CN114617848B - Adenosine cyclophosphate freeze-dried preparation for injection and preparation method thereof - Google Patents
Adenosine cyclophosphate freeze-dried preparation for injection and preparation method thereof Download PDFInfo
- Publication number
- CN114617848B CN114617848B CN202111026260.2A CN202111026260A CN114617848B CN 114617848 B CN114617848 B CN 114617848B CN 202111026260 A CN202111026260 A CN 202111026260A CN 114617848 B CN114617848 B CN 114617848B
- Authority
- CN
- China
- Prior art keywords
- adenosine cyclophosphate
- freeze
- inclusion
- preparation
- drying
- 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.)
- Active
Links
Classifications
-
- 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
- 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
- A61K47/06—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
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous 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
- A61P9/10—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)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dermatology (AREA)
- Urology & Nephrology (AREA)
- Hospice & Palliative Care (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Gastroenterology & Hepatology (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to the technical field of pharmaceutical preparations, and discloses a adenosine cyclophosphate freeze-dried preparation for injection and a preparation method thereof, wherein the freeze-dried preparation is prepared by freeze-drying a adenosine cyclophosphate inclusion compound solution, and the adenosine cyclophosphate inclusion compound solution comprises the following components in parts by weight: 20-40 parts of adenosine cyclophosphate; 30-60 parts of an inclusion agent; 1000-2000 parts of water. The preparation method comprises the following steps: preparing liquid: dissolving an inclusion agent in 96-98 ℃ water, uniformly stirring, adding adenosine cyclophosphate, and carrying out heat preservation and stirring until the mixture is clear to obtain a adenosine cyclophosphate inclusion compound solution; removing heat sources: adding active carbon into the adenosine cyclophosphate clathrate compound solution, stirring for 10-20 min, and standing for 30-40 min; rough filtering to remove active carbon; sterilizing and filtering; filling; and (5) freeze drying. The inclusion agent is used for inclusion of the adenosine cyclophosphate, so that the solubility and stability of the prepared adenosine cyclophosphate freeze-dried preparation can be effectively improved, and the curative effect and the medication safety of the medicine are ensured.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a adenosine cyclophosphate freeze-dried preparation for injection and a preparation method thereof.
Background
Adenosine cyclophosphate is a second messenger substance involved in regulating cell functions, and has a very wide effect, and injection of a large amount of adenosine cyclophosphate can enhance myocardial contractility, cause blood pressure increase and cardiac output increase. And has effects in dilating smooth muscle, dilating coronary artery, improving liver function, inhibiting skin outer epithelial cell division and abnormal cell transformation, promoting activity of respiratory chain oxidase, and improving myocardial anoxia.
Because of insufficient solubility of adenosine cyclophosphate, the existing injection is usually mixed with meglumine to increase the solubility of the injection, for example, the 'adenosine cyclophosphate meglumine injection and a preparation method thereof' disclosed in Chinese patent literature, publication No. CN102283804A, is prepared by taking a proper amount of injection water, adding sodium chloride, adenosine cyclophosphate and meglumine, stirring to completely dissolve the injection water, adding 0.05-0.2% (W/V) of active carbon for a needle according to the volume, stirring for 15-30 minutes, filtering to remove the carbon, supplementing the injection water to nearly the full amount, regulating the pH value to 6.0-6.5 by using phosphate buffer, supplementing the injection water to the full amount, filtering, filling and sealing (full-process nitrogen filling), sterilizing, performing light inspection and packaging after semi-finished products are qualified. However, in the existing meglumine adenosine cyclophosphate solution, adenosine cyclophosphate can be gradually separated out along with the extension of the preservation time, so that the liquid medicine is degenerated and turbid, the curative effect of the medicine is affected, and the safety of the medicine is affected; and the meglumine adenosine cyclophosphate solution is easy to degrade when meeting light in the preservation process of the solution state, so that the structure of the medicine is changed, and the clinical anaphylactic reaction or the curative effect is reduced.
Thus, adenosine cyclophosphate for injection is generally prepared into a freeze-dried preparation at present to improve its storage stability, for example, an "adenosine cyclophosphate for injection and its preparation process" disclosed in chinese patent literature, publication No. CN1579413, whose composition includes: the adenosine cyclophosphate, meglumine and excipient are prepared into freeze-dried powder injection, the weight parts of the adenosine cyclophosphate, the meglumine and the excipient are 1.7-63, 1.0-37 and 0.675-90, the weight part ratio of the adenosine cyclophosphate to the meglumine is 1.7:1, and the pH value is 3.5-9.0. However, the adenosine cyclophosphate freeze-dried powder for injection prepared in the prior art has poor solubility, is inconvenient to use, is easy to separate out after redissolving, not only reduces the content of the main medicine, but also can influence the safety of the medicine.
