CN113975236B - Voriconazole dry suspension and preparation process thereof - Google Patents
Voriconazole dry suspension and preparation process thereof Download PDFInfo
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- CN113975236B CN113975236B CN202111493290.4A CN202111493290A CN113975236B CN 113975236 B CN113975236 B CN 113975236B CN 202111493290 A CN202111493290 A CN 202111493290A CN 113975236 B CN113975236 B CN 113975236B
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- 239000000725 suspension Substances 0.000 title claims abstract description 87
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 title claims abstract description 83
- 229960004740 voriconazole Drugs 0.000 title claims abstract description 80
- 238000002360 preparation method Methods 0.000 title claims abstract description 51
- 239000002245 particle Substances 0.000 claims abstract description 42
- 239000008187 granular material Substances 0.000 claims abstract description 35
- 239000000843 powder Substances 0.000 claims abstract description 28
- 239000000080 wetting agent Substances 0.000 claims abstract description 25
- 238000001035 drying Methods 0.000 claims abstract description 20
- 239000000686 essence Substances 0.000 claims abstract description 20
- 239000003755 preservative agent Substances 0.000 claims abstract description 15
- 230000002335 preservative effect Effects 0.000 claims abstract description 15
- 239000000375 suspending agent Substances 0.000 claims abstract description 14
- 239000000945 filler Substances 0.000 claims abstract description 13
- 239000003605 opacifier Substances 0.000 claims abstract description 12
- 238000007580 dry-mixing Methods 0.000 claims abstract description 8
- 239000007864 aqueous solution Substances 0.000 claims abstract description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 45
- 238000002156 mixing Methods 0.000 claims description 25
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical group O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 22
- 229930006000 Sucrose Natural products 0.000 claims description 16
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical group [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 16
- 235000010234 sodium benzoate Nutrition 0.000 claims description 16
- 239000004299 sodium benzoate Substances 0.000 claims description 16
- 229960004106 citric acid Drugs 0.000 claims description 15
- 229960000999 sodium citrate dihydrate Drugs 0.000 claims description 14
- 229940082509 xanthan gum Drugs 0.000 claims description 14
- 239000000230 xanthan gum Substances 0.000 claims description 14
- 229920001285 xanthan gum Polymers 0.000 claims description 14
- 235000010493 xanthan gum Nutrition 0.000 claims description 14
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000005720 sucrose Substances 0.000 claims description 12
- 239000004408 titanium dioxide Substances 0.000 claims description 11
- 238000005469 granulation Methods 0.000 claims description 9
- 230000003179 granulation Effects 0.000 claims description 9
- 239000008119 colloidal silica Substances 0.000 claims description 7
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 5
- 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 3
- 125000000185 sucrose group Chemical group 0.000 claims description 3
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- 239000003814 drug Substances 0.000 abstract description 30
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- 230000000052 comparative effect Effects 0.000 description 12
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 12
- 102220042174 rs141655687 Human genes 0.000 description 10
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- 229960005196 titanium dioxide Drugs 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 229940121375 antifungal agent Drugs 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
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- 238000005550 wet granulation Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 3
- 241000223218 Fusarium Species 0.000 description 3
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- 239000003429 antifungal agent Substances 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 3
- 229960004884 fluconazole Drugs 0.000 description 3
- 229960003885 sodium benzoate Drugs 0.000 description 3
- 150000003852 triazoles Chemical class 0.000 description 3
- 229940010175 vfend Drugs 0.000 description 3
- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 description 2
- 206010017533 Fungal infection Diseases 0.000 description 2
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- 239000007787 solid Substances 0.000 description 2
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- 235000010215 titanium dioxide Nutrition 0.000 description 2
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 235000008495 Chrysanthemum leucanthemum Nutrition 0.000 description 1
- 235000000604 Chrysanthemum parthenium Nutrition 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
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- 241000233866 Fungi Species 0.000 description 1
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- 206010042938 Systemic candida Diseases 0.000 description 1
- 240000004460 Tanacetum coccineum Species 0.000 description 1
- 241000222126 [Candida] glabrata Species 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
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- 208000017773 candidemia Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 230000008686 ergosterol biosynthesis Effects 0.000 description 1
- 235000008384 feverfew Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 244000053095 fungal pathogen Species 0.000 description 1
- 238000011134 hematopoietic stem cell transplantation Methods 0.000 description 1
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- 230000002401 inhibitory effect Effects 0.000 description 1
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- 238000010902 jet-milling Methods 0.000 description 1
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- 235000020985 whole grains Nutrition 0.000 description 1
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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Abstract
The invention belongs to the field of pharmaceutical preparations, and particularly relates to voriconazole dry suspension and a preparation process thereof. The preparation process provided by the invention comprises the following steps: a) Premixing the filling agent, the suspending agent and the opacifier to obtain premix; b) Adding a wetting agent into the premix for granulating and drying to obtain dry granules; the wetting agent is an aqueous solution of a pH regulator; c) And (3) granulating the dry particles, and then carrying out dry mixing on the granulated dry particles, voriconazole powder, essence and preservative to obtain the voriconazole dry suspension. The invention designs a unique preparation process on the basis of the original medicine prescription, solves the problem of poor chemical stability of the voriconazole dry suspension, and the voriconazole dry suspension prepared by the process can be transported, stored and used at normal temperature, has low transportation and storage cost and high use convenience, and has good market prospect.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to voriconazole dry suspension and a preparation process thereof.
