CN110548009A - Freeze-drying method of adenosine cyclophosphate composition - Google Patents
Freeze-drying method of adenosine cyclophosphate composition Download PDFInfo
- Publication number
- CN110548009A CN110548009A CN201810551093.5A CN201810551093A CN110548009A CN 110548009 A CN110548009 A CN 110548009A CN 201810551093 A CN201810551093 A CN 201810551093A CN 110548009 A CN110548009 A CN 110548009A
- Authority
- CN
- China
- Prior art keywords
- parameters
- drying
- freeze
- slab
- freezing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- 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
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Dermatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Hospice & Palliative Care (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a freeze-drying method of adenosine cyclophosphate composition, which comprises the following steps: 1) dissolving and filtering the auxiliary materials, adding water for injection and adenosine cyclophosphate or adenosine cyclophosphate and meglumine, and stirring until the auxiliary materials are dissolved; 2) adjusting the pH value, filtering, sterilizing, filling and putting into a freeze-drying box; 3) and starting a freeze dryer, wherein the freeze drying process comprises the following steps: pre-freezing a first slab, pre-freezing a second slab, pre-freezing a third slab, preserving heat of the slabs, preparing a condenser, performing a first drying stage, performing a second drying stage, performing a third drying stage, and preserving heat; 4) and after freeze-drying, carrying out full-vacuum corking and vacuum discharging, discharging the box, rolling a cover, and carrying out lamp inspection and packaging.
Description
Technical Field
The invention belongs to the technical field of medicine processing, and particularly relates to a freeze-drying method of an adenosine cyclophosphate composition.
background
Adenosine cyclophosphate can be used for angina pectoris, myocardial infarction, myocarditis and cardiogenic shock. Has certain effect on improving symptoms of palpitation, shortness of breath, chest distress and the like of rheumatic heart disease. Can improve the curative effect of acute leukemia by combining chemotherapy and can also be used for inducing and relieving acute leukemia. In addition, it also has therapeutic effect on senile chronic bronchitis, various hepatitis and psoriasis.
After the cyclic adenosine monophosphate and meglumine are salified, the cyclic adenosine monophosphate can be used for heart failure, myocarditis, sick sinus syndrome, coronary heart disease and cardiomyopathy, and can also be used for the adjuvant therapy of arrhythmia.
The adenosine cyclophosphate composition comprises: adding dextran or mannitol as adjuvant, and adding dextran or mannitol after the cyclic adenosine monophosphate and meglumine are salified.
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.
However, in the prior art, the freeze-drying process product of the adenosine cyclophosphate composition adopts a three-step drying method, so that the phenomenon of atrophy is easy to occur, and the quality and the yield of the product are influenced.
Disclosure of Invention
In order to overcome the defects that the freeze-drying process product of the adenosine cyclophosphate composition in the prior art adopts a three-step drying method, the phenomenon of atrophy is easy to occur, and the product quality and yield are influenced, the invention provides a freeze-drying method of the adenosine cyclophosphate composition, which comprises the following steps:
1) adding dextran or mannitol as adjuvant into appropriate amount of water for injection, heating to dissolve completely, filtering to obtain filtrate, adding cooled water for injection into the filtrate, slowly adding adenosine cyclophosphate or adenosine cyclophosphate and meglumine under stirring, and stirring to dissolve;
2) adjusting the pH value of the liquid medicine to 5.0-7.0, and performing sterilization filtration on the liquid medicine through a 0.22 mu m cylinder filter; filling the sterilized and filtered liquid medicine into a treated bottle for half plugging and then putting the bottle into a freeze-drying box under the flow of the A-level layer;
3) And starting a freeze dryer, wherein the freeze drying process comprises the following steps: pre-freezing a first slab, pre-freezing a second slab, pre-freezing a third slab, preserving heat of the slabs, preparing a condenser, performing a first drying stage, performing a second drying stage, performing a third drying stage, and preserving heat;
Wherein the pre-freezing parameter of the first slab layer is that the operation is carried out for 30-60 min at-25 ℃ to-30 ℃; the second plate layer is pre-frozen for 90-150 min at the temperature of-25 ℃ to-30 ℃; the parameters of the third pre-freezing of the slab layer are-40 ℃ to-50 ℃ for 30-50 min, the parameters of the heat preservation of the slab layer are-40 ℃ to-50 ℃ for 50-100 min, and the parameters of the preparation of the condenser are-40 ℃ to-50 ℃ for 10-30 min;
The parameters of the first drying stage are 30-80 min at a vacuum degree of 0.1-0.3 mbar at-15 ℃ to-25 ℃; the parameters of the second drying stage are 10-20 ℃ and 400-750 min under the vacuum degree of 0.1-0.3 mbar; the parameter of the third drying stage is that the temperature is 35-45 ℃ and the vacuum degree is 0.1-0.3 mbar for 200-500 min; the heat preservation parameter is that the temperature is preserved for 270-360 min at 35-45 ℃;
4) and after freeze-drying, carrying out full-vacuum corking and vacuum discharging, discharging the box, rolling a cover, and carrying out lamp inspection and packaging.
