CN114617848A - 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
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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 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 the inclusion agent in water at 96-98 ℃, uniformly stirring, adding adenosine cyclophosphate, and stirring at a constant temperature until the solution is clear to obtain an adenosine cyclophosphate inclusion compound solution; heat source removal: adding activated carbon into the adenosine cyclophosphate inclusion compound solution, stirring for 10-20 min, and then standing for 30-40 min; rough filtering to remove active carbon; sterilizing and filtering; filling; and (5) freeze drying. The invention uses the inclusion agent to carry out inclusion on the adenosine cyclophosphate, can effectively improve the solubility and the stability of the prepared adenosine cyclophosphate freeze-dried preparation, and ensures the curative effect and the medication safety of the medicine.
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 which participates in the regulation of cell functions, has very wide effect, and can enhance myocardial contractility, cause the increase of blood pressure and increase of cardiac output by injecting large dose of adenosine cyclophosphate. It also has effects in relaxing smooth muscle, dilating coronary artery, improving liver function, inhibiting division of epithelial cells on skin, inhibiting abnormal cell function, promoting activity of respiratory chain oxidase, and improving myocardial anoxia.
The preparation process of the injection comprises the steps of taking a proper amount of water for injection, adding sodium chloride, adenosine cyclophosphate and meglumine into the water for injection, stirring the water for injection to be completely dissolved, adding 0.05-0.2% (W/V) of activated carbon for injection according to volume, stirring the mixture for 15-30 minutes, filtering the mixture to remove carbon, supplementing the water for injection to nearly the full amount, adjusting the pH value to 6.0-6.5 by using a phosphate buffer solution, supplementing the water for injection to the full amount, detecting the half-finished product, filtering, encapsulating (filling nitrogen in the whole process), sterilizing, inspecting by a lamp, and packaging. However, in the existing meglumine adenosine cyclophosphate solution, adenosine cyclophosphate is gradually separated out along with the prolonging of the preservation time, so that the liquid medicine is deteriorated and turbid, the curative effect of the medicine is influenced, and the safety of the medicine is influenced; in addition, the meglumine adenosine cyclophosphate solution is easily degraded by light in the process of storing in a solution state, so that the structure of the medicine is changed, and clinical anaphylactic reaction or curative effect is reduced.
Therefore, adenosine cyclophosphate for injection is generally prepared into a freeze-dried preparation to improve the storage stability, for example, a "meglumine adenosine cyclophosphate for injection and preparation process thereof" disclosed in chinese patent literature, publication No. CN1579413, which comprises the following components: the adenosine cyclophosphate, meglumine and excipient are prepared into a freeze-dried powder injection, the parts by weight of the adenosine cyclophosphate, the meglumine and the excipient are 1.7-63 parts of adenosine cyclophosphate, 1.0-37 parts of the meglumine and 0.675-90 parts of the excipient, the ratio of the parts by weight of the adenosine cyclophosphate to the parts by weight of 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 and inconvenient use, is easy to separate out after being dissolved again, not only reduces the content of the main drug, but also influences the safety of the medicine.
Disclosure of Invention
The invention aims to overcome the problems that the prepared adenosine cyclophosphate freeze-dried powder for injection in the prior art has poor solubility, inconvenient use and easy precipitation after re-dissolution, not only reduces the content of main drugs, but also influences the safety of the medicine, and provides the adenosine cyclophosphate freeze-dried preparation for injection and the preparation method thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
the adenosine cyclophosphate freeze-dried preparation for injection is prepared by freeze-drying adenosine cyclophosphate inclusion compound solution, and the components of the adenosine cyclophosphate inclusion compound solution comprise the following components in parts by weight:
20-40 parts of adenosine cyclophosphate;
30-60 parts of a packaging agent;
1000-2000 parts of water.