Background
Voriconazole, chemical name is (2r, 3s) -2- (2, 4-difluorophenyl) -3- (5-fluoro-4-pyrimidine) -1- (1H-1, 2, 4-triazol-1-yl) -2-butanol, molecular formula is C 16 H 14 F 3 N 5 O, is a second generation triazole antifungal compound.
Voriconazole is a broad spectrum triazole antifungal agent with indications including treatment of invasive aspergillosis, severe invasive infections caused by fluconazole-resistant candida species (including candida krusei), severe infections caused by podomycetes and fusarium species, and is used primarily to treat progressive, potentially life-threatening infections in immunodeficient patients. The mechanism of action of voriconazole is to inhibit the cytochrome P450-mediated demethylation of 14 α -sterols in fungi, thereby inhibiting the biosynthesis of ergosterol. In vitro experiments show that voriconazole has broad-spectrum antifungal effect. The product has antibacterial effect on Candida (including Candida krusei, candida glabrata and Candida albicans resistant strains with fluconazole resistance), and has antibacterial effect on all detected Aspergillus fungi. In addition, voriconazole has bactericidal effects in vitro against other pathogenic fungi, including those less sensitive to existing antifungal agents, such as podophyllotobacter and fusarium.
The dry suspension is a liquid preparation which is prepared by preparing insoluble medicines and appropriate auxiliary materials into powder or granules, and adding water and shaking the powder or granules to disperse the powder or granules into suspension for oral administration when the dry suspension is used. Advantages of dry suspensions include: (1) Has the characteristics of solid preparation, such as convenient carrying, convenient transportation, good stability and the like; (2) Has the advantages of liquid preparation, such as high bioavailability, convenient administration, and suitability for children and the elderly with dysphagia; (3) The dry suspension has good compliance for patients, and the dry suspension is generally added with sweetener and essence, so that the dry suspension has better taste and is easier to be accepted by patients.
Currently, voriconazole dry suspensions sold in the market are mainly of the variety of feverfew pharmaceutical products, and the trade name is Vfend (william). The specification of the medicine is 45g:3g, and packaging into 100ml High Density Polyethylene (HDPE) bottles, wherein the voriconazole concentration after adding 46ml water to prepare suspension is 40mg/ml when in use. The product is a broad-spectrum triazole antifungal agent, and is suitable for treating the following fungal infections of adults and children patients of 2 years and 2 years old or older: (1) invasive aspergillosis; (2) candidemia in non-neutropenic patients; (3) Severe invasive infections caused by fluconazole-resistant candida species (including candida krusei); (4) Severe infections caused by podophyllotoxins and fusarium. The product is mainly used for treating progressive and life-threatening fungal infection, and preventing invasive fungal infection of high-risk patients receiving allogeneic Hematopoietic Stem Cell Transplantation (HSCT). The storage condition of the medicine is that the medicine is stored in a refrigerator (2-8 ℃).
The reason why the storage condition of voriconazole is set to 2 ℃ to 8 ℃ for cold storage is that voriconazole has poor chemical stability in the suspension and is easily degraded at normal temperature to generate impurities. Therefore, it is necessary to develop a voriconazole dry suspension that can be transported, stored and used at normal temperature to reduce transportation and storage costs and improve convenience for patients in terms of stability of voriconazole.
Disclosure of Invention
In view of the above, the present invention aims to provide a voriconazole dry suspension and a preparation process thereof, wherein the voriconazole dry suspension prepared by the process of the present invention has stable chemical properties at room temperature, can be stored at room temperature, and has great advantages in transportation, storage, use, and the like.
The invention provides a preparation process of voriconazole dry suspension, which comprises the following steps:
a) Premixing the filling agent, the suspending agent and the opacifier to obtain premix;
b) Adding a wetting agent into the premix for granulating and drying to obtain dry granules; the wetting agent is an aqueous solution of a pH regulator;
c) And (3) granulating the dry particles, and then dry-mixing the granules with voriconazole powder, essence and preservative to obtain the voriconazole dry suspension.
