CN110812334A - Voriconazole pharmaceutical composition for injection and preparation method thereof - Google Patents
Voriconazole pharmaceutical composition for injection and preparation method thereof Download PDFInfo
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- CN110812334A CN110812334A CN201911219114.4A CN201911219114A CN110812334A CN 110812334 A CN110812334 A CN 110812334A CN 201911219114 A CN201911219114 A CN 201911219114A CN 110812334 A CN110812334 A CN 110812334A
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- voriconazole
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- pharmaceutical composition
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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
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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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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- 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
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- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
Abstract
The invention relates to a voriconazole pharmaceutical composition for injection and a preparation method thereof, belonging to the field of chemical bulk drug manufacturing, the active ingredients of the voriconazole pharmaceutical composition for injection and the preparation method thereof are provided, the active ingredients comprise voriconazole and hydroxypropyl- β -cyclodextrin, the pharmaceutical composition adopts an aqueous solution of hydroxypropyl- β -cyclodextrin to perform inclusion with an acid solution of voriconazole, mannitol is added and then stirred to be dissolved, a sodium hydroxide solution is used for adjusting the pH value, activated carbon adsorption, decarburization, microfiltration membrane fine filtration, and split charging and freeze drying are performed after a semi-finished product is inspected to be qualified, and the pharmaceutical composition is clinically provided with a chemical raw material pharmaceutical preparation for treating invasive fungal infection with good solubility and high stability.
Description
The invention relates to a voriconazole pharmaceutical composition for injection and a preparation method thereof, belonging to the field of chemical bulk drug preparation.
Background
In recent years, with the wide application of high-efficiency broad-spectrum antibiotics, immunosuppressants and anti-malignant tumor drugs, the intensive development of organ transplantation, catheter technology and other surgical intervention treatments, particularly the emergence of AIDS, the increase of systemic mycosis caused by conditionally pathogenic fungi, the continuous emergence of new pathogenic bacteria and the gradual increase of disease conditions. Mainly comprises candidiasis, aspergillosis, cryptococcosis, zygomycosis, marneffeta penicilliosis and the like. The clinical symptoms and signs of invasive fungal infection are not specific, an effective diagnostic tool is lacked, the disease course is fast to progress, and the prognosis is poor, so that the clinical symptoms and signs of invasive fungal infection become a big problem for clinicians. Meanwhile, the emergence of drug-resistant bacteria is a challenge for drug development. The drugs commonly used in clinical practice for treating fungal infections at present are: miconazole, fluconazole, voriconazole, flucytosine and the like, wherein voriconazole has become a first choice medicament for clinically treating invasive fungal infection.
Voriconazole is a derivative of fluconazole which is a triazole antifungal drug, and the triazole antifungal drug inhibits the conversion of lanosterol into ergosterol by inhibiting lanosterol-demethylase which is dependent on fungal cytochrome P450, so that the ergosterol on a fungal cell membrane is absent due to the synthesis inhibition of the ergosterol. Ergosterol is an important component constituting fungal cell membrane, and plays an important role in maintaining fluidity, biological regulation, and steric structure of cell membrane. The loss of ergosterol disrupts the integrity of the fungal cell, thereby affecting the fluidity, permeability and activity of many enzymes on the cell membrane, ultimately leading to fungal death. Meanwhile, the selectivity of voriconazole on fungal cytochrome P450 enzyme is higher than that of various mammals.
Clinically, the creation of a new formulation of voriconazole capable of intravenous administration has become an important issue due to the need of treatment of acute and severe fungal infections. Voriconazole has low solubility in water (0.2mg/mL, pH 3) and is unstable (recombines into an inactive enantiomer from hydrolysis of the retro-aldol product). Therefore, it is difficult to develop an intravenous aqueous preparation having a sufficiently long shelf life. This means that the compound cannot be dissolved by conventional means such as oils, surfactants or cosolvents. Thus, the instability and poor solubility of voriconazole are a problem in formulation. In addition, the voriconazole freeze-dried powder injection for injection on the market at present has the problems of poor stability, unstable diluent, easy precipitation and low purity.
Disclosure of Invention
The invention provides a voriconazole pharmaceutical composition for injection and a preparation method thereof, and provides an effective, safe and stable fungal therapeutic drug for clinic.