Disclosure of Invention
The invention aims to solve the problems that the adenosine cyclophosphate freeze-dried powder for injection prepared in the prior art is poor in solubility, inconvenient to use and easy to separate out after redissolving, so that the content of a main medicine is reduced, and the safety of medicines is affected.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the adenosine cyclophosphate freeze-dried preparation for injection is prepared by freeze-drying a adenosine cyclophosphate inclusion compound solution, and the adenosine cyclophosphate inclusion compound solution comprises the following components in parts by weight:
20-40 parts of adenosine cyclophosphate;
30-60 parts of a coating agent;
1000-2000 parts of water.
The invention utilizes the inclusion agent to carry out inclusion on the adenosine cyclophosphate to prepare the adenosine cyclophosphate inclusion compound, which can effectively improve the solubility of the adenosine cyclophosphate in water, prevent the adenosine cyclophosphate from precipitating and crystallizing before freeze-drying to cause difficult re-dissolution after freeze-drying, simultaneously improve the solubility of freeze-drying preparation during re-dissolution, avoid wall hanging phenomenon and ensure the safety after infusion; in addition, the inclusion agent can protect the adenosine cyclophosphate, avoid the change of the medicine structure of the adenosine cyclophosphate under the influence of external environment, and improve the stability of the medicine.
Preferably, the preparation method of the inclusion agent comprises the following steps: adding hydroxypropyl-beta-cyclodextrin into a mixed solution of sodium hydroxide and sodium carboxymethyl cellulose; uniformly stirring, adding epoxy chloropropane, and stirring at 85-95 ℃ for reaction for 30-40 min; then adding glycine and epichlorohydrin, wherein the mass ratio of the hydroxypropyl-beta-cyclodextrin to the sodium carboxymethyl cellulose to the glycine is 4-6:0.5-1:1; continuing to perform heat preservation and stirring reaction for 2-3 h, regulating the pH value of the system to be neutral, adding DMF for precipitation, filtering, and drying the product to obtain the inclusion agent.
The invention utilizes the hydroxypropyl-beta-cyclodextrin to clathrate the adenosine cyclophosphate, and the adenosine cyclophosphate is clathrated in the cavity structure of the adenosine cyclophosphate so as to improve the water solubility of the adenosine cyclophosphate; however, since the van der Waals force between the hydroxypropyl-beta-cyclodextrin and the adenosine cyclophosphate is weak and the inclusion stability is poor, the adenosine cyclophosphate is easy to be removed from the cavity of the hydroxypropyl-beta-cyclodextrin, so that the solubility of the freeze-dried preparation is limited when only the hydroxypropyl-beta-cyclodextrin is used as the inclusion agent. In order to improve the inclusion stability of the inclusion agent on the adenosine cyclophosphate, the invention uses sodium carboxymethyl cellulose to modify the hydroxypropyl-beta-cyclodextrin, and connects the sodium carboxymethyl cellulose with the hydroxypropyl-beta-cyclodextrin through the crosslinking action of the epichlorohydrin, thereby increasing the steric hindrance of the inclusion agent, ensuring that the adenosine cyclophosphate after inclusion is not easy to deviate from a cavity of the hydroxypropyl-beta-cyclodextrin, improving the inclusion stability of the adenosine cyclophosphate, and further improving the solubility and stability of the freeze-dried preparation. However, after the sodium carboxymethyl cellulose is used for modifying the hydroxypropyl-beta-cyclodextrin, the inclusion of the adenosine cyclophosphate is also unfavorable because of the increased steric hindrance and higher solution viscosity, so that the invention also adds glycine, and the sodium carboxymethyl cellulose are used for modifying the hydroxypropyl-beta-cyclodextrin together, and the inclusion effect of the inclusion agent on the adenosine cyclophosphate and the inclusion stability of the adenosine cyclophosphate can be effectively improved by controlling the dosage of the sodium carboxymethyl cellulose and the glycine, so that the adenosine cyclophosphate freeze-dried preparation can be effectively re-dissolved.
Preferably, in the mixed solution of sodium hydroxide and sodium carboxymethyl cellulose, the mass fraction of the sodium hydroxide is 3-5%, and the mass ratio of the sodium hydroxide to the sodium carboxymethyl cellulose is 0.1-0.2:1.
Preferably, the mass ratio of the epichlorohydrin to the hydroxypropyl-beta-cyclodextrin added for the first time is 1:5-6; the mass ratio of the epichlorohydrin to the hydroxypropyl-beta-cyclodextrin added for the second time is 1:4-6.
Preferably, the pH of the adenosine cyclophosphate clathrate solution is 5.2 to 6.2.