Preferably, the D90 particle size of the voriconazole powder is less than or equal to 60 mu m.
Preferably, the D90 particle size of the voriconazole powder is less than or equal to 30 μm.
Preferably, the rotation speed of the premixing is 100-500 rpm; the pre-mixing time is 5-20 min.
Preferably, step b) is specifically:
b1 Adding a wetting agent to the premix for granulation to obtain wet granules; drying the wet granules to obtain dry granules;
or b 2) adding a wetting agent into the premix for granulating and synchronously drying to obtain dry granules.
Preferably, in the step b 1), the mixing speed of the granulated materials is 100-500 rpm; the rotating speed of the granulating cutter is 1000-2000 rpm.
Preferably, the content of the voriconazole powder in the dry suspension is 3-10 wt%; the content of the filler in the dry suspension is 86-94 wt%; the content of the suspending agent in the dry suspension is 0.4 to 0.8 weight percent; the content of the pH regulator in the dry suspension is 0.7-1.5 wt%; the content of the opacifier in the dry suspension is 0.7 to 1.5 weight percent; the content of the essence in the dry suspension is 0.05-0.5 wt%; the content of the preservative in the dry suspension is 0.2-0.6 wt%.
Preferably, the filler is sucrose; the suspending agent is xanthan gum and colloidal silicon dioxide; the pH regulator is citric acid and sodium citrate dihydrate; the opacifier is titanium dioxide; the essence is orange powder essence; the preservative is sodium benzoate.
Preferably, the content of the sucrose in the dry suspension is 86-94 wt%; the content of the xanthan gum in the dry suspension is 0.15-0.4 wt%; the content of the colloidal silicon dioxide in the dry suspension is 0.25-0.5 wt%; the content of the citric acid in the dry suspension is 0.3-0.7 wt%; the content of the sodium citrate dihydrate in the dry suspension is 0.4-0.8 wt%; the content of the titanium dioxide in the dry suspension is 0.7-1.5 wt%; the content of the orange powder essence in the dry suspension is 0.05-0.5 wt%; the content of the sodium benzoate in the dry suspension is 0.2-0.6 wt%.
The invention also provides the voriconazole dry suspension prepared by the preparation process of the technical scheme.
Compared with the prior art, the invention provides voriconazole dry suspension and a preparation process thereof. The preparation process provided by the invention comprises the following steps: a) Premixing the filler, the suspending agent and the opacifier to obtain a premix; b) Adding a wetting agent into the premix for granulating and drying to obtain dry granules; the wetting agent is an aqueous solution of a pH regulator; c) And (3) granulating the dry particles, and then dry-mixing the granules with voriconazole powder, essence and preservative to obtain the voriconazole dry suspension. The invention designs a unique preparation process on the basis of the original medicine prescription, solves the problem of poor chemical stability of the voriconazole dry suspension, and the voriconazole dry suspension prepared by the process can be transported, stored and used at normal temperature, has low transportation and storage cost and high use convenience and has good market prospect.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.
Fig. 1 is a particle size distribution diagram of voriconazole bulk drug powder with D90=28 μm provided by an embodiment of the present invention;
fig. 2 is a particle size distribution diagram of voriconazole bulk drug powder with D90=44 μm provided by an embodiment of the present invention;
fig. 3 is a particle size distribution diagram of voriconazole bulk drug powder with D90=60 μm provided by an embodiment of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention provides a preparation process of voriconazole dry suspension, which comprises the following steps:
a) Premixing the filler, the suspending agent and the opacifier to obtain a premix;
b) Adding a wetting agent into the premix for granulating and drying to obtain dry granules;
c) And (3) granulating the dry particles, and then dry-mixing the granules with voriconazole powder, essence and preservative to obtain the voriconazole dry suspension.
In the preparation process provided by the invention, in the step a), the filler is preferably sucrose; the amount of filler in the dry suspension is preferably 86 to 94wt%, and specifically may be 86wt%, 86.5wt%, 87wt%, 87.5wt%, 88wt%, 88.5wt%, 89wt%, 89.5wt%, 90wt%, 90.5wt%, 91wt%, 91.5wt%, 92wt%, 92.5wt%, 93wt%, 93.5wt%, or 94wt%, and most preferably 90wt%.