A voriconazole pharmaceutical composition for injection mainly comprises voriconazole, hydroxypropyl- β -cyclodextrin diluent, pH regulator and water for injection.
Further, the mass ratio of voriconazole to hydroxypropyl- β -cyclodextrin in the voriconazole pharmaceutical composition for injection is 1: 5-40, and the mass ratio of voriconazole to diluent is 1: 40-75.
Further, the voriconazole pharmaceutical composition for injection contains a diluent selected from one or more of mannitol, lactose, dextran, glucose, glycine, hydrolyzed gelatin or povidone.
A preparation method of the voriconazole pharmaceutical composition for injection comprises the following specific operations:
a. adding hydroxypropyl- β -cyclodextrin into water for injection, and stirring to dissolve hydroxypropyl- β -cyclodextrin completely;
b. dissolving voriconazole with hydrochloric acid, controlling the temperature, adding the voriconazole into a well-dissolved hydroxypropyl- β -cyclodextrin water solution, and stirring while adding until the voriconazole is completely included;
c. adding mannitol into the above inclusion solution, stirring for dissolving; adjusting the pH value of the solution back by using a NaOH solution, and adjusting the pH value; continuously adding water for injection to adjust the concentration;
d. filtering to remove carbon, and fine filtering with microporous membrane;
e. and (5) freeze-drying.
6. The preparation method of voriconazole pharmaceutical composition for injection according to claim 4, which is characterized by comprising the following steps of a, 30-70% of water for injection, 400-800 g of hydroxypropyl- β -cyclodextrin;
b. 50-60 g of voriconazole and 250-300 mL of 2M hydrochloric acid, controlling the temperature at 30-50 ℃, and stirring for 30-60 minutes;
c. 200g to 240g of mannitol and 2M NaOH solution, and adjusting the pH value to 5.0 to 6.0;
d. preparing active carbon (for injection) with the liquid amount and the mass fraction of 0.01-0.05%, stirring for 10-20 minutes at the temperature of 45-55 ℃, and finely filtering by a microporous filter membrane of 0.20-0.22 micron;
f. performing clarity inspection; inspecting the semi-finished product;
g. filling the liquid medicine into a sterile antibiotic glass product after the clarity inspection is qualified;
h. freeze-drying in a freeze dryer:
h1, pre-freezing: setting the temperature of the heat conducting oil (shelf) of the freeze dryer to be about-55 ℃, starting the freeze dryer to refrigerate, reducing the temperature of the product to about-40 ℃, and preserving the heat for about 5 hours.
h2, sublimation drying: after the heat preservation is finished, vacuumizing and heating the partition plate are started, the temperature is increased from minus 40 ℃ to minus 25 ℃ at the rate of not higher than 13 ℃ per hour, and sublimation drying is carried out.
h3, heating and drying 1: the temperature of the shelf is gradually increased, and the drying is carried out at the temperature increasing rate of not higher than 25 ℃ per hour, and the temperature is increased to about 10 ℃.
h4, heating and drying 2: and (3) rapidly heating the shelf, drying at a heating rate of not higher than 30 ℃ per hour, heating from-10 ℃ to 60 ℃, and keeping the temperature at about 60 ℃ for about 4 hours.
i. After freeze-drying, plugging and capping;
j. and (6) fully inspecting the finished product, and packaging and warehousing.
Further, the effects of the components are as follows:
(1) voriconazole: a pharmaceutical ingredient, a triazole broad-spectrum antifungal agent;
(2) hydroxypropyl- β -cyclodextrin, a solubilizer;
(3) mannitol: a diluent;
(4) 2M hydrochloric acid: a solvent;
(5) 2M NaOH: a pH adjusting agent;
furthermore, the voriconazole pharmaceutical composition for injection can be used for intravenous injection or intramuscular injection.
Further, in the technical scheme, the content determination method of the voriconazole which is not included by the hydroxypropyl- β -cyclodextrin comprises the steps of taking a proper amount of inclusion compound solution, adding ethyl acetate with the same volume to quickly extract the non-included free voriconazole in the solution, determining the content of the free voriconazole after separation, and calculating the amount of the non-included voriconazole.
Calculating the inclusion rate according to the formulas (1) and (2):
(1): amount of voriconazole in the clathrate (g) ═ total amount of voriconazole added (g) — amount of voriconazole that was not included (g)
(2): inclusion rate/% (amount of voriconazole in the clathrate (g)/total amount of voriconazole added (g) × 100 ×
And if the inclusion rate reaches over 90.0 percent, judging that the voriconazole is completely included in the hydroxypropyl- β -cyclodextrin aqueous solution.