The invention also provides a preparation method of the adenosine cyclophosphate freeze-dried preparation for injection, which comprises the following steps:
(1) Preparing liquid: dissolving the inclusion agent in 96-98 ℃ water, uniformly stirring, adding adenosine cyclophosphate, and carrying out heat preservation and stirring until the mixture is clear to obtain a adenosine cyclophosphate inclusion compound solution;
(2) Removing heat sources: adding active carbon into the adenosine cyclophosphate clathrate compound solution, stirring for 10-20 min, and standing for 30-40 min;
(3) Rough filtering to remove active carbon;
(4) Sterilizing and filtering;
(5) Filling;
(6) And (5) freeze drying.
Preferably, a 0.22 and/or 0.45 μm polyethersulfone filter element is used for the rough filtration in step (3).
Preferably, a 0.2 μm polyethersulfone filter is used for the sterilization filtration in step (4).
Preferably, steps (1) to (4) are completed within 4 hours, and step (5) is completed within 10 hours.
Preferably, the freeze-drying step in step (6) is:
a) Pre-freezing: prefreezing for 3-7 h at the temperature of less than or equal to-40 ℃;
b) Sublimation drying: preserving heat for 2-3 h at the temperature of minus 5 ℃; heating to 0 ℃ and preserving heat for 4-6 h; heating to 5 ℃ and preserving heat for 3-10 h; finally, heating to 10 ℃ and preserving heat for 1-2 h;
c) And (5) drying: heating from 10 ℃ to 35 ℃ in 1-2 h, and then keeping constant temperature at 35 ℃ for 3-4 h.
The method carries out freeze drying on the adenosine cyclophosphate clathrate compound solution through three steps of prefreezing, sublimation drying and re-drying. The proper parameters are adopted for prefreezing, so that free water in the solution can be solidified, the dried product has the same form as before drying, and irreversible changes such as foaming, concentration, solute movement and the like are prevented from occurring during evacuation and drying. Sublimation drying is a critical stage of lyophilization, during which most of the water is sublimated, and if poorly controlled, directly affects the appearance quality of the product and lyophilization time, as well as affecting the solubility of the product. The pre-freezing and sublimation drying conditions are related to the types and the dosage of the inclusion agent, and the proper pre-freezing and sublimation drying method is selected according to the used inclusion agent, so that the prepared adenosine cyclophosphate freeze-dried preparation has good solubility, is not easy to separate out after redissolution, is convenient for the use of products, and improves the use safety of the products. Some water is adsorbed on capillary walls and polar groups of the dried substances and is not frozen in the sublimated and dried products, so that conditions are provided for the growth and propagation of microorganisms and certain chemical reactions, and the storage stability and the shelf life of the products are reduced. Therefore, the invention carries out re-drying after sublimation drying, further removes residual moisture and improves the shelf life of the product.
Therefore, the invention has the following beneficial effects:
(1) The inclusion agent is used for inclusion of the adenosine cyclophosphate, so that the solubility and stability of the prepared adenosine cyclophosphate freeze-dried preparation are effectively improved, and the curative effect and the medication safety of the medicine are ensured;
(2) The sodium carboxymethyl cellulose and the glycine modified hydroxypropyl-beta-cyclodextrin are used as the inclusion agent, so that the inclusion effect of the inclusion agent on the adenosine cyclophosphate and the inclusion stability of the inclusion agent can be effectively improved, and the adenosine cyclophosphate freeze-dried preparation can be effectively re-dissolved;
(3) Proper pre-freezing, sublimation drying and re-drying methods are adopted according to the types of inclusion agents, so that the prepared propyl gallate product for injection has longer quality guarantee period and good solubility, is not easy to separate out after re-dissolution, is convenient for use, and improves the use safety of the product.
Detailed Description
The invention is further described below in connection with the following detailed description.
In the present invention, unless otherwise specified, all equipment and materials are commercially available or commonly used in the industry, and all methods, unless otherwise specified, are conventional in the art.
Example 1:
the adenosine cyclophosphate freeze-dried preparation for injection is prepared by freeze-drying a adenosine cyclophosphate inclusion compound solution with the pH of 5.2-6.2, and comprises the following components in parts by weight: adenosine cyclophosphate 20g, inclusion agent 30g, and water for injection 1000g.
