range of 1:10-1:15, the shearing rotation speed is 30-40 Hz, the homogenizing pressure is 300-350 bar, and the dosage of the fine particles and the ratio of the fine particles of the preparation are not obvious from the reference preparation.
However, the proportion of fine particles and the dosage of fine particles in comparative examples 1 to 4 were relatively low. The result of the combination of the granularity shows that the budesonide suspension of the comparative example 4 adopts the wet heat sterilization after the auxiliary material solution is mixed with the raw material liquid medicine, the grain diameter is obviously increased, and further the dosage of the fine particles and the proportion of the fine particles are obviously reduced, the medicine quantity entering the lung is less, and the medicine effect is affected. Comparative example 5 was scaled up in bulk (comparative example 1), the formulation fine particle dose and the proportion of fine particles were significantly reduced, and the risk after batch scaling up was greater.
The foregoing is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Therefore, any simple modification, equivalent variation and modification of the above embodiments according to the technical substance of the present invention shall fall within the scope of the technical solution of the present invention.
Claims (9)
1. A process for the preparation of a budesonide suspension comprising the steps of:
(1) Dissolving a prescription amount of surfactant polysorbate 80 with partially purified water, adding a prescription amount of micronized budesonide, stirring and dispersing to obtain a raw material liquid medicine, and then carrying out damp-heat sterilization;
the dosage of the partially purified water is 0.5-1% of the volume of the suspension, the mass ratio of budesonide to water in the raw material liquid medicine is 1 (10-15), and the mass ratio of polysorbate 80 to water is 1 (25-37.5);
the micronized budesonide particle size D90 is less than 5 μm and D50 is less than 2 μm;
(2) Sequentially adding other auxiliary materials with the prescription amount into the purified water, adding water to a preset value after dissolving to obtain an auxiliary material solution, and then sterilizing and filtering;
(3) Uniformly stirring and mixing the filtered and sterilized auxiliary material solution and the raw material liquid medicine subjected to damp-heat sterilization to obtain a mixed solution;
(4) The mixed solution is sheared at high speed and homogenized at high pressure to obtain the budesonide suspension;
the high-speed shearing rotating speed is 30-45 Hz, and the high-pressure homogenizing pressure is 250-350 bar.
2. The process for the preparation of a budesonide suspension according to claim 1, wherein the micronized budesonide particle size D90 is less than 4 μm, D50 is less than 1.5 μm and the span is not more than 2.5.
3. The method for preparing a budesonide suspension according to claim 1 or 2, wherein the budesonide content in the budesonide suspension prescription is 0.25-0.5 g/L, and the polysorbate 80 content is 0.15-0.25 g/L.
4. The method of preparing budesonide suspension according to claim 1 or 2, wherein the other excipients comprise disodium edentate, sodium chloride, anhydrous citric acid and sodium citrate.
5. The method of claim 4, wherein the budesonide suspension is formulated with the following amounts of disodium edetate, sodium chloride, anhydrous citric acid, and sodium citrate:
6. the method of preparing budesonide suspension according to claim 1 or 2, wherein the wet heat sterilization temperature is above 121 ℃ for not less than 12min.
7. A process for the preparation of a budesonide suspension according to claim 1 or 2, wherein the high shear time is not less than 30min.
8. The process for the preparation of a budesonide suspension according to claim 1 or 2, wherein the budesonide suspension is prepared in an amount of 15 to 30L at a time.
9. A budesonide suspension, characterized in that the budesonide suspension is prepared by the process of any one of claims 1 to 8.
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| CN117761178A (en) * | 2023-12-01 | 2024-03-26 | 亿腾医药（苏州）有限公司 | Method for analyzing content of disodium edetate in budesonide suspension for inhalation |
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| CN114344264A (en) * | 2021-12-27 | 2022-04-15 | 湖南醇健制药科技有限公司 | Budesonide nasal spray and preparation method thereof |
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| CN113712942A (en) * | 2021-04-12 | 2021-11-30 | 上海方予健康医药科技有限公司 | Preparation method of budesonide suspension for inhalation |
| CN114344264A (en) * | 2021-12-27 | 2022-04-15 | 湖南醇健制药科技有限公司 | Budesonide nasal spray and preparation method thereof |
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| CN117761178A (en) * | 2023-12-01 | 2024-03-26 | 亿腾医药（苏州）有限公司 | Method for analyzing content of disodium edetate in budesonide suspension for inhalation |
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