In the preparation process provided by the invention, in step a), the suspending agent is preferably xanthan gum and colloidal silica; the content of the suspending agent in the dry suspension is preferably 0.4-0.8 wt%, specifically 0.4wt%, 0.45wt%, 0.5wt%, 0.55wt%, 0.6wt%, 0.61wt%, 0.65wt%, 0.7wt%, 0.75wt% or 0.8wt%, and most preferably 0.61wt%; the content of the xanthan gum in the dry suspension is preferably 0.15-0.4 wt%, specifically 0.15wt%, 0.2wt%, 0.25wt%, 0.26wt%, 0.3wt%, 0.35wt% or 0.4wt%, and most preferably 0.26wt%; the colloidal silica is preferably present in the dry suspension in an amount of 0.25 to 0.5wt%, and may specifically be 0.25wt%, 0.3wt%, 0.35wt%, 0.4wt%, 0.45wt%, or 0.5wt%, and most preferably 0.35wt%.
In the preparation process provided by the invention, in the step a), the opacifier is preferably titanium dioxide; the amount of opacifier in the dry suspension is preferably 0.7 to 1.5wt%, and may specifically be 0.7wt%, 0.75wt%, 0.8wt%, 0.85wt%, 0.9wt%, 0.95wt%, 1wt%, 1.05wt%, 1.1wt%, 1.15wt%, 1.2wt%, 1.25wt%, 1.3wt%, 1.35wt%, 1.4wt%, 1.45wt%, or 1.5wt%, and most preferably 1wt%.
In the preparation process provided by the invention, in the step a), the particle size of the filler is preferably more than or equal to 80 meshes; the particle size of the opacifier is preferably more than or equal to 80 meshes; the particle size of the solid suspending agent in the suspending agent is preferably more than or equal to 80 meshes. In the present invention, if the particle size of each reagent does not satisfy the requirement for use, it is preferable to pulverize and sieve each reagent.
In the preparation process provided by the invention, in the step a), the rotation speed of the premixing is preferably 100-500 rpm, specifically 100rpm, 150rpm, 200rpm, 250rpm, 300rpm, 350rpm, 400rpm, 450rpm or 500rpm, and most preferably 200rpm; the pre-mixing time is preferably 5-20 min, specifically 5min, 6min, 7min, 8min, 9min, 10min, 11min, 12min, 13min, 14min, 15min, 16min, 17min, 18min, 19min or 20min, and most preferably 10min.
In the preparation process provided by the invention, in step b), the wetting agent is an aqueous solution of a pH regulator, and the content of the pH regulator in the aqueous solution is preferably 30 to 50wt%, specifically 30wt%, 32wt%, 35wt%, 37wt%, 39wt%, 40wt%, 42wt%, 45wt%, 47wt% or 50wt%, and most preferably 39wt%. In the present invention, the pH adjusting agent is preferably citric acid and sodium citrate dihydrate; the content of the pH regulator in the dry suspension is preferably 0.7 to 1.5wt%, and specifically may be 0.7wt%, 0.75wt%, 0.8wt%, 0.85wt%, 0.9wt%, 0.95wt%, 1wt%, 1.05wt%, 1.1wt%, 1.12wt%, 1.15wt%, 1.2wt%, 1.25wt%, 1.3wt%, 1.35wt%, 1.4wt%, 1.45wt%, or 1.5wt%, and most preferably is 1.12wt%; the content of the citric acid in the dry suspension is preferably 0.3-0.7 wt%, specifically 0.3wt%, 0.35wt%, 0.4wt%, 0.45wt%, 0.5wt%, 0.52wt%, 0.55wt%, 0.6wt%, 0.65wt% or 0.7wt%, and most preferably 0.52wt%; the content of the sodium citrate dihydrate in the dry suspension is preferably 0.4-0.8 wt%, specifically 0.4wt%, 0.45wt%, 0.5wt%, 0.55wt%, 0.6wt%, 0.65wt%, 0.7wt%, 0.75wt% or 0.8wt%, and most preferably 0.6wt%.
In the preparation process provided by the invention, the step b) is specifically as follows: b1 Adding a wetting agent to the premix for granulation to obtain wet granules; drying the wet granules to obtain dry granules; or b 2) adding a wetting agent into the premix for granulation and synchronous drying to obtain dry granules.
In the preparation process provided by the invention, in the step b 1), the mixing rotation speed of the granulated material is preferably 100-500 rpm, specifically 100rpm, 150rpm, 200rpm, 250rpm, 300rpm, 350rpm, 400rpm, 450rpm or 500rpm, and most preferably 200rpm; the rotation speed of the cutter for granulating is preferably 1000-2000 rpm, specifically 1000rpm, 1100rpm, 1200rpm, 1300rpm, 1400rpm, 1500rpm, 1600rpm, 1700rpm, 1800rpm, 1900rpm or 2000rpm, and most preferably 1500rpm; the time for continuing shearing and mixing after the wetting agent is added is preferably 1-5 min, specifically 1min, 1.5min, 2min, 2.5min, 3min, 3.5min, 4min, 4.5min or 5min, and most preferably 3min.