The preparation method of the inclusion agent comprises the following steps: adding hydroxypropyl-beta-cyclodextrin into a mixed solution of sodium hydroxide and sodium carboxymethyl cellulose, wherein the mass fraction of sodium hydroxide in the mixed solution is 4%, and the mass ratio of sodium hydroxide to sodium carboxymethyl cellulose is 0.15:1; uniformly stirring, adding epoxy chloropropane with the mass ratio of the epoxy chloropropane to the hydroxypropyl-beta-cyclodextrin of 1:5.5, and stirring at 90 ℃ for reaction for 35min; then adding glycine and epichlorohydrin with the mass ratio of the hydroxypropyl-beta-cyclodextrin being 1:5, wherein the mass ratio of the hydroxypropyl-beta-cyclodextrin to the sodium carboxymethyl cellulose to the glycine is 5:0.8:1; continuing to carry out heat preservation and stirring reaction for 2.5h, regulating the pH value of the system to be neutral, adding DMF for precipitation, filtering, and drying the product to obtain the inclusion agent.
The preparation method of the adenosine cyclophosphate freeze-dried preparation for injection comprises the following steps:
(1) Preparing liquid: dissolving the inclusion agent in 97 ℃ water for injection, stirring uniformly, adding adenosine cyclophosphate, preserving heat, stirring until the mixture is clarified to obtain a adenosine cyclophosphate inclusion compound solution, sampling and measuring the pH value to be 5.2-6.2, and adjusting the pH value by using 1.0mol/L NaOH or 1.0mol/L HCl if the pH value is not in the process range;
(2) Removing heat sources: adding active carbon into the adenosine cyclophosphate clathrate compound solution, stirring for 15min, and standing for 35min; sampling and detecting the pH value to be 5.2-6.2, and if the pH value is not in the process range, adjusting the pH value by using 1.0mol/L HCl or 1.0mol/L NaOH solution;
(3) Rough filtering to remove active carbon: the adenosine cyclophosphate clathrate solution was filtered sequentially with a 0.45 μm and 0.22 μm polyethersulfone 10 inch cartridge (cylindrical filter);
(4) And (3) sterilizing and filtering: filtering the solution after rough filtration by using a 0.2 mu m polyethersulfone filter membrane filter;
(5) Immediately filling and half-plugging;
(6) And (3) freeze drying:
a) Pre-freezing: setting the temperature of an inner shelf of the freeze dryer at-40 ℃ and pre-freezing for 3 hours;
b) Sublimation drying: setting the temperature of the plate layer at-5 ℃, and preserving heat for 2 hours; heating to 0 ℃ and preserving heat for 4 hours; heating to 5 ℃ and preserving heat for 3 hours; finally, heating to 10 ℃ and preserving heat for 1h;
c) And (5) drying: heating from 10 ℃ to 35 ℃ in 1h, and then keeping constant temperature at 35 ℃ for 3h;
(7) Rolling the cover, checking with eyes, packing, putting into a warehouse to be checked, checking with lights, and putting into a finished product warehouse.
Example 2:
the adenosine cyclophosphate freeze-dried preparation for injection is prepared by freeze-drying a adenosine cyclophosphate inclusion compound solution with the pH of 5.2-6.2, and comprises the following components in parts by weight: 30g of adenosine cyclophosphate, 45g of inclusion agent and 1500g of water for injection.
The preparation method of the inclusion agent comprises the following steps: adding hydroxypropyl-beta-cyclodextrin into a mixed solution of sodium hydroxide and sodium carboxymethyl cellulose, wherein the mass fraction of sodium hydroxide in the mixed solution is 3%, and the mass ratio of sodium hydroxide to sodium carboxymethyl cellulose is 0.1:1; uniformly stirring, adding epichlorohydrin with the mass ratio of the hydroxypropyl-beta-cyclodextrin being 1:5, and stirring at 85 ℃ for reacting for 40min; then adding glycine and epichlorohydrin with the mass ratio of the hydroxypropyl-beta-cyclodextrin of 1:6, wherein the mass ratio of the hydroxypropyl-beta-cyclodextrin to the sodium carboxymethyl cellulose to the glycine is 4:0.5:1; and continuing to perform heat preservation and stirring reaction for 2 hours, regulating the pH value of the system to be neutral, adding DMF for precipitation, and drying the product after filtration to obtain the inclusion agent.