Advantageous effects
The inventor effectively improves the solubility and stability of voriconazole by adjusting the proportion of voriconazole and hydroxypropyl- β -cyclodextrin and the quality control of the product encapsulation rate, achieves the effect that the product diluent is stable and does not separate out, and solves the problems that the commercially available voriconazole freeze-dried powder injection for injection has poor stability, the diluent is unstable and is easy to separate out and the like, thereby obtaining a stable and uniform inclusion compound and ensuring the quality of the product.
Detailed Description
Comparative example (Sichuan Dameikanghua pharmaceutical Co., Ltd., batch No. 11110201, specification: 0.1g, solvent for exclusive use: 5mL)
Example 1 (specification 50mg)
The weight of each component in the prescription for preparing 1000 voriconazole pharmaceutical compositions for injection is as follows:
| name (R) | Dosage of |
| Lying on the groundKenazole | 50g |
| Hydroxypropyl- β -cyclodextrin | 400g |
| Mannitol | 200g |
| 2M hydrochloric acid | 250mL |
| 2M NaOH (adjusting pH to 5.5) | - |
| Water for injection | 5L |
The preparation process comprises the following steps:
weighing 30% of injection water, adding 400g of hydroxypropyl- β -cyclodextrin, stirring to completely dissolve hydroxypropyl- β -cyclodextrin, precisely weighing 50g of voriconazole, dissolving the voriconazole by 250mL of 2M hydrochloric acid, controlling the temperature to 40 ℃, adding the voriconazole into a well-dissolved hydroxypropyl- β -cyclodextrin aqueous solution, stirring while adding, continuing stirring for 30 minutes to completely include the voriconazole, precisely weighing 200g of mannitol, adding the mannitol into the above-mentioned mixture, stirring to dissolve, adjusting the pH value of the above-mentioned solution back by using 2M NaOH solution to about 5.5, continuing adding injection water to full amount, adding 0.05% of active carbon (for injection), keeping the temperature for 10 minutes, filtering to remove carbon, fine-filtering by using a 0.22 micron microporous filter membrane, checking the clarity, checking semi-finished product, checking the clarity, filling the liquid medicine into an antibiotic glass product after the clarity check is qualified, freeze-drying in a freeze-drying machine, adding a stopper, capping, packaging, checking the finished product, and filling into a roll warehouse.
Example 2 (specification 50mg)
The weight of each component in the prescription for preparing 1000 voriconazole pharmaceutical compositions for injection is as follows:
| name (R) | Dosage of |
| Voriconazole | 50g |
| Hydroxypropyl- β -cyclodextrin | 450g |
| Mannitol | 205g |
| 2M hydrochloric acid | 250mL |
| 2M NaOH (adjusting pH to 5.5) | - |
| Water for injection | 5L |
The preparation process comprises the following steps:
weighing 30% of injection water, adding 450g of hydroxypropyl- β -cyclodextrin, stirring to completely dissolve hydroxypropyl- β -cyclodextrin, precisely weighing 50g of voriconazole, dissolving the voriconazole by 250mL of 2M hydrochloric acid, controlling the temperature to 40 ℃, adding the voriconazole into a well-dissolved hydroxypropyl- β -cyclodextrin aqueous solution, stirring while adding, continuing stirring for 30 minutes to completely include the voriconazole, precisely weighing 205g of mannitol, adding the mannitol into the above-mentioned mixture, stirring to dissolve, adjusting the pH value of the above-mentioned solution back by using 2M NaOH solution to about 5.5, continuing adding injection water to full amount, adding 0.05% of active carbon (for injection), keeping the temperature for 10 minutes, filtering to remove carbon, fine filtering by using a 0.22 micron microporous filter membrane, checking the clarity, checking the semi-finished product, checking the clarity, filling the liquid medicine into an antibiotic glass product after the clarity check is qualified, freeze-drying in a freeze-drying machine, adding a stopper, covering, packaging, checking the finished product, and filling into a roll warehouse.