The adenosine cyclophosphate inclusion compound is prepared by inclusion of the inclusion compound, so that the solubility of the adenosine cyclophosphate in water can be effectively improved, the phenomenon that the adenosine cyclophosphate is difficult to dissolve again after freeze drying due to crystallization before freeze drying is prevented, the solubility of the freeze-dried preparation during redissolution is improved, the phenomenon of wall hanging is avoided, and the safety after infusion is ensured; in addition, the clathrating agent can protect adenosine cyclophosphate, so that the change of the drug structure of adenosine cyclophosphate under the influence of the external environment is avoided, and the stability of the drug is improved.
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 and reacting at 85-95 ℃ for 30-40 min; then adding glycine and epoxy chloropropane, wherein the addition mass ratio of the hydroxypropyl-beta-cyclodextrin, the sodium carboxymethylcellulose and the glycine is 4-6: 0.5-1: 1; and continuously preserving heat, stirring and reacting for 2-3 h, adjusting the pH value of the system to be neutral, adding DMF (dimethyl formamide) for precipitation, filtering, and drying the product to obtain the inclusion agent.
The invention uses hydroxypropyl-beta-cyclodextrin to carry out inclusion on the adenosine cyclophosphate, and the adenosine cyclophosphate is included in a cavity structure of the adenosine cyclophosphate so as to improve the water solubility of the adenosine cyclophosphate; however, the van der waals force between the hydroxypropyl-beta-cyclodextrin and the adenosine cyclophosphate is weak, the inclusion stability is poor, and the adenosine cyclophosphate is easy to be separated from a cavity of the hydroxypropyl-beta-cyclodextrin, so that when only the hydroxypropyl-beta-cyclodextrin is used as an inclusion agent, the improvement effect on the solubility of the freeze-dried preparation is limited. In order to improve the inclusion stability of the clathrating agent on the adenosine cyclophosphate, the sodium carboxymethylcellulose is used for modifying the hydroxypropyl-beta-cyclodextrin, the sodium carboxymethylcellulose is connected with the hydroxypropyl-beta-cyclodextrin through the crosslinking effect of the epichlorohydrin, the steric hindrance of the clathrating agent is increased, the clathrated adenosine cyclophosphate can not be easily separated from a cavity of the hydroxypropyl-beta-cyclodextrin, the clathrating stability of the adenosine cyclophosphate is improved, and therefore the solubility and the stability of the freeze-drying preparation are improved. However, after the hydroxypropyl-beta-cyclodextrin is modified by the sodium carboxymethylcellulose, the steric hindrance is increased, the solution viscosity is higher, and the modification is not beneficial to the inclusion of the adenosine cyclophosphate, so that the glycine is added to modify the hydroxypropyl-beta-cyclodextrin together with the sodium carboxymethylcellulose, and the inclusion effect and the inclusion stability of the inclusion agent on the adenosine cyclophosphate can be effectively improved by controlling the dosage of the sodium carboxymethylcellulose and the glycine, so that the freeze-dried preparation of the adenosine cyclophosphate can be effectively redissolved.
Preferably, in the mixed solution of sodium hydroxide and sodium carboxymethyl cellulose, the mass fraction of sodium hydroxide is 3-5%, and the mass ratio of sodium hydroxide to sodium carboxymethyl cellulose is 0.1-0.2: 1.
Preferably, the mass ratio of the epoxy chloropropane to the hydroxypropyl-beta-cyclodextrin added for the first time is 1: 5-6; the mass ratio of the epoxy chloropropane to the hydroxypropyl-beta-cyclodextrin added for the second time is 1: 4-6.
Preferably, the pH value of the adenosine cyclophosphate inclusion compound solution is 5.2-6.2.
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 water at 96-98 ℃, uniformly stirring, adding adenosine cyclophosphate, keeping the temperature, and stirring until the solution is clear to obtain an adenosine cyclophosphate inclusion compound solution;
(2) heat source removal: adding activated carbon into the adenosine cyclophosphate inclusion 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 cartridge is used for the coarse filtration in step (3).