The preparation method of the adenosine cyclophosphate freeze-dried preparation for injection comprises the following steps:
(1) Preparing liquid: dissolving the inclusion agent in 96 ℃ water for injection, stirring uniformly, adding adenosine cyclophosphate, preserving heat, stirring until the mixture is clarified to obtain a adenosine cyclophosphate inclusion compound solution, sampling and measuring the pH value to be 5.2-6.2, and adjusting the pH value by using 1.0mol/L NaOH or 1.0mol/L HCl if the pH value is not in the process range;
(2) Removing heat sources: adding active carbon into the adenosine cyclophosphate clathrate compound solution, stirring for 10min, and standing for 40min; sampling and detecting the pH value to be 5.2-6.2, and if the pH value is not in the process range, adjusting the pH value by using 1.0mol/L HCl or 1.0mol/L NaOH solution;
(3) Rough filtering to remove active carbon: the adenosine cyclophosphate clathrate solution was filtered sequentially with a 0.45 μm and 0.22 μm polyethersulfone 10 inch cartridge (cylindrical filter);
(4) And (3) sterilizing and filtering: filtering the solution after rough filtration by using a 0.2 mu m polyethersulfone filter membrane filter;
(5) Immediately filling and half-plugging;
(6) And (3) freeze drying:
a) Pre-freezing: setting the temperature of an inner shelf of the freeze dryer at-40 ℃ and pre-freezing for 6 hours;
b) Sublimation drying: setting the temperature of the plate layer at-5 ℃, and preserving heat for 2.5 hours; heating to 0 ℃ and preserving heat for 5 hours; heating to 5 ℃ and preserving heat for 4 hours; finally, heating to 10 ℃ and preserving heat for 1.5h;
c) And (5) drying: raising the temperature from 10 ℃ to 35 ℃ in 1.5h, and then keeping the temperature at 35 ℃ for 3.5h;
(7) Rolling the cover, checking with eyes, packing, putting into a warehouse to be checked, checking with lights, and putting into a finished product warehouse.
Example 3:
the adenosine cyclophosphate freeze-dried preparation for injection is prepared by freeze-drying a adenosine cyclophosphate inclusion compound solution with the pH of 5.2-6.2, and comprises the following components in parts by weight: 40g of adenosine cyclophosphate, 60g of inclusion agent and 2000g of water for injection.
The preparation method of the inclusion agent comprises the following steps: adding hydroxypropyl-beta-cyclodextrin into a mixed solution of sodium hydroxide and sodium carboxymethyl cellulose, wherein the mass fraction of sodium hydroxide in the mixed solution is 5%, and the mass ratio of sodium hydroxide to sodium carboxymethyl cellulose is 0.2:1; uniformly stirring, adding epichlorohydrin with the mass ratio of the hydroxypropyl-beta-cyclodextrin being 1:6, and stirring and reacting for 30min at 95 ℃; then adding glycine and epichlorohydrin with the mass ratio of the hydroxypropyl-beta-cyclodextrin being 1:4, wherein the mass ratio of the hydroxypropyl-beta-cyclodextrin to the sodium carboxymethyl cellulose to the glycine is 6:1:1; continuing to carry out heat preservation and stirring reaction for 3 hours, regulating the pH value of the system to be neutral, adding DMF for precipitation, and drying the product after filtration to obtain the inclusion agent.
The preparation method of the adenosine cyclophosphate freeze-dried preparation for injection comprises the following steps:
(1) Preparing liquid: dissolving the inclusion agent in 98 ℃ water for injection, stirring uniformly, adding adenosine cyclophosphate, preserving heat, stirring until the mixture is clarified to obtain a adenosine cyclophosphate inclusion compound solution, sampling and measuring the pH value to be 5.2-6.2, and adjusting the pH value by using 1.0mol/L NaOH or 1.0mol/L HCl if the pH value is not in the process range;
(2) Removing heat sources: adding active carbon into the adenosine cyclophosphate clathrate compound solution, stirring for 20min, and standing for 30min; sampling and detecting the pH value to be 5.2-6.2, and if the pH value is not in the process range, adjusting the pH value by using 1.0mol/L HCl or 1.0mol/L NaOH solution;
(3) Rough filtering to remove active carbon: the adenosine cyclophosphate clathrate solution was filtered sequentially with a 0.45 μm and 0.22 μm polyethersulfone 10 inch cartridge (cylindrical filter);
(4) And (3) sterilizing and filtering: filtering the solution after rough filtration by using a 0.2 mu m polyethersulfone filter membrane filter;
(5) Immediately filling and half-plugging;
(6) And (3) freeze drying:
a) Pre-freezing: setting the temperature of an inner shelf of the freeze dryer at-40 ℃ and pre-freezing for 7h;
b) Sublimation drying: setting the temperature of the plate layer at-5 ℃, and preserving heat for 3 hours; heating to 0 ℃ and preserving heat for 6 hours; heating to 5 ℃ and preserving heat for 10 hours; finally, heating to 10 ℃ and preserving heat for 2 hours;
c) And (5) drying: heating from 10 ℃ to 35 ℃ in 2h, and then keeping constant temperature at 35 ℃ for 4h;
(7) Rolling the cover, checking with eyes, packing, putting into a warehouse to be checked, checking with lights, and putting into a finished product warehouse.