Example 3 (specification 50mg)
The weight of each component in the prescription for preparing 1000 voriconazole pharmaceutical compositions for injection is as follows:
| name (R) | Dosage of |
| Voriconazole | 50g |
| Hydroxypropyl- β -cyclodextrin | 500g |
| Mannitol | 210g |
| 2M hydrochloric acid | 250mL |
| 2M NaOH (adjusting pH to 5.5) | - |
| Water for injection | 5L |
The preparation process comprises the following steps:
weighing 40% of injection water, adding 500g of hydroxypropyl- β -cyclodextrin, stirring to completely dissolve hydroxypropyl- β -cyclodextrin, precisely weighing 50g of voriconazole, dissolving the voriconazole by 250mL of 2M hydrochloric acid, controlling the temperature to 50 ℃, adding the voriconazole into a well-dissolved hydroxypropyl- β -cyclodextrin aqueous solution, stirring while adding, continuing stirring for 20 minutes to completely include the voriconazole, precisely weighing 210g of mannitol, adding the mannitol into the above-mentioned mixture, stirring to dissolve, adjusting the pH value of the above-mentioned solution back by using 2M NaOH solution to about 5.5, continuing adding injection water to full amount, adding 0.05% of active carbon (for injection), keeping the temperature for 10 minutes, filtering to remove carbon, fine-filtering by using a 0.22 micron microporous filter membrane, checking the clarity, checking semi-finished product, checking the clarity, filling the liquid medicine into an antibiotic glass product after the clarity check is qualified, freeze-drying in a freeze-drying machine, adding a stopper, covering, packaging, checking the finished product, and filling into a roll-in a warehouse.
Example 4 (specification 50mg)
The weight of each component in the prescription for preparing 1000 voriconazole pharmaceutical compositions for injection is as follows:
| name (R) | Dosage of |
| Voriconazole | 50g |
| Hydroxypropyl- β -cyclodextrin | 550g |
| Mannitol | 220g |
| 2M hydrochloric acid | 250mL |
| 2M NaOH (adjusting pH to 5.5) | - |
| Water for injection | 5L |
The preparation process comprises the following steps:
weighing 50% of injection water, adding 550g of hydroxypropyl- β -cyclodextrin, stirring to completely dissolve hydroxypropyl- β -cyclodextrin, precisely weighing 50g of voriconazole, dissolving the voriconazole by 250mL of 2M hydrochloric acid, controlling the temperature to 40 ℃, adding the voriconazole into a well-dissolved hydroxypropyl- β -cyclodextrin aqueous solution, stirring while adding, continuing to stir for 40 minutes to completely wrap the voriconazole, precisely weighing 220g of mannitol, adding the mannitol into the above-mentioned wrapping liquid, stirring to dissolve, adjusting the pH value of the above-mentioned solution back by using 2M NaOH solution to about 5.5, continuing to add injection water to full dose, adding 0.05% of active carbon (for injection), keeping the temperature for 10 minutes, filtering to remove carbon, fine filtering by using a 0.22 micron microporous filter membrane, checking the clarity, checking semi-finished product, checking the clarity, filling the liquid medicine into an antibiotic glass product after the clarity check is qualified, freeze-drying, filling the freeze-dried product into a freeze-drying machine, capping, packaging, and checking the finished product, and filling and warehousing.
Example 5 (specification 50mg)
The weight of each component in the prescription for preparing 1000 voriconazole pharmaceutical compositions for injection is as follows:
| name (R) | Dosage of |
| Voriconazole | 50g |
| Hydroxypropyl- β -cyclodextrin | 600g |
| Mannitol | 230g |
| 2M hydrochloric acid | 250mL |
| 2M NaOH (adjusting pH to 5.5) | - |
| Water for injection | 5L |
The preparation process comprises the following steps:
weighing 60% of injection water, adding 600g of hydroxypropyl- β -cyclodextrin, stirring to completely dissolve hydroxypropyl- β -cyclodextrin, precisely weighing 50g of voriconazole, dissolving the voriconazole by 250mL of 2M hydrochloric acid, controlling the temperature to be 30 ℃, adding the voriconazole into a well-dissolved hydroxypropyl- β -cyclodextrin aqueous solution, stirring while adding, continuing stirring for 30 minutes to completely include the voriconazole, precisely weighing 230g of mannitol, adding the mannitol into the above-mentioned mixture, stirring to dissolve, adjusting the pH value of the above-mentioned solution back by using 2M NaOH solution to about 5.5, continuing adding injection water to full amount, adding 0.05% of active carbon (for injection), keeping the temperature for 10 minutes, filtering to remove carbon, fine-filtering by using a 0.22 micron microporous filter membrane, checking the clarity, checking semi-finished product, checking the clarity, filling the liquid medicine into an antibiotic glass product after the clarity check is qualified, freeze-drying, filling the freeze-dried antibiotic glass product into a freeze-drying machine, capping, packaging, and packaging the finished product.