In the preparation process provided by the invention, in the step b 1), the drying temperature is preferably 40-80 ℃, specifically 40 ℃, 45 ℃,50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃ or 80 ℃, and most preferably 60 ℃.
In the preparation process provided by the present invention, if the dry granules are prepared in the manner of step b 1), the premixing and the granulation are preferably performed in a wet granulator; the drying is carried out in a fluidized bed.
In the preparation process provided by the invention, in the step b 2), the temperature rise end point temperature for granulating and synchronously drying is preferably 40-80 ℃, specifically 40 ℃, 45 ℃,50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃ or 80 ℃, and most preferably 60 ℃; the time for adding the wetting agent into the premix is preferably 5-15 ℃ lower than the end point temperature in the system temperature rising process, and specifically 5 ℃, 6 ℃, 7 ℃,8 ℃, 9 ℃,10 ℃, 11 ℃, 12 ℃, 13 ℃, 14 ℃ or 15 ℃ lower than the end point temperature; the time for continuing drying after the wetting agent is added is preferably 10-30 min, specifically 10min, 11min, 12min, 13min, 14min, 15min, 16min, 17min, 18min, 19min, 20min, 23min, 25min, 27min or 30min, and most preferably 15min.
In the preparation process provided by the present invention, if the dry granules are prepared in the manner of step b 2), the premixing, granulating and drying are preferably all carried out in a fluidized bed.
In the preparation process provided by the invention, in the step c), the whole grains are preferably sieved; the particle size of the dry granules obtained after size stabilization is preferably not less than 60 mesh.
In the preparation process provided by the present invention, in step c), the content of voriconazole powder in the dry suspension is preferably 3 to 10wt%, specifically 3wt%, 3.5wt%, 4wt%, 4.5wt%, 5wt%, 5.5wt%, 6wt%, 6.5wt%, 6.67wt%, 7wt%, 7.5wt%, 8wt%, 8.5wt%, 9wt%, 9.5wt%, or 10wt%, and most preferably 6.67wt%.
In the preparation process provided by the invention, in the step c), the D90 particle size of the voriconazole powder is preferably less than or equal to 60 μm, more preferably less than or equal to 44 μm, most preferably less than or equal to 30 μm, and most preferably less than or equal to 28 μm. In the present invention, if the particle size of the voriconazole powder does not satisfy the use requirements, the voriconazole powder is preferably subjected to jet milling.
In the preparation process provided by the invention, in the step c), the essence is preferably orange powder essence; the content of the essence in the dry suspension is preferably 0.05 to 0.5wt%, and specifically may be 0.05wt%, 0.07wt%, 0.1wt%, 0.12wt%, 0.15wt%, 0.17wt%, 0.2wt%, 0.23wt%, 0.25wt%, 0.27wt%, 0.3wt%, 0.32wt%, 0.35wt%, 0.37wt%, 0.4wt%, 0.42wt%, 0.45wt%, 0.47wt%, or 0.5wt%, and most preferably is 0.2wt%.
In the preparation process provided by the invention, in the step c), the preservative is preferably sodium benzoate; the preservative is preferably present in the dry suspension in an amount of 0.2 to 0.6wt%, and specifically may be 0.2wt%, 0.23wt%, 0.25wt%, 0.27wt%, 0.3wt%, 0.32wt%, 0.35wt%, 0.37wt%, 0.4wt%, 0.42wt%, 0.45wt%, 0.47wt%, 0.5wt%, 0.52wt%, 0.55wt%, 0.57wt%, or 0.6wt%, and most preferably 0.4wt%.
In the preparation process provided by the invention, in the step c), the particle size of the preservative is preferably larger than or equal to 80 meshes. In the present invention, if the particle size of the preservative does not satisfy the requirement for use, the preservative is preferably pulverized and sieved.
In the preparation process provided by the invention, in the step c), the rotation speed of the dry mixing is preferably 5-20 rpm, specifically 5rpm, 6rpm, 7rpm, 8rpm, 9rpm, 10rpm, 11rpm, 12rpm, 13rpm, 14rpm, 15rpm, 16rpm, 17rpm, 18rpm, 19rpm or 20rpm, and most preferably 10rpm; the dry mixing time is preferably 20-60 min, specifically 20min, 25min, 30min, 35min, 40min, 45min, 55min or 60min, and most preferably 40min; the dry blending is preferably carried out in a three-dimensional mixer.