Comparative example 1 (hydroxypropyl-beta-cyclodextrin was used as inclusion agent):
in the adenosine cyclophosphate clathrate solution of comparative example 1, hydroxypropyl- β -cyclodextrin was used as the clathrate, and the rest was the same as in example 1.
Comparative example 2 (sodium carboxymethyl cellulose modified hydroxypropyl-beta-cyclodextrin was used as inclusion agent):
the preparation method of the inclusion agent in comparative example 2 comprises the following steps: adding hydroxypropyl-beta-cyclodextrin into a mixed solution of sodium hydroxide and sodium carboxymethyl cellulose, wherein the mass fraction of sodium hydroxide in the mixed solution is 4%, the mass ratio of sodium hydroxide to sodium carboxymethyl cellulose is 0.15:1, and the mass ratio of the added hydroxypropyl-beta-cyclodextrin to sodium carboxymethyl cellulose is 5:0.8; uniformly stirring, adding epichlorohydrin with the mass ratio of 1:5.5 to hydroxypropyl-beta-cyclodextrin, stirring at 90 ℃ for reaction for 3 hours, regulating the pH value of the system to be neutral, adding DMF for precipitation, filtering, and drying the product to obtain the inclusion agent. The remainder was the same as in example 1.
Comparative example 3 (glycine modified hydroxypropyl-beta-cyclodextrin was used as inclusion agent):
the preparation method of the inclusion agent in comparative example 3 comprises the following steps: adding hydroxypropyl-beta-cyclodextrin into a mixed solution of sodium hydroxide and glycine, wherein the mass fraction of sodium hydroxide in the mixed solution is 4%, and the mass ratio of sodium hydroxide to glycine is 0.15:1; the mass ratio of the added hydroxypropyl-beta-cyclodextrin to glycine is 5:1; uniformly stirring, adding epichlorohydrin with the mass ratio of 1:5.5 to hydroxypropyl-beta-cyclodextrin, stirring at 90 ℃ for reaction for 3 hours, regulating the pH value of the system to be neutral, adding DMF for precipitation, filtering, and drying the product to obtain the inclusion agent. The remainder was the same as in example 1.
Comparative example 4 (sodium carboxymethylcellulose and glycine reacted simultaneously with hydroxypropyl-beta-cyclodextrin):
the preparation method of the inclusion agent in comparative example 4 is: adding hydroxypropyl-beta-cyclodextrin into a mixed solution of sodium hydroxide and sodium carboxymethyl cellulose, wherein the mass fraction of sodium hydroxide in the mixed solution is 4%, and the mass ratio of sodium hydroxide to sodium carboxymethyl cellulose is 0.15:1; after being stirred uniformly, glycine and epoxy chloropropane with the mass ratio of 2:5 with hydroxypropyl-beta-cyclodextrin are added, wherein the mass ratio of the hydroxypropyl-beta-cyclodextrin to the sodium carboxymethyl cellulose to the glycine is 5:0.8:1; stirring at 90 ℃ for reaction for 3 hours, regulating the pH value of the system to be neutral, adding DMF for precipitation, filtering, and drying the product to obtain the inclusion agent. The remainder was the same as in example 1.
Propyl gallate for injection prepared in the above examples and comparative examples was stored at 25℃and subjected to performance test, wherein 40mg of the lyophilized preparation was dissolved in 250mL of water for injection at the time of clarity test of the solution after reconstitution, and the test of the remaining parameters was conducted by referring to the method in the second edition of Chinese pharmacopoeia 2020, and the results are shown in Table 1.
Table 1: and (5) testing the performance of the adenosine cyclophosphate freeze-dried preparation.
As can be seen from Table 1, the adenosine cyclophosphate freeze-dried preparations prepared by the formulations and the methods in examples 1 to 3 have good stability within two years, good re-dissolution performance and no crystal precipitation after re-dissolution. In contrast, in comparative example 1, the inclusion stability was poor due to the use of unmodified hydroxypropyl- β -cyclodextrin as the inclusion agent, and a part of adenosine cyclophosphate was easily removed from the inclusion agent during the subsequent filtration and lyophilization, resulting in a lyophilized preparation having reduced storage stability and reconstitution properties as compared with those in example 1. In the inclusion agent used in comparative example 2, only sodium carboxymethylcellulose is used for modifying hydroxypropyl-beta-cyclodextrin, and the storage stabilizer and the re-solubility of the freeze-dried preparation are also reduced, probably because the steric hindrance of the inclusion agent is increased after sodium carboxymethylcellulose is used for modifying hydroxypropyl-beta-cyclodextrin, the solution viscosity is higher, inclusion of adenosine cyclophosphate is not facilitated, and part of adenosine cyclophosphate cannot enter the cavity of beta-cyclodextrin. The modification of hydroxypropyl-beta-cyclodextrin with glycine alone in the inclusion compound of comparative example 3 was insufficient to prevent the removal of adenosine cyclophosphate from the cavities of beta-cyclodextrin, and the stability and reconstitution properties of the lyophilized formulation were also reduced. When the inclusion agent in comparative example 4 was prepared, sodium carboxymethyl cellulose and glycine were reacted with hydroxypropyl- β -cyclodextrin at the same time, which resulted in a decrease in the grafting ratio of sodium carboxymethyl cellulose to hydroxypropyl- β -cyclodextrin, and also affected the stability and re-solubility of the lyophilized preparation.