further, sodium hydroxide or meglumine is adopted to adjust the pH value of the liquid medicine in the step 2).
further, the parameter of pre-freezing the plate layer in the step 3) is to operate for 30min at-30 ℃; the second slab layer is pre-frozen with the parameter of running for 90min at minus 30 ℃; the parameters of the slab prefreezing step three are 30min at minus 45 ℃, the parameters of the slab heat preservation step three are 70min at minus 45 ℃, and the parameters of the condenser preparation step three are 20min at minus 45 ℃;
The first drying stage has parameters of-20 deg.C under vacuum degree of 0.1mbar for 50 min; the parameters of the second drying stage are 15 deg.C under vacuum degree of 0.1mbar for 600 min; the parameters of the third drying stage are 300min at 40 deg.C under a vacuum degree of 0.1 mbar; the heat preservation parameter is that the temperature is preserved for 330min at 40 ℃.
Has the advantages that: the crystal nucleus quantity and size of the solution crystallization are influenced by the speed of the solution prefreezing, and the quantity and size of the crystal nucleus can influence whether the product can be atrophied or not when the product is sublimated and dried. The invention adopts the secondary prefreezing method, so that the number and the size of crystal nuclei of the product solution reach an optimal degree, the invention adopts the secondary prefreezing method, so that the number and the size of the crystal nuclei of the product solution reach an optimal degree, the phenomenon of product atrophy is reduced by more than 5%, the dried product is more loose and porous, and is more easily dissolved after water is added, and the product quality is improved; the redissolution time of the original freeze-drying process product is as follows: 15s +/-3 s, the redissolution time of the freeze-dried product after the secondary pre-freezing method is adopted is as follows: 10s + -2 s.
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.
Examples
A freeze-drying method of adenosine cyclophosphate composition comprises the following steps:
1) Adding dextran or mannitol as auxiliary material into proper amount of water for injection, heating to be completely dissolved, filtering the filtrate, adding cooled water for injection into the filtrate to reach 70% of the prescription amount in the process, slowly adding adenosine cyclophosphate or adenosine cyclophosphate and meglumine with the prescription amount while stirring, and stirring to be dissolved;
2) adjusting pH to 6.0, and sterilizing and filtering the medicinal liquid with 0.22 μm cylindrical filter; filling the sterilized and filtered liquid medicine into a treated bottle for half plugging and then putting the bottle into a freeze-drying box under the flow of the A-level layer;
3) and starting a freeze dryer, wherein the freeze drying process comprises the following steps: pre-freezing a first slab, pre-freezing a second slab, pre-freezing a third slab, preserving heat of the slabs, preparing a condenser, performing a first drying stage, performing a second drying stage, performing a third drying stage, and preserving heat; lyophilization was performed according to the following table procedure.
| freeze-drying stage | Temperature control (. degree.C.) | vacuum control (mbar) | Run time (min) |
| The sheet layer is pre-frozen to | -30 | / | 30 |
| Pre-freezing two sheets | -30 | / | 90 |
| Laminated prefreezing | -45 | / | 30 |
| sheet layer heat preservation | -45 | / | 70 |
| Condenser preparation | -45 | / | 20 |
| first drying stage | -20 | 0.1 | 50 |
| Second drying stage | 15 | 0.1 | 600 |
| Third drying stage | 40 | 0.1 | 300 |
| heat preservation | 40 | / | 330 |
| in total | 25:20 |
4) And after freeze-drying, carrying out full-vacuum corking and vacuum discharging, discharging the box, rolling a cover, and carrying out lamp inspection and packaging.
The invention adopts a secondary prefreezing method, so that the number and the size of crystal nuclei of a product solution reach an optimal degree, the phenomenon of product atrophy is reduced by more than 5%, the dried product is more loose and porous, and is more easily dissolved after water is added, and the product quality is improved. The redissolution time of the original freeze-drying process product is as follows: 15s +/-3 s, the redissolution time of the freeze-dried product after the secondary pre-freezing method is adopted is as follows: 10s + -2 s.
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 freeze-drying method of adenosine cyclophosphate composition is characterized by comprising the following steps:
1) Adding dextran or mannitol as adjuvant into appropriate amount of water for injection, heating to dissolve completely, filtering to obtain filtrate, adding cooled water for injection into the filtrate, slowly adding adenosine cyclophosphate or adenosine cyclophosphate and meglumine under stirring, and stirring to dissolve;
2) Adjusting the pH value of the liquid medicine to 5.0-7.0, and performing sterilization filtration on the liquid medicine through a 0.22 mu m cylinder filter; filling the sterilized and filtered liquid medicine into a treated bottle for half plugging and then putting the bottle into a freeze-drying box under the flow of the A-level layer;
3) and starting a freeze dryer, wherein the freeze drying process comprises the following steps: pre-freezing a first slab, pre-freezing a second slab, pre-freezing a third slab, preserving heat of the slabs, preparing a condenser, performing a first drying stage, performing a second drying stage, performing a third drying stage, and preserving heat;
Wherein the pre-freezing parameter of the first slab layer is that the operation is carried out for 30-60 min at-25 ℃ to-30 ℃; the second plate layer is pre-frozen for 90-150 min at the temperature of-25 ℃ to-30 ℃; the parameters of the third pre-freezing of the slab layer are-40 ℃ to-50 ℃ for 30-50 min, the parameters of the heat preservation of the slab layer are-40 ℃ to-50 ℃ for 50-100 min, and the parameters of the preparation of the condenser are-40 ℃ to-50 ℃ for 10-30 min;
The parameters of the first drying stage are 30-80 min at a vacuum degree of 0.1-0.3 mbar at-15 ℃ to-25 ℃; the parameters of the second drying stage are 10-20 ℃ and 400-750 min under the vacuum degree of 0.1-0.3 mbar; the parameter of the third drying stage is that the temperature is 35-45 ℃ and the vacuum degree is 0.1-0.3 mbar for 200-500 min; the heat preservation parameter is that the temperature is preserved for 270-360 min at 35-45 ℃;
4) And after freeze-drying, carrying out full-vacuum corking and vacuum discharging, discharging the box, rolling a cover, and carrying out lamp inspection and packaging.
2. The method for lyophilizing an adenosine cyclophosphate composition according to claim 1, wherein the pH of the liquid medicine is adjusted using sodium hydroxide or meglumine in the step 2).
3. The method for lyophilizing a adenosine cyclophosphate composition according to claim 1, wherein the parameter for pre-freezing the plate layer in the step 3) is running at-30 ℃ for 30 min; the second slab layer is pre-frozen with the parameter of running for 90min at minus 30 ℃; the parameters of the slab prefreezing step three are 30min at minus 45 ℃, the parameters of the slab heat preservation step three are 70min at minus 45 ℃, and the parameters of the condenser preparation step three are 20min at minus 45 ℃;
The first drying stage has parameters of-20 deg.C under vacuum degree of 0.1mbar for 50 min; the parameters of the second drying stage are 15 deg.C under vacuum degree of 0.1mbar for 600 min; the parameters of the third drying stage are 300min at 40 deg.C under a vacuum degree of 0.1 mbar; the heat preservation parameter is that the temperature is preserved for 330min at 40 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810551093.5A CN110548009A (en) | 2018-05-31 | 2018-05-31 | Freeze-drying method of adenosine cyclophosphate composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810551093.5A CN110548009A (en) | 2018-05-31 | 2018-05-31 | Freeze-drying method of adenosine cyclophosphate composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110548009A true CN110548009A (en) | 2019-12-10 |
Family
ID=68734231
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810551093.5A Withdrawn CN110548009A (en) | 2018-05-31 | 2018-05-31 | Freeze-drying method of adenosine cyclophosphate composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110548009A (en) |
-
2018
- 2018-05-31 CN CN201810551093.5A patent/CN110548009A/en not_active Withdrawn
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100506213C (en) | Lansoprazole freeze-dried powder for injection and preparing method thereof | |
| US20190133953A1 (en) | Preparation Method of Azacitidine for Injection | |
| CN107375220A (en) | A kind of Tedizolid Phosphate freeze drying powder injection and preparation method thereof | |
| CN102133199A (en) | Doxofylline lyophilized preparation for injection and preparation method thereof | |
| CN110693821A (en) | Method for preparing pantoprazole sodium for injection | |
| CN112006999A (en) | Preparation method of famotidine preparation for injection | |
| CN110548009A (en) | Freeze-drying method of adenosine cyclophosphate composition | |
| CN110613688A (en) | Freeze-drying method for preparing ganciclovir | |
| CN113730360A (en) | Freeze-drying method for preparing coenzyme A | |
| CN104473967A (en) | Pig gall powder preparing process | |
| CN104173299B (en) | A kind of freeze-drying method of hydrochloride for injection ligustrazine | |
| CN102058548A (en) | Ambroxol hydrochloride composition for injection and preparation method thereof | |
| CN101829065B (en) | Lansoprazole composition freeze-dried powder for injection | |
| CN114557970A (en) | Ophthalmic mitomycin freeze-dried powder and preparation method thereof | |
| CN109331040B (en) | Preparation method of bear gall powder and bear gall powder | |
| CN112691083B (en) | Freeze-drying process of vancomycin hydrochloride | |
| CN112552361A (en) | Cytarabine crystal, cytarabine freeze-dried powder and freeze-drying method | |
| TWI519304B (en) | A preserving method of growth factors derived from platelets | |
| CN113143868B (en) | Papaverine hydrochloride for injection and preparation method thereof | |
| CN113908129B (en) | Rifampicin freeze-dried powder for injection and production method thereof | |
| CN114191396B (en) | Omeprazole sodium for injection and preparation method thereof | |
| CN105078907B (en) | The freeze-drying method of hydrochloride for injection ligustrazine lyophilized preparation | |
| CN114306568A (en) | Preparation method of octreotide acetate freeze-dried powder injection for injection | |
| CN108992672B (en) | Wogonin pharmaceutical composition for treating tumor | |
| CN106389402B (en) | Application of convection heat transfer mode in preparation process of dianhydrogalactitol freeze-dried powder |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20191210 |