In the preparation process provided by the invention, the preparation process preferably further comprises the following steps: and c), subpackaging the voriconazole dry suspension obtained by dry mixing in the step c).
The invention also provides the voriconazole dry suspension prepared by the preparation process of the technical scheme. The dry suspension has good chemical stability, and can be transported, stored and used at normal temperature.
The invention designs a unique preparation process on the basis of the original medicine prescription, solves the problem of poor chemical stability of the voriconazole dry suspension, and the voriconazole dry suspension prepared by the process can be transported, stored and used at normal temperature, has low transportation and storage cost and high use convenience and has good market prospect.
For the sake of clarity, the following examples and comparative examples are described in detail below.
In the following examples and comparative examples provided by the present invention, the formulations were prepared using the same formulations, and the specific formulations are shown in table 1:
table 1 prescription of voriconazole dry suspension
| Composition (I) | Function of the components | Content (wt%) | Prescription amount (g) |
| Voriconazole | Active ingredient | 6.67 | 53.36 |
| Sucrose | Filler | 90.00 | 720.00 |
| Xanthan gum | Suspending aid | 0.26 | 2.08 |
| Colloidal silica | Suspending agent | 0.35 | 2.80 |
| Citric acid | pH regulator | 0.52 | 4.16 |
| Sodium citrate dihydrate | PH regulator | 0.60 | 4.80 |
| Titanium dioxide | Light-shading agent | 1.00 | 8.00 |
| Orange flavourPowdered essence | Essence | 0.20 | 1.60 |
| Sodium benzoate | Preservative | 0.40 | 3.20 |
Example 1
The voriconazole dry suspension is prepared by adopting a total mixing process after efficient wet granulation, and the specific steps are as follows:
(1) Crushing and sieving: airflow crushing bulk drug voriconazole to a particle size D90=28 μm; pulverizing sucrose, xanthan gum and sodium benzoate, and sieving with 80 mesh sieve; the specific particle size distribution of the crushed voriconazole bulk drug is shown in table 2 and fig. 1:
TABLE 2D90=28 μm voriconazole bulk drug powder particle size distribution information table
(2) Preparing a wetting agent: citric acid and sodium citrate dihydrate were dissolved in 14g of purified water and stirred until clear for use.
(3) Premixing: the sucrose, colloidal silicon dioxide, titanium dioxide and xanthan gum are poured into a high-efficiency wet granulator and mixed for 10min at 200 rpm.
(4) And (3) granulating: keeping the material mixing speed of a granulator at 200rpm, and setting the shearing speed of a cutter at 1500rpm; spraying the wetting agent solution onto the premixed material, continuing to shear for 3min after the wetting agent is added, and discharging to obtain wet granules.
(5) And (3) drying: and (3) placing the wet granules into a fluidized bed, and carrying out boiling drying at the air inlet temperature of 60 ℃ to obtain dry granules.
(6) Straightening: the dried granules were sieved through a 60 mesh sieve to remove agglomerated material.
(7) Total mixing: adding voriconazole, essence, sodium benzoate and the above-mentioned whole granule into a three-dimensional mixer, mixing for 40min under 10 rpm.
(8) Subpackaging: subpackaging with a subpackaging machine, wherein each bottle contains 45g.
Example 2
The technical process of preparing the voriconazole dry suspension by adopting the efficient wet granulation process is the same as that of the example 1, and the difference is only that the bulk drug voriconazole is airflow-pulverized to the particle size D90=44 μm; the specific particle size distribution of the crushed voriconazole bulk drug is shown in table 3 and fig. 2:
table 3 table of particle size distribution information of voriconazole bulk drug powder of d90=44 μm
Example 3
The technical process of preparing the voriconazole dry suspension by adopting the efficient wet granulation process is the same as that of the example 1, and the difference is only that the bulk drug voriconazole is airflow-pulverized to the particle size D90=60 μm; the specific particle size distribution of the crushed voriconazole bulk drug is shown in table 4 and fig. 3:
table 4d90=60 μm voriconazole bulk drug powder particle size distribution information table
Example 4
The voriconazole dry suspension is prepared by adopting a total mixing process after fluidized bed granulation, and the preparation method comprises the following specific steps:
(1) Crushing and sieving: airflow crushing the bulk drug voriconazole to a particle size of D90=22 μm (the specific particle size distribution is shown in Table 2 and figure 1); the cane sugar, the xanthan gum and the sodium benzoate are crushed and sieved by a 80-mesh sieve for standby.
(2) Preparing a wetting agent: dissolving citric acid and sodium citrate in 14g of purified water, and stirring until the solution is clear for later use.
(3) Premixing: placing sucrose, colloidal silicon dioxide, titanium dioxide and xanthan gum in a fluidized bed, setting the air inlet temperature at 60 ℃, starting a fan, and preparing for one-step granulation.
(4) Granulating and synchronously drying: spraying a wetting agent when the temperature of the material rises to about 50 ℃; after the wetting agent was added, drying was continued for 15min to obtain dry granules.
(5) Straightening: the dried granules were sieved through a 60 mesh sieve to remove agglomerated material.
(6) Total mixing: adding voriconazole, essence, sodium benzoate and the above-mentioned materials into a three-dimensional mixer, mixing together at 10rpm for 40min.
(7) Subpackaging: subpackaging with a subpackaging machine, wherein each bottle contains 45g.
Comparative example 1
In the case of the preparation method, the voriconazole dry suspension is prepared by adopting a common direct mixing process, and the preparation method comprises the following specific steps:
(1) Crushing and sieving: airflow crushing bulk drug voriconazole to a particle size of D90=28 μm (the specific particle size distribution is shown in table 2 and fig. 1); the cane sugar, the citric acid, the sodium citrate dihydrate and the sodium benzoate are crushed and sieved by a 80-mesh sieve for standby.
(2) Premixing: sucrose, xanthan gum, citric acid, sodium citrate dihydrate, titanium dioxide and colloidal silica were placed in a three-dimensional mixer and mixed for 40min at 10 rpm.
(3) Total mixing: adding voriconazole benzene, sodium benzoate and essence into the above three-dimensional mixer, and mixing for 40min.
(4) Sieving: the material was taken out and sieved through a 40 mesh sieve.
(5) And (3) remixing: the sieved materials were again placed in the three-dimensional mixer and mixed together at 10rpm for 20min.
(6) Subpackaging: subpackaging with a subpackaging machine, wherein each bottle contains 45g.
Comparative example 2
In this case, the voriconazole dry suspension is prepared by a high shear mixing process, which comprises the following specific steps:
(1) Crushing and sieving: airflow crushing the bulk drug voriconazole to a particle size of D90=28 μm (the specific particle size distribution is shown in Table 2 and figure 1); the cane sugar, the citric acid, the sodium citrate dihydrate and the sodium benzoate are crushed and sieved by a 80-mesh sieve for standby.
(2) Premixing: the sucrose, xanthan gum, citric acid, sodium citrate dihydrate, titanium dioxide, sodium benzoate and colloidal silica were placed in a high performance wet granulator and mixed for 10min at 200 rpm.
(3) Shearing: mixing at 200rpm and shearing at 1500rpm for 30min in the same high-efficiency wet granulator.
(4) Total mixing: the materials, voriconazole and essence are added into a three-dimensional mixer and mixed together for 40min at 10 rpm.
(5) Sieving: the material was taken out and sieved with 40 mesh sieve.
(6) And (3) remixing: the sieved material was again placed in the three-dimensional mixer and mixed together at 10rpm for 20min.
(7) Subpackaging: subpackaging with a subpackaging machine, wherein each bottle contains 45g.
Comparative example 3
The voriconazole dry suspension is prepared by adopting a co-crushing and mixing process, and the preparation method comprises the following specific steps:
(1) Crushing and sieving: airflow crushing the bulk drug voriconazole to a particle size of D90=28 μm (the specific particle size distribution is shown in Table 2 and figure 1); the cane sugar, the citric acid, the sodium citrate dihydrate and the sodium benzoate are crushed and sieved by a 80-mesh sieve for standby.
(2) Premixing: the sucrose, xanthan gum, citric acid, sodium citrate dihydrate, titanium dioxide, sodium benzoate and colloidal silica were placed in a three-dimensional mixer and mixed for 10min at 10 rpm.
(3) Crushing: taking out the materials from the three-dimensional mixer, and co-pulverizing the materials in a pulverizer for 15min.
(4) Total mixing: adding the materials, voriconazole and essence into a three-dimensional mixer, and mixing for 40min at 10 rpm.
(5) Sieving: the material was taken out and sieved through a 40 mesh sieve.
(6) And (3) remixing: the sieved material was again placed in the three-dimensional mixer and mixed together at 10rpm for 20min.
(7) Subpackaging: subpackaging with a subpackaging machine, wherein each bottle contains 45g.