Preferably, a 0.2 μm polyethersulfone filter is used for the sterile filtration in step (4).
Preferably, steps (1) to (4) are completed within 4h, and step (5) is completed within 10 h.
Preferably, the freeze-drying step in step (6) is:
A) pre-freezing: pre-freezing for 3-7 h at the temperature of less than or equal to-40 ℃;
B) sublimation drying: keeping the temperature at minus 5 ℃ for 2-3 h; heating to 0 ℃ and preserving the heat for 4-6 h; then heating to 5 ℃ and preserving the heat for 3-10 h; finally, heating to 10 ℃ and preserving the heat for 1-2 h;
C) and (3) drying again: heating from 10 ℃ to 35 ℃ within 1-2 h, and then keeping the temperature at 35 ℃ for 3-4 h.
The adenosine cyclophosphate inclusion compound solution is subjected to freeze drying through three steps of prefreezing, sublimation drying and re-drying. The prefreezing is carried out by adopting proper parameters, free water in the solution can be solidified, the dried product has the same shape as that before the drying, and the irreversible changes of foaming, concentration, solute movement and the like during the evacuation drying are prevented. Sublimation drying is a critical stage of lyophilization, and most of water is sublimated in the stage, and if the control is not good, the appearance quality and the lyophilization time of the product are directly influenced, and the solubility of the product is influenced. The prefreezing and sublimation drying conditions are related to the type and the dosage of the inclusion agent, and according to the inclusion agent, the invention selects a proper prefreezing and sublimation drying method, so that the prepared adenosine cyclophosphate freeze-dried preparation has good solubility, is not easy to separate out after being redissolved, is convenient for the use of the product, and improves the use safety of the product. A part of water in the product after sublimation and drying is adsorbed on the capillary wall and the polar groups of the dried substance and is not frozen, 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 product are reduced. Therefore, the invention carries out re-drying after sublimation drying, further removes residual moisture and prolongs the shelf life of the product.
Therefore, the invention has the following beneficial effects:
(1) the clathration agent is used for clathrating 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) sodium carboxymethylcellulose and glycine-modified hydroxypropyl-beta-cyclodextrin are used as an inclusion agent, so that the inclusion effect and inclusion stability of the inclusion agent on adenosine cyclophosphate can be effectively improved, and the adenosine cyclophosphate freeze-dried preparation can be effectively redissolved;
(3) the proper pre-freezing, sublimation drying and re-drying methods are adopted according to the types of the inclusion agents, so that the prepared propyl gallate product for injection has longer quality guarantee period and good solubility, is not easy to precipitate after re-dissolution, is convenient for use and improves the use safety of the product.
Detailed Description
The invention is further described with reference to specific embodiments.
In the present invention, all the equipments and materials are commercially available or commonly used in the industry, and all the methods are conventional in the art unless otherwise specified.
Example 1:
a freeze-dried adenosine cyclophosphate preparation for injection is prepared by freeze-drying an adenosine cyclophosphate inclusion compound solution with the pH value of 5.2-6.2, and the adenosine cyclophosphate inclusion compound solution comprises the following components in parts by weight: 20g of adenosine cyclophosphate, 30g of inclusion agent and 1000g 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 the sodium hydroxide in the mixed solution is 4%, and the mass ratio of the sodium hydroxide to the sodium carboxymethyl cellulose is 0.15: 1; uniformly stirring, adding epoxy chloropropane with the mass ratio of 1:5.5 to hydroxypropyl-beta-cyclodextrin, and stirring and reacting for 35min at 90 ℃; then adding glycine and epoxy chloropropane with the mass ratio of 1:5 to hydroxypropyl-beta-cyclodextrin, wherein the addition mass ratio of hydroxypropyl-beta-cyclodextrin, sodium carboxymethylcellulose and glycine is 5:0.8: 1; and continuously preserving heat, stirring and reacting for 2.5h, adjusting the pH value of the system to be neutral, adding DMF (dimethyl formamide) 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 water for injection at 97 ℃, adding adenosine cyclophosphate after uniformly stirring, keeping the temperature and stirring until the mixture is clear to obtain an adenosine cyclophosphate inclusion compound solution, sampling and measuring 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 NaOH or 1.0mol/L HCl;
(2) heat source removal: adding activated carbon into the adenosine cyclophosphate clathrate solution, stirring for 15min, and standing for 35 min; sampling and detecting that the pH value is 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 filtration to remove active carbon: sequentially filtering the adenosine cyclophosphate inclusion compound solution by using a polyether sulfone 10-inch filter element (a cylindrical filter) with the particle size of 0.45 mu m and 0.22 mu m;
(4) and (3) degerming and filtering: filtering the solution after coarse 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 a shelf in a freeze dryer at-40 ℃ and pre-freezing for 3 h;
B) sublimation drying: setting the temperature of the plate layer at-5 ℃, and preserving heat for 2 hours; heating to 0 ℃ and preserving the heat for 4 h; then heating to 5 ℃ and preserving the heat for 3 h; finally, heating to 10 ℃ and preserving the heat for 1 h;
C) and (3) drying again: heating from 10 ℃ to 35 ℃ within 1h, and then keeping the temperature at 35 ℃ for 3 h;
(7) and (4) rolling a cover, visually inspecting, performing outer packaging, then putting into a warehouse to be inspected, and putting into a finished product warehouse after lamp inspection.
Example 2:
a freeze-dried adenosine cyclophosphate preparation for injection is prepared by freeze-drying an adenosine cyclophosphate inclusion compound solution with the pH value of 5.2-6.2, and the adenosine cyclophosphate inclusion compound solution 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 the sodium hydroxide in the mixed solution is 3%, and the mass ratio of the sodium hydroxide to the sodium carboxymethyl cellulose is 0.1: 1; uniformly stirring, adding epoxy chloropropane with the mass ratio of 1:5 to hydroxypropyl-beta-cyclodextrin, and stirring and reacting for 40min at 85 ℃; then adding glycine and epoxy chloropropane with the mass ratio of 1:6 to hydroxypropyl-beta-cyclodextrin, wherein the addition mass ratio of hydroxypropyl-beta-cyclodextrin, sodium carboxymethylcellulose and glycine is 4:0.5: 1; and continuously preserving heat, stirring and reacting for 2h, adjusting the pH value of the system to be neutral, adding DMF (dimethyl formamide) 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 water for injection at 96 ℃, uniformly stirring, adding adenosine cyclophosphate, keeping the temperature, stirring until the mixture is clear to obtain an adenosine cyclophosphate inclusion compound solution, sampling, measuring the pH value to be 5.2-6.2, and adjusting by using 1.0mol/L NaOH or 1.0mol/L HCl if the pH value is not in the process range;
(2) heat source removal: adding activated carbon into the adenosine cyclophosphate clathrate solution, stirring for 10min, and standing for 40 min; sampling and detecting that the pH value is 5.2-6.2, and if the pH value is not in the process range, adjusting by using 1.0mol/L HCl or 1.0mol/L NaOH solution;
(3) rough filtration to remove active carbon: sequentially filtering the adenosine cyclophosphate inclusion compound solution by using a polyether sulfone 10-inch filter element (a cylindrical filter) with the particle size of 0.45 mu m and 0.22 mu m;
(4) and (3) degerming and filtering: filtering the solution after coarse 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 a shelf in a 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 h; heating to 0 ℃ and preserving the heat for 5 hours; then heating to 5 ℃ and preserving the heat for 4 hours; finally, heating to 10 ℃ and preserving the heat for 1.5 h;
C) and (3) drying again: heating from 10 ℃ to 35 ℃ within 1.5h, and then keeping the temperature at 35 ℃ for 3.5 h;
(7) and (4) rolling a cover, visually inspecting, performing outer packaging, then putting into a warehouse to be inspected, and putting into a finished product warehouse after lamp inspection.
Example 3:
a adenosine cyclophosphate freeze-dried preparation for injection is prepared by freeze-drying an adenosine cyclophosphate inclusion compound solution with the pH of 5.2-6.2, and the adenosine cyclophosphate inclusion compound solution 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 the sodium hydroxide in the mixed solution is 5%, and the mass ratio of the sodium hydroxide to the sodium carboxymethyl cellulose is 0.2: 1; uniformly stirring, adding epoxy chloropropane with the mass ratio of 1:6 to hydroxypropyl-beta-cyclodextrin, and stirring and reacting for 30min at 95 ℃; then adding glycine and epoxy chloropropane with the mass ratio of 1:4 to hydroxypropyl-beta-cyclodextrin, wherein the addition mass ratio of hydroxypropyl-beta-cyclodextrin, sodium carboxymethylcellulose and glycine is 6:1: 1; and continuously preserving heat, stirring and reacting for 3 hours, adjusting the pH value of the system to be neutral, adding DMF (dimethyl formamide) 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 a liquid: dissolving the inclusion agent in water for injection at 98 ℃, uniformly stirring, adding adenosine cyclophosphate, keeping the temperature, stirring until the mixture is clear to obtain an adenosine cyclophosphate inclusion compound solution, sampling, measuring the pH value to be 5.2-6.2, and adjusting by using 1.0mol/L NaOH or 1.0mol/L HCl if the pH value is not in the process range;
(2) heat source removal: adding activated carbon into the adenosine cyclophosphate clathrate solution, stirring for 20min, and standing for 30 min; sampling and detecting that the pH value is 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 filtration to remove active carbon: sequentially filtering the adenosine cyclophosphate inclusion compound solution by using a polyether sulfone 10-inch filter element (a cylindrical filter) with the particle size of 0.45 mu m and 0.22 mu m;
(4) and (3) degerming and filtering: filtering the solution after coarse 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 a shelf in a freeze dryer at-40 ℃ and pre-freezing for 7 hours;
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 h; then heating to 5 ℃ and preserving the heat for 10 hours; finally, heating to 10 ℃ and preserving the heat for 2 h;
C) and (3) drying again: heating from 10 ℃ to 35 ℃ within 2h, and then keeping the temperature at 35 ℃ for 4 h;
(7) and (4) rolling a cover, visually inspecting, performing outer packaging, then putting into a warehouse to be inspected, and putting into a finished product warehouse after lamp inspection.
Comparative example 1 (using hydroxypropyl-beta-cyclodextrin as inclusion agent):
in the adenosine cyclophosphate inclusion compound solution in comparative example 1, hydroxypropyl-beta-cyclodextrin was used as an inclusion agent, and the rest was the same as in example 1.
Comparative example 2 (using sodium carboxymethylcellulose modified hydroxypropyl- β -cyclodextrin as inclusion agent):
the preparation method of the inclusion agent in comparative example 2 was: adding hydroxypropyl-beta-cyclodextrin into a mixed solution of sodium hydroxide and sodium carboxymethyl cellulose, wherein the mass fraction of the sodium hydroxide in the mixed solution is 4%, the mass ratio of the sodium hydroxide to the sodium carboxymethyl cellulose is 0.15:1, and the mass ratio of the added hydroxypropyl-beta-cyclodextrin to the sodium carboxymethyl cellulose is 5: 0.8; uniformly stirring, adding epoxy chloropropane with the mass ratio of hydroxypropyl-beta-cyclodextrin being 1:5.5, stirring and reacting for 3h at 90 ℃, adjusting the pH of the system to be neutral, adding DMF (dimethyl formamide) for precipitation, filtering, and drying the product to obtain the clathrating agent. The rest of the process was the same as in example 1.
Comparative example 3 (using glycine modified hydroxypropyl-beta-cyclodextrin as inclusion agent):
the preparation method of the inclusion agent in comparative example 3 was: adding hydroxypropyl-beta-cyclodextrin into a mixed solution of sodium hydroxide and glycine, wherein the mass fraction of the sodium hydroxide in the mixed solution is 4%, and the mass ratio of the sodium hydroxide to the glycine is 0.15: 1; the mass ratio of the added hydroxypropyl-beta-cyclodextrin to the added glycine is 5: 1; and (3) adding epoxy chloropropane with the mass ratio of 1:5.5 to hydroxypropyl-beta-cyclodextrin after uniformly stirring, reacting for 3 hours under stirring at 90 ℃, adjusting the pH of the system to be neutral, adding DMF (dimethyl formamide) for precipitation, filtering, and drying the product to obtain the clathrating agent. The rest is the same as in example 1.
Comparative example 4 (sodium carboxymethylcellulose and glycine were simultaneously reacted with hydroxypropyl- β -cyclodextrin):
the preparation method of the inclusion agent in comparative example 4 was: adding hydroxypropyl-beta-cyclodextrin into a mixed solution of sodium hydroxide and sodium carboxymethyl cellulose, wherein the mass fraction of the sodium hydroxide in the mixed solution is 4%, and the mass ratio of the sodium hydroxide to the sodium carboxymethyl cellulose is 0.15: 1; uniformly stirring, adding glycine and epoxy chloropropane with the mass ratio of 2:5 to hydroxypropyl-beta-cyclodextrin, wherein the addition mass ratio of hydroxypropyl-beta-cyclodextrin, sodium carboxymethylcellulose and glycine is 5:0.8: 1; stirring and reacting for 3h at 90 ℃, adjusting the pH of the system to be neutral, adding DMF (dimethyl formamide) for precipitation, filtering, and drying the product to obtain the inclusion agent. The rest is the same as in example 1.
The propylgallate for injection prepared in the above examples and comparative examples was stored at 25 ℃ and tested for properties, wherein, when the clarity of the solution after reconstitution was tested, 40mg of the lyophilized formulation was dissolved in 250mL of water for injection, and the remaining parameters were tested according to the methods in the second part of the "Chinese pharmacopoeia" 2020 edition, with the results shown in Table 1.
Table 1: and (3) 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 formula and the method in the invention in the embodiments 1 to 3 have good stability within two years, good redissolution performance and no crystal precipitation after redissolution. In the comparative example 1, unmodified hydroxypropyl-beta-cyclodextrin is used as an inclusion agent, the inclusion stability is poor, part of adenosine cyclophosphate is easy to separate from the inclusion agent in the subsequent filtration and freeze-drying processes, and the storage stability and the redissolution performance of the freeze-dried preparation are reduced compared with those in the example 1. In the inclusion agent used in comparative example 2, only sodium carboxymethylcellulose is used for modifying hydroxypropyl-beta-cyclodextrin, the storage stabilizer and the redissolution performance of the freeze-dried preparation are also reduced, and probably because the steric hindrance of the inclusion agent is increased after the sodium carboxymethylcellulose modifies hydroxypropyl-beta-cyclodextrin, the solution viscosity is higher, the inclusion of adenosine cyclophosphate is not facilitated, and part of adenosine cyclophosphate cannot enter the cavity of beta-cyclodextrin. The inclusion agent of comparative example 3, in which hydroxypropyl- β -cyclodextrin was modified with only glycine, was insufficient to prevent adenosine cyclophosphate from escaping from the cavity of β -cyclodextrin, and the stability and re-solubility of the lyophilized formulation were also reduced. In the preparation of the inclusion agent in comparative example 4, the sodium carboxymethylcellulose and the glycine are simultaneously reacted with the hydroxypropyl-beta-cyclodextrin, which may cause the graft ratio of the sodium carboxymethylcellulose and the hydroxypropyl-beta-cyclodextrin to be reduced, and may also affect the stability and re-solubility of the lyophilized preparation.
Claims (10)
1. The adenosine cyclophosphate freeze-dried preparation for injection is characterized by being prepared by freeze-drying an 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 packaging agent;
1000-2000 parts of water.
2. The freeze-dried adenosine cyclophosphate preparation for injection as claimed in claim 1, wherein the preparation method of the inclusion agent is as follows: adding hydroxypropyl-beta-cyclodextrin into a mixed solution of sodium hydroxide and sodium carboxymethyl cellulose; after uniformly stirring, adding epoxy chloropropane, and stirring and reacting for 30-40 min at 85-95 ℃; then adding glycine and epoxy chloropropane, wherein the addition mass ratio of the hydroxypropyl-beta-cyclodextrin, the sodium carboxymethylcellulose and the glycine is 4-6: 0.5-1: 1; and continuously preserving heat, stirring and reacting for 2-3 h, adjusting the pH value of the system to be neutral, adding DMF (dimethyl formamide) for precipitation, filtering, and drying the product to obtain the inclusion agent.
3. The freeze-dried adenosine cyclophosphate preparation for injection as claimed in claim 2, wherein in the mixed solution of sodium hydroxide and sodium carboxymethyl cellulose, the mass fraction of sodium hydroxide is 3-5%, and the mass ratio of sodium hydroxide to sodium carboxymethyl cellulose is 0.1-0.2: 1.
4. The freeze-dried adenosine cyclophosphate preparation for injection as claimed in claim 2, wherein the mass ratio of the epichlorohydrin added for the first time to the hydroxypropyl-beta-cyclodextrin is 1: 5-6; the mass ratio of the epoxy chloropropane to the hydroxypropyl-beta-cyclodextrin added for the second time is 1: 4-6.
5. The freeze-dried adenosine cyclophosphate preparation for injection according to claim 1, wherein the pH of the adenosine cyclophosphate inclusion compound solution is 5.2-6.2.
6. The preparation method of the adenosine cyclophosphate freeze-dried preparation for injection as claimed in any one of claims 1 to 5, which is characterized by comprising the following steps:
(1) preparing liquid: dissolving the inclusion agent in water at 96-98 ℃, uniformly stirring, adding adenosine cyclophosphate, and stirring at a constant temperature until the solution is clear to obtain an adenosine cyclophosphate inclusion compound solution;
(2) heat source removal: adding activated carbon into the adenosine cyclophosphate inclusion 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.
7. The method for preparing the adenosine cyclophosphate freeze-dried preparation for injection according to claim 6, wherein a 0.22 and/or 0.45 μm polyethersulfone filter core is adopted for rough filtration in the step (3).
8. The method for preparing the adenosine cyclophosphate lyophilized preparation for injection according to claim 6, wherein the step (4) of sterilizing and filtering is performed by using a 0.2 μm polyethersulfone filter membrane.
9. The preparation method of the adenosine cyclophosphate freeze-dried preparation for injection according to claim 6, wherein the steps (1) - (4) are completed within 4h, and the step (5) is completed within 10 h.
10. The method for preparing the adenosine cyclophosphate lyophilized preparation for injection according to claim 6, wherein the freeze-drying step in the step (6) is:
A) pre-freezing: pre-freezing for 3-7 h at the temperature of less than or equal to-40 ℃;
B) sublimation drying: keeping the temperature at minus 5 ℃ for 2-3 h; heating to 0 ℃ and preserving the heat for 4-6 h; then heating to 5 ℃ and preserving the heat for 3-10 h; finally, heating to 10 ℃ and preserving the heat for 1-2 h;
C) and (3) drying again: heating from 10 ℃ to 35 ℃ within 1-2 h, and then keeping the temperature at 35 ℃ for 3-4 h.
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