Example 6 (specification 50mg)
The weight of each component in the prescription for preparing 1000 voriconazole pharmaceutical compositions for injection is as follows:
| name (R) | Dosage of |
| Voriconazole | 50g |
| Hydroxypropyl- β -cyclodextrin | 650g |
| Mannitol | 240g |
| 2M hydrochloric acid | 250mL |
| 2M NaOH (adjusting pH to 5.5) | - |
| Water for injection | 5L |
The preparation process comprises the following steps:
weighing 70% of injection water, adding 650g of hydroxypropyl- β -cyclodextrin, stirring to completely dissolve hydroxypropyl- β -cyclodextrin, precisely weighing 50g of voriconazole, dissolving the voriconazole by 250mL of 2M hydrochloric acid, controlling the temperature to 50 ℃, adding the voriconazole into a well-dissolved hydroxypropyl- β -cyclodextrin aqueous solution, stirring while adding, continuing to stir for 40 minutes to completely wrap the voriconazole, precisely weighing 240g of mannitol, adding the mannitol into the above-mentioned wrapping liquid, stirring to dissolve, adjusting the pH value of the above-mentioned solution back by using 2M NaOH solution to about 5.5, continuing to add injection water to full dose, adding 0.05% of active carbon (for injection), keeping the temperature for 10 minutes, filtering to remove carbon, fine filtering by using a 0.22 micron microporous filter membrane, checking the clarity, checking semi-finished product, checking the clarity, filling the liquid medicine into an antibiotic glass product after the clarity check is qualified, freeze-drying, filling the freeze-dried product into a freeze-drying machine, capping, packaging, and rolling and warehousing.
Example 7 (specification 50mg)
The weight of each component in the prescription for preparing 1000 voriconazole pharmaceutical compositions for injection is as follows:
| name (R) | Dosage of |
| Voriconazole | 50g |
| Hydroxypropyl- β -cyclodextrin | 700g |
| Mannitol | 245g |
| 2M hydrochloric acid | 250mL |
| 2M NaOH (adjusting pH to 5.5) | - |
| Water for injection | 5L |
The preparation process comprises the following steps:
weighing 70% of injection water, adding 700g of hydroxypropyl- β -cyclodextrin, stirring to completely dissolve hydroxypropyl- β -cyclodextrin, precisely weighing 50g of voriconazole, dissolving the voriconazole by 250mL of 2M hydrochloric acid, controlling the temperature to 50 ℃, adding the voriconazole into a well-dissolved hydroxypropyl- β -cyclodextrin aqueous solution, stirring while adding, continuing to stir for 40 minutes to completely wrap the voriconazole, precisely weighing 245g of mannitol, adding the mannitol into the above-mentioned wrapping liquid, stirring to dissolve, adjusting the pH value of the above-mentioned solution back by using 2M NaOH solution to about 5.5, continuing to add injection water to full dose, adding 0.05% of active carbon (for injection), keeping the temperature for 10 minutes, filtering to remove carbon, fine filtering by using a 0.22 micron microporous filter membrane, checking the clarity, checking semi-finished product, checking the clarity, filling the liquid medicine into an antibiotic glass product after the clarity check is qualified, freeze-drying, filling the freeze-dried antibiotic glass product into a freeze-drying machine, capping, packaging, and checking the finished product, and filling and warehousing.