Stability survey
Samples obtained in the above examples and comparative examples are all sampled and examined at a high temperature of 60 ℃, and are respectively sampled with 0, 5, 10 and 30 days; simultaneously, sampling at 30 ℃ in 0, 1,2, 3 and 6 months, and inspecting the stability of the sample; meanwhile, the Vfend of the original medicine of the commercial preparation is considered at the same time for comparison study, and the specific results are shown in tables 5 and 6:
TABLE 5 comparison of impurities in samples at 60 deg.C
TABLE 6 comparison of impurities in samples at 30 deg.C
As can be seen from tables 5 to 6, compared with the commercially available medicine Vblend and comparative examples 1 to 3, the stability of the examples 1 to 4 under the harsh condition of 60 ℃ and the room temperature of 30 ℃ is greatly improved, and the impurity water level is obviously reduced; the adoption of fluidized bed granulation (example 4) has the disadvantages of relatively low stability, easy blockage of dustproof filter bags due to material subdivision in the preparation process and the like, so the high-efficiency wet granulation process (examples 1 to 3) is preferred in the invention.
Investigation of dissolution behavior
3g of the samples obtained in the above examples and comparative examples were dissolved in 900mL of a medium with pH =1.0, and the dissolution rate was calculated; the original drug Vfend of the commercially available formulation was also examined for comparative studies, and the specific results are shown in table 7:
TABLE 7 dissolution rate of samples in pH =1.0 medium (Paddle method, 50 rpm)
As can be seen from table 7, the particle size of the bulk drug has a large influence on the dissolution behavior. When the particle size of the bulk drug is controlled to be less than or equal to 30 mu m (such as comparative example 1, comparative example 2, comparative example 3, example 1 and example 4), the dissolution behavior of the suspension is very close to that of a commercially available product Venden; with the increase of the particle size of the bulk drug (44 μm and 60 μm for D90 of the bulk drug in examples 2 and 3, respectively), the dissolution gradually becomes slow, even the dissolution is incomplete, and the dissolution of example 3 is even lower than 80%.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (6)
1. A preparation process of voriconazole dry suspension comprises the following steps:
a) Premixing the filling agent, the suspending agent and the opacifier to obtain premix;
b) Adding a wetting agent into the premix for granulating and drying to obtain dry granules; the wetting agent is an aqueous solution of a pH regulator;
c) After finishing the particles, dry-mixing the particles with voriconazole powder, essence and preservative to obtain voriconazole dry suspension;
the content of the voriconazole powder in the dry suspension is 3-10wt%; the content of the filler in the dry suspension is 86-94wt%; the content of the suspending agent in the dry suspension is 0.4 to 0.8wt%; the content of the pH regulator in the dry suspension is 0.7 to 1.5wt%; the content of the opacifier in the dry suspension is 0.7 to 1.5wt%; the content of the essence in the dry suspension is 0.05 to 0.5wt%; the content of the preservative in the dry suspension is 0.2 to 0.6wt%;
the D90 particle size of the voriconazole powder is less than or equal to 30 mu m; the filler is sucrose; the suspending agent is xanthan gum and colloidal silica; the pH regulator is citric acid and sodium citrate dihydrate; the opacifier is titanium dioxide; the essence is orange powder essence; the preservative is sodium benzoate.
2. The preparation process according to claim 1, wherein the rotation speed of the pre-mixing is 100 to 500rpm; the pre-mixing time is 5 to 20min.
3. The preparation process according to claim 1, wherein step b) is specifically:
b1 Adding a wetting agent to the premix for granulation to obtain wet granules; drying the wet granules to obtain dry granules;
or b 2) adding a wetting agent into the premix for granulation and synchronous drying to obtain dry granules.
4. The preparation process according to claim 3, wherein in the step b 1), the mixing speed of the granulated material is 100 to 500rpm; the rotation speed of a cutter for granulating is 1000 to 2000rpm.
5. The preparation process of claim 1, wherein the sucrose content in the dry suspension is 86-94wt%; the content of the xanthan gum in the dry suspension is 0.15-0.4 wt%; the content of the colloidal silicon dioxide in the dry suspension is 0.25 to 0.5wt%; the content of the citric acid in the dry suspension is 0.3 to 0.7wt%; the content of the sodium citrate dihydrate in the dry suspension is 0.4 to 0.8wt%; the content of the titanium dioxide in the dry suspension is 0.7 to 1.5wt%; the content of the orange powder essence in the dry suspension is 0.05 to 0.5wt%; the content of the sodium benzoate in the dry suspension is 0.2 to 0.6wt%.
6. Voriconazole dry suspension prepared by the preparation process according to any one of claims 1 to 5.
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Denomination of invention: A dry suspension of fluconazole and its preparation process Effective date of registration: 20231122 Granted publication date: 20230331 Pledgee: Huaxia Bank Co.,Ltd. Haikou Branch Pledgor: Hainan xinkaiyuan Pharmaceutical Technology Co.,Ltd. Registration number: Y2023980067130 |