Claims (9)
1. The adenosine cyclophosphate freeze-dried preparation for injection is characterized by being prepared by freeze-drying a adenosine cyclophosphate inclusion compound solution, and the adenosine cyclophosphate inclusion compound solution comprises the following components in parts by weight:
20-40 parts of adenosine cyclophosphate;
30-60 parts of a coating agent;
1000-2000 parts of water;
the preparation method of the inclusion agent comprises the following steps: adding hydroxypropyl-beta-cyclodextrin into a mixed solution of sodium hydroxide and sodium carboxymethyl cellulose; uniformly stirring, adding epoxy chloropropane, and stirring at 85-95 ℃ for reaction for 30-40 min; then adding glycine and epichlorohydrin, wherein the mass ratio of the hydroxypropyl-beta-cyclodextrin to the sodium carboxymethyl cellulose to the glycine is 4-6:0.5-1:1; continuing to perform heat preservation and stirring reaction for 2-3 h, regulating the pH value of the system to be neutral, adding DMF for precipitation, filtering, and drying the product to obtain the inclusion agent.
2. The adenosine cyclophosphate freeze-dried preparation for injection according to claim 1, wherein the mass fraction of sodium hydroxide in the mixed solution of sodium hydroxide and sodium carboxymethylcellulose is 3-5%, and the mass ratio of sodium hydroxide to sodium carboxymethylcellulose is 0.1-0.2:1.
3. The adenosine cyclophosphate freeze-dried preparation for injection according to claim 1, wherein the mass ratio of the epichlorohydrin to the hydroxypropyl-beta-cyclodextrin added for the first time is 1:5-6; the mass ratio of the epichlorohydrin to the hydroxypropyl-beta-cyclodextrin added for the second time is 1:4-6.
4. The lyophilized preparation of adenosine cyclophosphate for injection according to claim 1, wherein the pH of the adenosine cyclophosphate clathrate solution is 5.2 to 6.2.
5. A method for preparing the adenosine cyclophosphate freeze-dried preparation for injection according to any one of claims 1 to 4, which is characterized by comprising the following steps:
(1) Preparing liquid: dissolving the inclusion agent in 96-98 ℃ water, uniformly stirring, adding adenosine cyclophosphate, and carrying out heat preservation and stirring until the mixture is clear to obtain a adenosine cyclophosphate inclusion compound solution;
(2) Removing heat sources: adding active carbon into the adenosine cyclophosphate clathrate compound solution, stirring for 10-20 min, and standing for 30-40 min;
(3) Rough filtering to remove active carbon;
(4) Sterilizing and filtering;
(5) Filling;
(6) And (5) freeze drying.
6. The method for preparing a freeze-dried preparation of adenosine cyclophosphate for injection according to claim 5, wherein the step (3) adopts a polyether sulfone filter core of 0.22 and/or 0.45 μm for rough filtration.
7. The method for preparing a lyophilized formulation of adenosine cyclophosphate for injection according to claim 5, wherein the sterilization filtration in step (4) is performed by using a 0.2 μm polyethersulfone filter.
8. The method for preparing a lyophilized formulation of adenosine cyclophosphate for injection according to claim 5, wherein steps (1) to (4) are completed within 4 hours, and step (5) is completed within 10 hours.
