CN110613688A - Freeze-drying method for preparing ganciclovir - Google Patents
Freeze-drying method for preparing ganciclovir Download PDFInfo
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- CN110613688A CN110613688A CN201910914643.XA CN201910914643A CN110613688A CN 110613688 A CN110613688 A CN 110613688A CN 201910914643 A CN201910914643 A CN 201910914643A CN 110613688 A CN110613688 A CN 110613688A
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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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- 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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- 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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- 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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F26—DRYING
- F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
- F26B5/00—Drying solid materials or objects by processes not involving the application of heat
- F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
- F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing
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Abstract
The invention discloses a ganciclovir freeze-drying method, wherein the condensation temperature is set to be-30 to-20 ℃, the vacuum degree is controlled to be 0.1 to 0.3mbar, the operation time is 2200min, the temperature is set to be 30 to 40 ℃, the vacuum degree is controlled to be 0.1 to 0.3mbar, and the operation time is 300 min; then preserving the heat for 60-120 min at 30-40 ℃; the freeze-drying method adopts constant temperature gradient to freeze-dry in each freeze-drying stage, so that the number and the size of crystal nuclei of a product solution reach the most appropriate degree, the phenomenon of atrophy of the product is greatly reduced, and the dried product is more loose and porous and is more easily dissolved after water is added.
Description
Technical Field
The invention relates to a freeze-drying method for preparing ganciclovir.
Background
The ganciclovir composition comprises: and adding dextran or mannitol as an auxiliary material after the ganciclovir and sodium hydroxide are salified. Ganciclovir for injection is used primarily for the prevention and treatment of life-threatening or vision-compromised patients with immunodeficiency infected by cytomegalovirus, and for the prevention of organ transplant patients associated with cytomegalovirus infection. Lyophilized preparations are prepared by subjecting the drug to a low temperature, vacuum environment to remove water from the material. Therefore, the production process of the lyophilized preparation is generally performed in three steps, i.e., pre-freezing, sublimation drying (or referred to as first-stage drying), and desorption drying (or referred to as second-stage drying). The dried product is loose and porous and is spongy, and can be quickly and completely dissolved after water is added. In addition, the freeze-dried product is dried under vacuum, and oxygen is very little, so that the freeze-dried preparation is not easy to hydrolyze and oxidize compared with a water-soluble injection, namely the product quality is more stable. The safety of the medicine taking of the patient is ensured.
The invention patent with publication number CN 104666303A 'a freeze-drying process of ganciclovir for injection' divides sublimation drying into five stages, wherein the temperature of the first sublimation drying is-30 ℃ to-10 ℃; the temperature of the second sublimation drying is-10 ℃ to 0 ℃; the third sublimation drying is carried out at the temperature of 0 ℃; the fourth sublimation drying temperature is 0-10 ℃, the fifth sublimation drying temperature is 10-20 ℃, the drying temperature rise is carried out by adopting a slow continuous temperature rise method in the stage, the period is long, and about 20 hours are needed. The freeze-dried ganciclovir obtained by the patent is easy to have an atrophy phenomenon, and the quality and the yield of the product are influenced.
Disclosure of Invention
The invention aims to solve the technical problem that ganciclovir freeze-drying technology products in the prior art are easy to have atrophy phenomenon, and influence the product quality and yield, and provides a ganciclovir freeze-drying method.
In order to solve the technical problems, the invention provides the following technical scheme:
a method of lyophilizing ganciclovir comprising the steps of:
s1, adding dextran or mannitol as adjuvant into water for injection, heating to dissolve completely, and filtering;
s2, adding cooled water for injection into the filtrate to 60% -80% of the prescription amount in the process, and then slowly adding ganciclovir of the prescription amount while stirring to dissolve;
s3, adjusting the pH value to 11.0-13.0, and adding water for injection to the amount of the prescription;
s4, sterilizing and filtering the liquid medicine;
s5, filling the sterilized and filtered liquid medicine into a treated bottle according to the dose of each bottle to perform half stoppering under the flow of the A-level layer;
and S6, putting the filled liquid medicine into a freeze-drying box.
S7, starting a freeze dryer for freeze drying, wherein the freeze drying procedure is as follows:
pre-freezing the slab layer at a set temperature of-30 to-45 ℃ for 120 to 240 min;
setting the temperature of a condenser to be-30 to-45 ℃ and the running time to be 120 to 240 min;
setting the condensation temperature to-30 to-20 ℃, controlling the vacuum degree to 0.1 to 0.3mbar and the operation time to 2000-plus-one 2200min, and then setting the temperature to 30 to 40 ℃, controlling the vacuum degree to 0.1 to 0.3mbar and the operation time to 100-plus-one 300min during condensation; then preserving the heat for 60-120 min at 30-40 ℃;
s8, after freeze-drying is finished, and full vacuum corking and vacuum discharging are carried out, the box is taken out by filling personnel, and the box-out product is conveyed to a capping chamber for capping through a conveying track;
and S9, performing light inspection and packaging on the product after the cover is rolled.
Further, in S3, sodium hydroxide or meglumine is used to adjust the pH of the solution.
Further, the liquid medicine of S4 was sterilized by passing through a 0.22 μm cartridge filter.
The invention has the following beneficial effects: the speed of the pre-freezing speed of the solution can seriously affect the quantity and the size of crystal nuclei of the solution crystals, and the quantity and the size of the crystal nuclei can influence whether the product can be atrophied or not when the product is sublimated and dried. In each freeze-drying stage, the freeze-drying is carried out by adopting a constant temperature gradient, so that the number and the size of crystal nuclei of a product solution reach an optimal degree, the phenomenon of atrophy of the product is greatly reduced, and the dried product is more loose and porous and is more easily dissolved after being added with water.
The invention carries out pre-freezing at the temperature of-30 to-45 ℃ to ensure that the crystal nucleus quantity and size of the solution crystallization are in the optimum range, and the constant temperature rise is carried out at the temperature of-30 to-20 ℃, thus reducing the water residue of ganciclovir injection, leading the freeze-dried product to have the same upper and lower structure, more uniform, loose and porous, avoiding the phenomenon of product atrophy and greatly improving the product quality and yield.
Detailed Description
The following description of the preferred embodiments of the present invention is provided for the purpose of illustration and description, and is in no way intended to limit the invention.
Example 1
A method of lyophilizing ganciclovir comprising the steps of:
s1, adding dextran or mannitol as adjuvant into water for injection, heating to dissolve completely, and filtering;
s2, adding cooled water for injection into the filtrate to 70% of the prescription amount in the process, and then slowly adding ganciclovir of the prescription amount while stirring to dissolve;
s3, adjusting the pH value to 12.0 by adopting sodium hydroxide, and adding water for injection to the prescription amount;
s4, sterilizing the liquid medicine through a 0.22 mu m cylinder filter, and sterilizing and filtering the liquid medicine;
s5, filling the sterilized and filtered liquid medicine into a treated bottle according to the dose of each bottle to perform half stoppering under the flow of the A-level layer;
and S6, putting the filled liquid medicine into a freeze-drying box.
S7, starting a freeze dryer for freeze drying, wherein the freeze drying procedure is as follows:
pre-freezing the slab layer at-35 deg.C for 200 min;
setting the temperature of a condenser to be-30 ℃ and the running time to be 120 min;
setting the condensation temperature at-20 deg.C, vacuum degree at 0.1mbar, and operation time at 2000min, then setting the temperature at 30 deg.C, vacuum degree at 0.2mbar, and operation time at 180 min; then preserving the heat for 120min at 30 ℃;
s8, after freeze-drying is finished, and full vacuum corking and vacuum discharging are carried out, the box is taken out by filling personnel, and the box-out product is conveyed to a capping chamber for capping through a conveying track;
and S9, performing light inspection and packaging on the product after the cover is rolled.
Example 2
A method of lyophilizing ganciclovir comprising the steps of:
s1, adding dextran or mannitol as adjuvant into water for injection, heating to dissolve completely, and filtering;
s2, adding cooled water for injection into the filtrate to 60% of the prescription amount in the process, and then slowly adding ganciclovir of the prescription amount while stirring to dissolve;
s3, adjusting the pH value to 11.0 by adopting sodium hydroxide, and adding water for injection to the prescription amount;
s4, sterilizing the liquid medicine through a 0.22 mu m cylinder filter, and sterilizing and filtering the liquid medicine;
s5, filling the sterilized and filtered liquid medicine into a treated bottle according to the dose of each bottle to perform half stoppering under the flow of the A-level layer;
and S6, putting the filled liquid medicine into a freeze-drying box.
S7, starting a freeze dryer for freeze drying, wherein the freeze drying procedure is as follows:
pre-freezing the plate layer at-40 deg.C for 220 min;
setting the temperature of a condenser to be-30 ℃ and the running time to be 200 min;
setting the condensation temperature at-20 deg.C, vacuum degree at 0.1mbar, and operation time at 2100min, then setting the temperature at 35 deg.C, vacuum degree at 0.2mbar, and operation time at 180 min; then preserving the heat for 120min at 35 ℃;
s8, after freeze-drying is finished, and full vacuum corking and vacuum discharging are carried out, the box is taken out by filling personnel, and the box-out product is conveyed to a capping chamber for capping through a conveying track;
and S9, performing light inspection and packaging on the product after the cover is rolled.
Example 3
A method of lyophilizing ganciclovir comprising the steps of:
s1, adding dextran or mannitol as adjuvant into water for injection, heating to dissolve completely, and filtering;
s2, adding cooled water for injection into the filtrate to 80% of the prescription amount in the process, and then slowly adding ganciclovir of the prescription amount while stirring to dissolve;
s3, adjusting the pH value to 13.0 by adopting sodium hydroxide, and adding water for injection to the prescription amount;
s4, sterilizing the liquid medicine through a 0.22 mu m cylinder filter, and sterilizing and filtering the liquid medicine;
s5, filling the sterilized and filtered liquid medicine into a treated bottle according to the dose of each bottle to perform half stoppering under the flow of the A-level layer;
and S6, putting the filled liquid medicine into a freeze-drying box.
S7, starting a freeze dryer for freeze drying, wherein the freeze drying procedure is as follows:
pre-freezing the plate layer at-40 deg.C for 200 min;
setting the temperature of a condenser to be-30 ℃ and the running time to be 200 min;
setting the condensation temperature at-25 deg.C, vacuum degree at 0.1mbar, and operation time at 2200min, setting the temperature at 40 deg.C, vacuum degree at 0.2mbar, and operation time at 180 min; then preserving the heat for 120min at 40 ℃;
s8, after freeze-drying is finished, and full vacuum corking and vacuum discharging are carried out, the box is taken out by filling personnel, and the box-out product is conveyed to a capping chamber for capping through a conveying track;
and S9, performing light inspection and packaging on the product after the cover is rolled.
Comparative example
A method of lyophilizing ganciclovir comprising the steps of:
s1, adding dextran or mannitol as adjuvant into water for injection, heating to dissolve completely, and filtering;
s2, adding cooled water for injection into the filtrate to 70% of the prescription amount in the process, and then slowly adding ganciclovir of the prescription amount while stirring to dissolve;
s3, adjusting the pH value to 12.0 by adopting sodium hydroxide, and adding water for injection to the prescription amount;
s4, sterilizing the liquid medicine through a 0.22 mu m cylinder filter, and sterilizing and filtering the liquid medicine;
s5, filling the sterilized and filtered liquid medicine into a treated bottle according to the dose of each bottle to perform half stoppering under the flow of the A-level layer;
and S6, putting the filled liquid medicine into a freeze-drying box.
S7, starting a freeze dryer for freeze drying, wherein the freeze drying procedure is as follows:
firstly, reducing the temperature of the front box product to-40 ℃, and then refrigerating the rear box to-45 ℃; when the temperature of the product is reduced to 0 ℃, nitrogen is filled into the box, the pressure in the box is kept at 0.20MPa, and then the temperature of the product is reduced to-28 ℃. Starting to vacuumize, and keeping the vacuum degree less than 0.30 mbar;
A. the oil was warmed to-20 ℃ at a rate of 4 ℃/hour for 5 hours;
B. then the oil is heated to-10 ℃ at the speed of 5 ℃/hour and is kept for 3 hours;
C. heating the oil to 0 ℃ at a rate of 3 ℃/hour and keeping the temperature for 1 hour;
D. the oil was warmed to 18 ℃ at a rate of 5 ℃/hour and held for 5 hours;
E. after the temperature of the product is reduced to 12 ℃, the product is rapidly heated to the heat preservation temperature of 45 ℃ at the speed of 10 ℃/hour, and the heat preservation is carried out for 3 hours.
S8, after freeze-drying is finished, and full vacuum corking and vacuum discharging are carried out, the box is taken out by filling personnel, and the box-out product is conveyed to a capping chamber for capping through a conveying track;
and S9, performing light inspection and packaging on the product after the cover is rolled.
TABLE 1 atrophy stratification and defective percentage
| Phenomenon(s) | Comparative example 1 | Example 1 | Example 2 | Example 3 |
| Rate of atrophic stratification | 4.2％ | 1.2％ | 1.3％ | 1.4 |
| Defective percentage | 5.8％ | 1.6％ | 1.8％ | 1.9％ |
TABLE 2 proportion of dissolution time samples
| Item | Comparative example 1 | Example 1 | Example 2 | Example 3 |
| Less than 30 seconds | 10.2％ | 26.3％ | 26.1％ | 25.9％ |
| 30 seconds to 45 seconds | 36.5％ | 59.8％ | 58.9％ | 60.2％ |
| Greater than 45 seconds | 53.3％ | 13.9％ | 15.0％ | 13.9％ |
The atrophy stratification rate and the defective rate are shown in table 1, and the dissolution time is shown in table 2. Therefore, the freeze-drying process greatly reduces the phenomenon of product atrophy, the dried product is more loose and porous, and is more easily dissolved after being added with water, and the product quality is improved.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (3)
1. A method for lyophilizing ganciclovir, comprising the steps of:
s1, adding dextran or mannitol as adjuvant into water for injection, heating to dissolve completely, and filtering;
s2, adding cooled water for injection into the filtrate to 60% -80% of the prescription amount in the process, and then slowly adding ganciclovir of the prescription amount while stirring to dissolve;
s3, adjusting the pH value to 11.0-13.0, and adding water for injection to the amount of the prescription;
s4, sterilizing and filtering the liquid medicine;
s5, filling the sterilized and filtered liquid medicine into a treated bottle according to the dose of each bottle to perform half stoppering under the flow of the A-level layer;
and S6, putting the filled liquid medicine into a freeze-drying box.
S7, starting a freeze dryer for freeze drying, wherein the freeze drying procedure is as follows:
pre-freezing the slab layer at a set temperature of-30 to-45 ℃ for 120 to 240 min;
setting the temperature of a condenser to be-30 to-45 ℃ and the running time to be 120 to 240 min;
setting the condensation temperature to-30 to-20 ℃, controlling the vacuum degree to 0.1 to 0.3mbar and the operation time to 2000-plus-one 2200min, and then setting the temperature to 30 to 40 ℃, controlling the vacuum degree to 0.1 to 0.3mbar and the operation time to 100-plus-one 300min during condensation; then preserving the heat for 60-120 min at 30-40 ℃;
s8, after freeze-drying is finished, and full vacuum corking and vacuum discharging are carried out, the box is taken out by filling personnel, and the box-out product is conveyed to a capping chamber for capping through a conveying track;
and S9, performing light inspection and packaging on the product after the cover is rolled.
2. The method of claim 1, wherein the pH of the solution is adjusted using sodium hydroxide or meglumine in S3.
3. The method of claim 1, wherein the liquid of S4 is sterilized by passing through a 0.22 μm cartridge filter.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113476413A (en) * | 2021-08-09 | 2021-10-08 | 海南海灵化学制药有限公司 | Preparation method of ganciclovir sodium freeze-dried powder for injection |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103054819A (en) * | 2013-01-31 | 2013-04-24 | 南京正宽医药科技有限公司 | Ganciclovir for injection and preparation method thereof |
| CN103330687A (en) * | 2013-07-16 | 2013-10-02 | 成都天台山制药有限公司 | Stable ganciclovir freeze-dried powder injection |
| CN104666303A (en) * | 2015-01-30 | 2015-06-03 | 湖南科伦制药有限公司 | Freeze-drying process for ganciclovir for injection |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103054819A (en) * | 2013-01-31 | 2013-04-24 | 南京正宽医药科技有限公司 | Ganciclovir for injection and preparation method thereof |
| CN103330687A (en) * | 2013-07-16 | 2013-10-02 | 成都天台山制药有限公司 | Stable ganciclovir freeze-dried powder injection |
| CN104666303A (en) * | 2015-01-30 | 2015-06-03 | 湖南科伦制药有限公司 | Freeze-drying process for ganciclovir for injection |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113476413A (en) * | 2021-08-09 | 2021-10-08 | 海南海灵化学制药有限公司 | Preparation method of ganciclovir sodium freeze-dried powder for injection |
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Application publication date: 20191227 |