Example 8 (specification 50mg)
The weight of each component in the prescription for preparing 1000 voriconazole pharmaceutical compositions for injection is as follows:
the preparation process comprises the following steps:
weighing 70% of injection water, adding 750g of hydroxypropyl- β -cyclodextrin, stirring to completely dissolve hydroxypropyl- β -cyclodextrin, precisely weighing 50g of voriconazole, dissolving the voriconazole by 250mL of 2M hydrochloric acid, controlling the temperature to 50 ℃, adding the voriconazole into a well-dissolved hydroxypropyl- β -cyclodextrin aqueous solution, stirring while adding, continuing to stir for 40 minutes to completely wrap the voriconazole, precisely weighing 250g of mannitol, adding the mannitol into the above-mentioned wrapping liquid, stirring to dissolve, adjusting the pH value of the above-mentioned solution back by using 2M NaOH solution to about 5.5, continuing to add injection water to full dose, adding 0.05% of active carbon (for injection), keeping the temperature for 10 minutes, filtering to remove carbon, fine filtering by using a 0.22 micron microporous filter membrane, checking the clarity, checking semi-finished product, checking the clarity, filling the liquid medicine into an antibiotic glass product after the clarity check is qualified, freeze-drying, filling the freeze-dried antibiotic glass product into a freeze-drying machine, capping, packaging, and packaging the finished product.
Example 9 (specification 50mg)
The weight of each component in the prescription for preparing 1000 voriconazole pharmaceutical compositions for injection is as follows:
| name (R) | Dosage of |
| Voriconazole | 50g |
| Hydroxypropyl- β -cyclodextrin | 800g |
| Mannitol | 260g |
| 2M hydrochloric acid | 250mL |
| 2M NaOH (adjusting pH to 5.5) | - |
| Water for injection | 5L |
The preparation process comprises the following steps:
weighing 70% of injection water, adding 800g of hydroxypropyl- β -cyclodextrin, stirring to completely dissolve hydroxypropyl- β -cyclodextrin, precisely weighing 50g of voriconazole, dissolving the voriconazole by 250mL of 2M hydrochloric acid, controlling the temperature to 50 ℃, adding the voriconazole into a well-dissolved hydroxypropyl- β -cyclodextrin aqueous solution, stirring while adding, continuing to stir for 40 minutes to completely wrap the voriconazole, precisely weighing 260g of mannitol, adding the mannitol into the above-mentioned wrapping liquid, stirring to dissolve, adjusting the pH value of the above-mentioned solution back by using 2M NaOH solution to about 5.5, continuing to add injection water to full dose, adding 0.05% of active carbon (for injection), keeping the temperature for 10 minutes, filtering to remove carbon, fine filtering by using a 0.22 micron microporous filter membrane, checking the clarity, checking semi-finished product, checking the clarity, filling the liquid medicine into an antibiotic glass product after the clarity check is qualified, freeze-drying, adding a stopper, covering, packaging, and filling into a whole antibiotic glass warehouse.
A sample solution of voriconazole pharmaceutical composition for injection of example 1-example 9 at a concentration of 2mg/m L was dispensed, analyzed by UV-2501PC UV-vis spectrophotometer, and λ ═ 256 ± 1 nm, absorbance was measured, and the absorbance was measured 1 time every 1h and 7 times in total, the results in days are shown in table 1, which indicates that the stability of the sample solution was good within 5 h.
Each solution prepared from a sample of voriconazole pharmaceutical composition for injection of examples 1 to 9 was dispensed into a Nami colorimetric tube, and the change in properties was observed after leaving the tube for a different period of time, insoluble fine particles were examined by a microscopic counting method, and the pH value was measured, as shown in Table 1. from Table 1, the properties of the solution and the number of insoluble fine particles did not change when the solution containing hydroxypropyl- β -cyclodextrin as a solubilizing agent was left to stand for 5 hours, whereas when the infusion solution of comparative example was left to stand for 3 hours or more, white turbidity began to appear with naked eyes, polygonal-shaped drug crystals were observed under a microscope, and the longer the time the more crystals precipitated, and the larger the size of the large-sized crystals was 400 μm or more.
Precision weighing samples of voriconazole pharmaceutical compositions for injection of examples 1-9 were taken, diluted with water to precision of 3 concentrations of 30, 40 and 50 μ g/mL, 3 parts each were prepared, and the average recovery rate of each sample was 99.50% as measured using the corresponding aqueous solution as a blank.
Table 1 (stability of voriconazole pharmaceutical composition for injection):
table 2 (stability of voriconazole pharmaceutical composition for injection):
note: "-" aseptically grown, "+" bacterially grown, plus sign indicates the degree of bacterial growth.
The inventor effectively improves the solubility and stability of voriconazole by adjusting the proportion of voriconazole and hydroxypropyl- β -cyclodextrin and the quality control of the product encapsulation rate, achieves the effect that the product diluent is stable and does not separate out, and solves the problems that the commercially available voriconazole freeze-dried powder injection for injection has poor stability, the diluent is unstable and is easy to separate out and the like, thereby obtaining a stable and uniform inclusion compound and ensuring the quality of the product.
Claims (7)
1. A voriconazole pharmaceutical composition for injection is characterized in that the components of the voriconazole pharmaceutical composition comprise voriconazole, hydroxypropyl- β -cyclodextrin, a diluent and a pH regulator.
2. The voriconazole pharmaceutical composition for injection as claimed in claim 1, wherein the mass ratio of voriconazole to hydroxypropyl- β -cyclodextrin is 1: 5-40.
3. The voriconazole pharmaceutical composition for injection according to claim 1, wherein the diluent is selected from one or more of mannitol, lactose, dextran, glucose, glycine, hydrolyzed gelatin, and povidone.
4. The voriconazole pharmaceutical composition for injection as claimed in claim 1, wherein the mass ratio of voriconazole to diluent is 1: 40-75.
5. A preparation method of voriconazole pharmaceutical composition for injection is characterized by comprising the following steps:
a. adding hydroxypropyl- β -cyclodextrin into water for injection, and stirring to dissolve hydroxypropyl- β -cyclodextrin completely;
b. dissolving voriconazole with hydrochloric acid, controlling the temperature, adding the voriconazole into a well-dissolved hydroxypropyl- β -cyclodextrin water solution, and stirring while adding until the voriconazole is completely included;
c. adding mannitol into the above inclusion solution, stirring for dissolving; adjusting the pH value of the solution back by using a NaOH solution, and adjusting the pH value; continuously adding water for injection to adjust the concentration;
d. filtering to remove carbon, and fine filtering with microporous membrane;
e. and (5) freeze-drying.
6. The preparation method of voriconazole pharmaceutical composition for injection according to claim 4, wherein a, 30-70% of water for injection, 400-800 g of hydroxypropyl- β -cyclodextrin are mixed;
b. mixing 50 g-60 g of voriconazole and 250-600 mL of 2M hydrochloric acid, controlling the temperature at 30-50 ℃, and stirring for 30-60 minutes;
c. mixing 200-240 g of mannitol and 2M NaOH solution, and adjusting the pH value to 5.0-6.0;
d. activated carbon (for injection) with the weight percentage of 0.01-0.05 percent of the prepared liquid, stirring for 10-20 minutes at the temperature of 30-75 ℃, and then finely filtering by using a 0.20-0.22 micron microporous filter membrane.
7. The voriconazole pharmaceutical composition for injection as claimed in claim 1, wherein the voriconazole pharmaceutical composition for injection is used for intravenous injection.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113509436A (en) * | 2021-06-18 | 2021-10-19 | 陕西省眼科研究所 | Preparation method of eye drops |
| CN114432252A (en) * | 2022-02-21 | 2022-05-06 | 珠海亿邦制药有限责任公司 | Preparation method of voriconazole for injection |
| CN114632075A (en) * | 2022-05-19 | 2022-06-17 | 奥信阳光(北京)药业科技有限公司 | Voriconazole aerosol inhalation and application |
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| CN1788725A (en) * | 2004-12-15 | 2006-06-21 | 北京博尔达生物技术开发有限公司 | Voriconazole freeze-drying powder injection and its preparation process |
| CN103251565A (en) * | 2013-04-09 | 2013-08-21 | 珠海亿邦制药股份有限公司 | Voriconazole freeze-dried powder injection for injection and preparation method thereof |
| CN108187069A (en) * | 2018-03-04 | 2018-06-22 | 珠海亿邦制药股份有限公司 | A kind of voriconazole pharmaceutical composition and its preparation |
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| CN113509436A (en) * | 2021-06-18 | 2021-10-19 | 陕西省眼科研究所 | Preparation method of eye drops |
| CN114432252A (en) * | 2022-02-21 | 2022-05-06 | 珠海亿邦制药有限责任公司 | Preparation method of voriconazole for injection |
| CN114632075A (en) * | 2022-05-19 | 2022-06-17 | 奥信阳光(北京)药业科技有限公司 | Voriconazole aerosol inhalation and application |
| CN114632075B (en) * | 2022-05-19 | 2022-07-15 | 奥信阳光(北京)药业科技有限公司 | Voriconazole aerosol inhalation and application |
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