9. The method for preparing a lyophilized formulation of adenosine cyclophosphate for injection according to claim 5, wherein the step of freeze-drying in step (6) comprises:
a) Pre-freezing: prefreezing for 3-7 h at the temperature of less than or equal to-40 ℃;
b) Sublimation drying: preserving heat for 2-3 h at the temperature of minus 5 ℃; heating to 0 ℃ and preserving heat for 4-6 h; heating to 5 ℃ and preserving heat for 3-10 h; finally, heating to 10 ℃ and preserving heat for 1-2 h;
c) And (5) drying: heating from 10 ℃ to 35 ℃ in 1-2 h, and then keeping constant temperature at 35 ℃ for 3-4 h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111026260.2A CN114617848B (en) | 2021-09-02 | 2021-09-02 | Adenosine cyclophosphate freeze-dried preparation for injection and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111026260.2A CN114617848B (en) | 2021-09-02 | 2021-09-02 | Adenosine cyclophosphate freeze-dried preparation for injection and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114617848A CN114617848A (en) | 2022-06-14 |
| CN114617848B true CN114617848B (en) | 2023-08-08 |
Family
ID=81896616
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111026260.2A Active CN114617848B (en) | 2021-09-02 | 2021-09-02 | Adenosine cyclophosphate freeze-dried preparation for injection and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114617848B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115414377B (en) * | 2022-09-21 | 2024-01-30 | 广东宏远集团药业有限公司 | Composition containing adenosine cyclophosphate and preparation method thereof |
| CN115669904A (en) * | 2022-10-27 | 2023-02-03 | 上海宝鼎酿造有限公司 | Preparation method of seasoning cooking wine and seasoning cooking wine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010040312A8 (en) * | 2008-10-10 | 2010-08-12 | Chen Dong | Hollow mesoporous silica sphere coated with gold and preparation method thereof and use in cancer therapy |
| CN102846557A (en) * | 2012-09-20 | 2013-01-02 | 浙江亚太药业股份有限公司 | Adenosine cyclophosphate freeze-drying preparation and preparation method thereof |
-
2021
- 2021-09-02 CN CN202111026260.2A patent/CN114617848B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010040312A8 (en) * | 2008-10-10 | 2010-08-12 | Chen Dong | Hollow mesoporous silica sphere coated with gold and preparation method thereof and use in cancer therapy |
| CN102846557A (en) * | 2012-09-20 | 2013-01-02 | 浙江亚太药业股份有限公司 | Adenosine cyclophosphate freeze-drying preparation and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 王如军.羧甲基纤维素/β-环糊精水凝胶的制备及其工业废水处理应用研究.《中国优秀硕士学位论文全文数据库》.2014,摘要. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114617848A (en) | 2022-06-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114617848B (en) | Adenosine cyclophosphate freeze-dried preparation for injection and preparation method thereof | |
| US5036060A (en) | Cyclophosphamide | |
| JP6869941B2 (en) | A method for producing a lyophilized pharmaceutical composition having a certain content of mitomycin C. | |
| CN101283986A (en) | Omeprazole freeze-dried powder injection and preparation method thereof | |
| CN101744778B (en) | Voriconazole phosphate ester for injection and preparation method thereof | |
| CN101129368B (en) | Freeze-dried powder needle containing lansoprazole | |
| KR101468153B1 (en) | 5α-ANDROSTANE-3β,5,6β-TRIOL INJECTION AND PREPARATION METHOD THEREFOR | |
| CN105213330B (en) | A kind of SC 69124 sodium freeze-dried preparation and preparation method thereof | |
| PT85561B (en) | PROCESS FOR THE PREPARATION OF NEW FORMS OF APPLICATION OF HIGH INTERFERENCE (OES) | |
| CN103736078A (en) | mPEG (Ethyl Glycolate)-HM-3 polypeptide lyophilized powder injection preparation as well as preparation method and application thereof | |
| CN104971049B (en) | A kind of lyophilized preparation and preparation method thereof containing Fosaprepitant | |
| CN105878193B (en) | A kind of Lansoprazole freeze-dried powder for injection and preparation method thereof | |
| AU2007341231B2 (en) | Freeze-dried injectable pharmaceutical combination of semisynthetic vinca alkaloids and carbohydrate stable at room temperature | |
| CN100457098C (en) | Freeze-dried powder injection of nafamostat mesylate and its preparing method | |
| CN108606955A (en) | The Pharmaceutical composition and preparation method thereof of trainingization Xihai sea horse peptide | |
| CN106692081B (en) | A kind of freeze-dried powder injection of pantoprazole sodium and preparation method | |
| CN114159396A (en) | Espressol omeprazole sodium freeze-dried preparation for injection and preparation method thereof | |
| CN103040737B (en) | Drug composition containing lansoprazole compound and preparation method of drug composition | |
| CN112535725A (en) | Reduced glutathione for injection and preparation method thereof | |
| CN105853377B (en) | A kind of sodium rebeilazole for injection use preparation and preparation method thereof | |
| CN116421569B (en) | Parafaxib sodium pharmaceutical composition for injection and preparation method thereof | |
| CN114685581B (en) | Troxerutin for injection and preparation process thereof | |
| CN103735498A (en) | Method for preparing fructose diphosphate injection | |
| CN104107172B (en) | The preparation method of sivelestat sodium injection freeze-dried powder | |
| CN114042048B (en) | Preparation process of cefepime hydrochloride for injection |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |