CN111249229B - Stable fampicin injection and preparation method thereof - Google Patents
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
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- 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
- A61K47/40—Cyclodextrins; Derivatives thereof
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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Abstract
The invention relates to a stable injection of famprivir and a preparation method thereof, wherein the injection comprises famprivir, a solubilizer of sulfobutyl ether-beta-cyclodextrin sodium and an acid-base regulator.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a stable fampicin injection and a preparation method thereof.
Background
Favipiravir (favipiravir), chemical name 6-fluoro-3-hydroxy pyrazine-2-carboxamide, is an RNA-dependent RNA polymerase inhibitor broad-spectrum antiviral drug developed by Fushan chemical industry Co., ltd., marketed in Japan in month 7 of 2014 in the form of tablets with a specification of 200 mg/tablet for the treatment of new or recurrent influenza virus infection.
The fapirrevir is shown in the following structural formula:
fapirrevir is metabolized in cells to ribose triphosphate (Fapirrevir RTP), which selectively inhibits replication-associated RNA polymerase of influenza virus, and its inhibition IC of humanized RNA polymerase 50 The value was 905. Mu.ml/L. In view of this, in order to achieve higher blood concentration in vivo, oral tablet dosage of famprivir is administeredLarger, the single daily dose can reach 3200 mg/day, and the medicine is taken twice, wherein 1600mg is equivalent to 8 dosage units (8 tablets) each time. This causes great difficulty in taking medicine for patients with dysphagia such as children, elderly people, etc., and compliance of patients is difficult to ensure. Therefore, the public searches for an injection formulation which can significantly improve the drug administration compliance of patients, has rapid onset of action, higher bioavailability, safety and stability.
However, there are significant challenges in developing an injectable formulation of fampicvir, due to: 1) The fampicin has low solubility in water medium in a wide pH range, and the medicine solution is placed at room temperature or is easy to crystallize and separate out after compatibility; 2) The stability of the aqueous solution of the fampicin is poor, particularly alkali degradation is easy to occur in an alkaline aqueous solution, and related substances 6-fluoro-3-hydroxy pyrazinyl-2-formic acid are generated. The increased content of the related substances can cause color change of the liquid medicine and affect the administration safety.
Therefore, all the technical means disclosed at present are that the fampicvir is developed into freeze-dried powder injection for injection. For example, patent TW201934539a reports a method for preparing a freeze-dried formulation of famprivir sodium salt for injection, and after sodium hydroxide and fampride Wei Cheng salt are used by the inventor, the freeze-dried formulation of fampride sodium is prepared by a conventional method, but the re-solubility of the freeze-dried formulation is very poor, which affects the clinical use convenience. Patent CN103209967a discloses a freeze-dried preparation of an injection of a valepin Wei Pujia amine salt, and the formed compound has excellent re-solubility, so that the problem that the freeze-drying of sodium salt is difficult to re-dissolve is solved.
However, those skilled in the art still expect to find a liquid injection of fampicin which can be directly administered intravenously, not only because the clinical use of the injection is more convenient and faster than that of a freeze-dried preparation, but also the production process is simpler, the production period is shorter, and the production cost is lower. Of course, any such intravenous formulation must exhibit chemical and physical stability over the shelf life of the product.
Disclosure of Invention
The fampicin is a medicine with weak acidity and poor water solubility, the solubility of acidic and neutral hot water solutions is only 5mg/mL, and the solution is easy to crystallize and separate out when being placed at room temperature. Although the solubility is slightly increased under alkaline conditions, it is unstable under strongly alkaline conditions, alkali degradation is liable to occur, and the solubility of an alkaline aqueous solution thereof still cannot satisfy the intravenous administration dose.
The precondition for developing the fampicin injection for intravenous injection is as follows: 1) Sufficient solubilization, the desired concentration of the drug solution is 30mg/mL or more; 2) Sufficient solution stability, neutral or weakly alkaline drug solution is desirable to prevent or inhibit the production of alkaline degradation products.
The inventor finds through experiments that: the modified beta-cyclodextrin, especially sodium sulfobutyl ether-beta-cyclodextrin (SBECD), has good solubilization to the fampicvir. The inventors determined the pH-dependent effect of water and alkalized sodium sulfobutyl ether- β -cyclodextrin (SBECD) in aqueous solution on the solubility of laplacian Wei Baohe at different sodium sulfobutyl ether- β -cyclodextrin (SBECD) concentrations and the results are shown in fig. 1. The fampicin solubility increases non-linearly with increasing sulfobutyl ether-beta-cyclodextrin Sodium (SBECD) concentration at pH 7.0 and 8.5. When the sulfobutyl ether-beta-cyclodextrin Sodium (SBECD) concentration reached 400mg/mL, the concentration of fampicvir was able to reach the desired concentration of 30mg/mL even in neutral solution (pH 7.0).
The inventors also determined the solubility of fapira Wei Baohe in aqueous solutions at 400mg/mL of sulfobutyl ether-beta-cyclodextrin Sodium (SBECD) at a pH in the range of 6.5 to 8.5, and the level (%) of the index degradation product 6-fluoro-3-hydroxypyrazinyl-2-carboxylic acid (base degradation product) after terminal sterilization (121 ℃,12 min) of the fapiran solution, see fig. 2. The test significance is remarkable, and the test significance scientifically and intuitively reflects that when the concentration of the solubilizer sulfobutyl ether-beta-cyclodextrin Sodium (SBECD) is 400mg/mL, a certain solubilization effect (30 mg/mL of fampicvir) is simultaneously satisfied, and the liquid medicine is thermally stable, and can resist the pH range of terminal sterilization, namely, the pH range is 6.8-7.6.
Therefore, the invention aims to provide a stable fampicin injection and a preparation method thereof.
The stable injection provided by the invention comprises the fampicvir, the solubilizer sulfobutyl ether-beta-cyclodextrin Sodium (SBECD) and a small amount of acid-base regulator.
In some embodiments, the concentration of fampicvir in the injection is 25-40 mg/mL and the concentration of sodium sulfobutyl ether- β -cyclodextrin (SBECD) is 300-500 mg/mL.
Preferably, in some further embodiments, the concentration of fampicvir in the injection is 30mg/mL and the concentration of sodium sulfobutyl ether- β -cyclodextrin (SBECD) is 400mg/mL.
In some embodiments, the pH of the stabilized famprivir injection is about 6.8 to 7.6.
Preferably, in some further embodiments, the pH of the stable injection is about 7.2.
The acid-base regulator is selected from ammonia water, sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid or a combination thereof.
The single-dose preparation filling amount of the stable fampicin injection prepared by the invention is 5-50 mL, preferably 10-40 mL, and particularly preferably 20mL.
The invention also provides a method for preparing the stable fampicin injection, which comprises the following steps:
(1) Taking 60-90% of water for injection, heating to 50-80 ℃, adding sulfobutyl ether-beta-cyclodextrin sodium, and stirring to dissolve. Adding an alkaline regulator solution, and alkalizing a sulfobutyl ether-beta-cyclodextrin sodium solution;
(2) Adding fampicin, stirring for 0.25-2 h to obtain a clear solution, regulating the pH value of the solution to between 6.8 and 7.6 by using an acid-base regulator, supplementing water to the full amount, and filtering by using a 0.22 mu m filter membrane;
(3) Filling the filtrate into a penicillin bottle or an ampoule bottle, sealing, sterilizing by terminal moist heat (generally at 115-126 ℃ for 10-40 min), packaging and storing.
The fampicin injection prepared according to the proportion and the method can be administrated in the forms of intravenous drip and intravenous infusion.
The fampicin injection provided by the invention has good characteristic properties, such as stability and safety.
Detailed Description
The invention is further illustrated by the following examples, including but not limited to the following examples.
Example 1:
100 prescriptions
Preparation method
(1) Taking 60% of water for injection, heating to 60-70 ℃, adding sodium sulfobutyl ether-beta-cyclodextrin, and stirring to dissolve. Adding 1M sodium hydroxide solution, alkalizing sulfobutyl ether-beta-cyclodextrin sodium solution, and measuring the pH value to be 8.5-9.5;
(2) Adding the fampicin, stirring for 0.25-0.5 h to obtain a clear solution, regulating the pH of the solution to be between 6.8 and 7.6 by using 1M hydrochloric acid or 1M sodium hydroxide solution, preferably pH 7.2, supplementing water to the full amount, and filtering by using a 0.22 mu M filter membrane;
(3) Filling filtrate into ampoule bottles with 10mL of each bottle, sealing, sterilizing with terminal moist heat (121deg.C, sterilizing for 12 min), packaging, and storing.
Example 2:
100 prescriptions
Preparation method
(1) Taking water for injection with the prescription amount of 70%, heating to the temperature of between 60 and 70 ℃, adding sodium sulfobutyl ether-beta-cyclodextrin, and stirring to dissolve. Adding 10% ammonia water solution, alkalizing sulfobutyl ether-beta-cyclodextrin sodium solution, and measuring the pH value to be 8.5-9.5;
(2) Adding the fampicin, stirring for 0.25-0.5 h to obtain a clear solution, regulating the pH of the solution to be between 6.8 and 7.6 by using 1M hydrochloric acid or 10% ammonia water solution, preferably pH 7.2, supplementing water to the full amount, and filtering by using a 0.22 mu M filter membrane;
(3) Filling the filtrate into 15 or 20mL penicillin bottles, sealing, sterilizing with terminal moist heat (121 ℃ C., sterilizing for 12 min), packaging and storing.
Example 3:
100 prescriptions
Preparation method
(1) Taking water for injection with the prescription amount of 70%, heating to the temperature of between 60 and 70 ℃, adding sodium sulfobutyl ether-beta-cyclodextrin, and stirring to dissolve. Adding 1M potassium hydroxide solution, alkalizing sulfobutyl ether-beta-cyclodextrin sodium solution, and measuring the pH value to be 8.5-9.5;
(2) Adding the fampicin, stirring for 0.25-0.5 h to obtain a clear solution, regulating the pH of the solution to be between 6.8 and 7.6 by using a 1M potassium hydroxide solution or a 6M phosphoric acid solution, preferably, supplementing water to the full amount, and filtering by using a 0.22 mu M filter membrane;
(3) Filling the filtrate into 15 or 20mL penicillin bottles, sealing, sterilizing with terminal moist heat (121 ℃ C., sterilizing for 12 min), packaging and storing.
Example 4:
100 prescriptions
Preparation method
(1) Taking water for injection with the prescription amount of 70%, heating to the temperature of between 60 and 75 ℃, adding sodium sulfobutyl ether-beta-cyclodextrin, and stirring to dissolve. Adding 1M sodium hydroxide solution, alkalizing sulfobutyl ether-beta-cyclodextrin sodium solution, and measuring the pH value to be 8.5-9.5;
(2) Adding the fampicin, stirring for 0.25-1 h to obtain a clear solution, regulating the pH of the solution to be between 6.8 and 7.6 by using 1M hydrochloric acid or 1M sodium hydroxide solution, preferably pH 7.2, supplementing water to the full amount, and filtering by using a 0.22 mu M filter membrane;
(3) Filling filtrate into ampoule bottles with 10mL of each bottle, sealing, sterilizing with terminal moist heat (121deg.C, sterilizing for 12 min), packaging, and storing.
Example 5:
100 prescriptions
Preparation method
(1) Taking water for injection with the prescription amount of 70%, heating to the temperature of between 60 and 80 ℃, adding sodium sulfobutyl ether-beta-cyclodextrin, and stirring to dissolve. Adding 10% ammonia water solution, alkalizing sulfobutyl ether-beta-cyclodextrin sodium solution, and measuring the pH value to be 8.5-9.5;
(2) Adding the fampicin, stirring for 0.25-1 h to obtain a clear solution, regulating the pH of the solution to be between 6.8 and 7.6 by using 1M hydrochloric acid or 10% ammonia water solution, preferably pH 7.2, supplementing water to the whole amount, and filtering by using a 0.22 mu M filter membrane;
(3) Filling the filtrate into 15 or 20mL penicillin bottles, sealing, sterilizing with terminal moist heat (121 ℃ C., sterilizing for 15 min), packaging and storing.
Example 6:
100 prescriptions
Preparation method
(1) Taking 80% of water for injection, heating to 70-80 ℃, adding sulfobutyl ether-beta-cyclodextrin sodium, and stirring to dissolve. Adding 1M potassium hydroxide solution, alkalizing sulfobutyl ether-beta-cyclodextrin sodium solution, and measuring the pH value to be 8.5-9.5;
(2) Adding the fampicin, stirring for 0.5-1.5 h to obtain a clear solution, regulating the pH of the solution to be between 6.8 and 7.6 by using a 6M phosphoric acid solution or a 1M potassium hydroxide solution, preferably, supplementing water to the full amount, and filtering by using a 0.22 mu M filter membrane;
(3) Filling filtrate into ampoule bottles with 10mL of each bottle, sealing, sterilizing with terminal moist heat (121deg.C, sterilizing for 12 min), packaging, and storing.
Example 7:
100 prescriptions
Preparation method
(1) Taking 90% of water for injection, heating to 70-80 ℃, adding sulfobutyl ether-beta-cyclodextrin sodium, and stirring to dissolve. Adding 1M sodium hydroxide solution, alkalizing sulfobutyl ether-beta-cyclodextrin sodium solution, and measuring the pH value to be 8.5-9.5;
(2) Adding the fampicin, stirring for 1.0-2.0 h to obtain a clear solution, regulating the pH of the solution to be between 6.8 and 7.6 by using 1M hydrochloric acid or 1M sodium hydroxide solution, preferably pH 7.2, supplementing water to the full amount, and filtering by using a 0.22 mu M filter membrane;
(3) Filling filtrate into ampoule bottles with 10mL of each bottle, sealing, sterilizing with terminal moist heat (121deg.C, sterilizing for 12 min), packaging, and storing.
Example 8:
100 prescriptions
Preparation method
(1) Taking 90% of water for injection, heating to 70-80 ℃, adding sulfobutyl ether-beta-cyclodextrin sodium, and stirring to dissolve. Adding 10% ammonia water solution, alkalizing sulfobutyl ether-beta-cyclodextrin sodium solution, and measuring the pH value to be 8.5-9.5;
(2) Adding the fampicin, stirring for 1.0-2.0 h to obtain a clear solution, regulating the pH of the solution to be between 6.8 and 7.6 by using 1M hydrochloric acid or 10% ammonia water solution, preferably pH 7.2, supplementing water to the full amount, and filtering by using a 0.22 mu M filter membrane;
(3) Filling filtrate into ampoule bottles with 10mL of each bottle, sealing, sterilizing with terminal moist heat (121deg.C, sterilizing for 12 min), packaging, and storing.
Example 9:
100 prescriptions
Preparation method
(1) Taking 90% of water for injection, heating to 70-80 ℃, adding sulfobutyl ether-beta-cyclodextrin sodium, and stirring to dissolve. Adding 1M potassium hydroxide solution, alkalizing sulfobutyl ether-beta-cyclodextrin sodium solution, and measuring the pH value to be 8.5-9.5;
(2) Adding the fampicin, stirring for 1.0-2.0 h to obtain a clear solution, regulating the pH of the solution to be between 6.8 and 7.6 by using a 6M phosphoric acid solution or a 1M potassium hydroxide solution, preferably, supplementing water to the full amount, and filtering by using a 0.22 mu M filter membrane;
(3) Filling the filtrate into 15 or 20mL penicillin bottles, sealing, sterilizing with terminal moist heat (121 ℃ C., sterilizing for 12 min), packaging and storing.
Example 10:
100 prescriptions
Preparation method
(1) Taking 90% of water for injection, heating to 70-80 ℃, adding sulfobutyl ether-beta-cyclodextrin sodium, and stirring to dissolve. Adding 1M sodium hydroxide solution, alkalizing sulfobutyl ether-beta-cyclodextrin sodium solution, and measuring the pH value to be 8.5-9.5;
(2) Adding the fampicin, stirring for 1.0-2.0 h to obtain a clear solution, regulating the pH of the solution to be between 6.8 and 7.6 by using 1M hydrochloric acid or 1M sodium hydroxide solution, preferably pH 7.2, supplementing water to the full amount, and filtering by using a 0.22 mu M filter membrane;
(3) Filling the filtrate into 15 or 20mL penicillin bottles, sealing, sterilizing with terminal moist heat (121 ℃ C., sterilizing for 15 min), packaging, and storing.
Test example 1:
according to the drug stability research guidelines in the Chinese pharmacopoeia 2015 edition, the injection of the fampicin prepared in the representative example 1, the example 4 and the example 7 is subjected to long-term and accelerated stability test investigation. The influence factors are considered to be the stability of the injection under strong light and high temperature conditions, and the specific conditions are as follows: intense light (4500.+ -. 500 LX), high temperature (60 ℃ C.). The long-term test investigation condition is that the temperature is 25+/-2 ℃ and the relative humidity is 60+/-10%; the accelerated test conditions are that the temperature is 40+/-2 ℃ and the relative humidity is 75+/-5%. The stability study items were: solution color, pH, related substances, content, etc.
The amount of fampicin in the fampicin injection can be determined by reference to the following HPLC conditions: chromatographic column: octadecylsilane chemically bonded silica column (Agela MP C) 18 (2) (4.6 x 250mm,5 μm); column temperature: 25 ℃; mobile phase: 0.6% aqueous trifluoroacetic acid (pH adjusted to 2.6 with triethylamine) -acetonitrile (92:8); flow rate: 1.0ml/min; sample injection volume: 20 μl; a detector: UV detector (wavelength 323 nm); system applicability: the separation degree of the chromatographic peak of the impurity E (6-fluoro-3-hydroxy pyrazinyl-2-formic acid) and the peak of the Fapila Wei Sepu is not less than 4.0, and the theoretical plate number is not less than 3000 calculated according to the Fapila Wei Feng. The method can be used for measuring the fampicin with the purity of more than 99.5% and impurities thereof as a reference substance. In the present invention, unless otherwise specified, the amount or relative amount of fampicin in the composition or drug substance is determined by the method of HPLC conditions described above.
The determination of related substances of the fampicvir in the fampicvir injection can be determined by referring to the same HPLC conditions of the content determination, and the known impurities and the unknown impurities in the composition or the bulk drug are quantitatively calculated according to a main component self-dilution control method.
Other evaluation indexes of the Fabry-Perot injection, such as solution color, such as pH value, can be measured by referring to the recognized pharmacopoeia method of ICH member state or the verified method by adopting proper instruments and equipment.
Table 1, representative example 1, example 4 and example 7 product impact test results
Note that: * Impurity E is Fapila Wei Jianxing degradation product, and has chemical name of 6-fluoro-3-hydroxy pyrazinyl-2-carboxylic acid
Table 2, representative example 1, example 4 and example 7 product long term and accelerated stability test results
Note that: * Impurity E is Fapila Wei Jianxing degradation product, and has chemical name of 6-fluoro-3-hydroxy pyrazinyl-2-carboxylic acid
Conclusion of study: under the conditions of acceleration test, long-term test, strong light and high temperature, the quality attributes of the injection solution of the invention are not obviously changed, the stability is good, and the requirements of medicine production, transportation and storage can be completely met. It is particularly pointed out that the basic degradation product impurities are not significantly increased and are always within the threshold of 0.5%.
Test example 2:
since the injection administration program of the famprivir injection is to be recommended clinically, the method comprises the following steps: the injection is diluted by normal saline or 5% glucose and then is injected or instilled by intravenous injection. In order to examine the possibility of precipitation and crystallization during dilution, the concentration of sodium sulfobutyl ether-beta-cyclodextrin was reduced (solubilization effect was also significantly reduced). Therefore, we studied the stability of the injection solutions of example 1 (the minimum sulfobutyl ether-beta-cyclodextrin sodium concentration) and example 10 (the maximum sulfobutyl ether-beta-cyclodextrin sodium concentration) in compatibility (clinical use) with physiological saline and 5% dextrose injection.
One piece of the fampicin injection was diluted to 500mL with physiological saline or 5% dextrose injection. The prepared medicinal liquid was left at room temperature for 12 hours, and the appearance, pH and content of the prepared medicinal liquid before and after leaving were measured, and the measurement results were shown in Table 3 below.
Table 3, representative example 1, example 10 stability test results for compatibility of injections
* Relative to the initial content after dilution
Conclusion of study: the fampicin injection prepared in example 1 and example 10 has no obvious change in appearance (color), pH and content within 12 hours of compatibility, and can meet the clinical use requirement.
Test example 3:
safety evaluation was performed using the fampicin injections prepared in representative example 4, example 5 and example 6.
3.1 method of hemolytic test of Piracvir injection liquid in vitro method
The study was performed using New Zealand rabbit red blood cells (2.5 ml of 2% red blood cell suspension) and 2.5ml distilled water as a positive control. The volumes of the fampicin injection are respectively 0.5mL, 0.4mL, 0.3mL, 0.2mL and 0.1mL, the concentrations of the fampicin injection are 0.6mg/mL, and the fampicin injection is incubated at 37+/-0.5 ℃ for 3 hours, and if the solution is clear red, the fampicin injection is considered to have hemolysis. If not, the labeling results in no hemolysis.
3.2 systemic active allergy test of guinea pigs by Fabry-Perot injection
And (3) selecting guinea pigs as experimental objects, setting up a negative control group, a positive control group and a high-low dose group of the Fapiravir injection, and carrying out a systemic active allergy experiment. The groups of guinea pigs were sensitized by intraperitoneal injection (ip) of 0.5 mL/dose of sodium chloride injection, 3mg/mL of ovalbumin solution and 3 times of fapirovir solution with concentrations of 30mg/mL and 20mg/mL, respectively, every other day. The toe vein is rapidly injected with the corresponding concentration of the medicine for excitation at days 14 and 21 after the last sensitization, and the concentration is 1.0 ml/patient. Each time 1/2 animals were challenged, the male and female halves. Systemic allergic symptoms were then observed and ranked according to the systemic sensitization evaluation criteria. If there is no obvious allergic symptom, it is judged as "-".
3.3 New Zealand rabbit vascular irritation test with Fabry-Perot injection
New Zealand rabbits are selected as test objects, and a self-comparison method of the left side and the right side of the same body is adopted for testing. The right ear margin of each New Zealand rabbit is administrated with the solution of the Fabry-Perot injection with the concentration of 0.6mg/mL, and the left ear margin is administrated with the same volume of sodium chloride injection. The administration volume was 11.18mL/kg, and the injection was performed at a rate of 4.2mL/min using a microinjection pump. The administration was 1 time per day, followed by 6d. Part of animals (male and female halves) were sacrificed 72h after the last dose, and the remaining animals were sacrificed after the end of the recovery period observation. The ear edge tissue containing blood vessels is cut, and obvious macroscopic irritation symptoms such as thrombosis, endothelial injury and the like are observed. 10% neutral formalin fixation, conventional tissue sections were examined for histopathology. And judging the stimulation score according to the histopathological scoring standard, comparing the stimulation score with the control score, and taking the difference value as a final assessment basis.
The above test results are summarized in table 4 below:
TABLE 4 safety evaluation test results of Fabry-Perot injection
Conclusion of study: the fampicin injection prepared in example 4, example 5 and example 6 does not show hemolysis, allergy and vascular irritation, has good safety, and indicates clinical medication safety and applicability of various acid-base regulators in injection formulations.
Drawings
FIG. 1 is a graph of Fabry-Perot Wei Baohe solubility as a function of sulfobutylether-beta-cyclodextrin Sodium (SBECD) concentration and pH, wherein the abscissa indicates SBECD concentration (mg/mL) and the ordinate indicates Fabry-Perot solubility (mg/mL).
FIG. 2 is a graph of the solubility of Fabry Wei Baohe in 40% (w/v) (400 mg/mL) SBECD solution as a function of impurity E levels and pH after terminal sterilization of the solution, wherein the abscissa represents different pH values, the left Y-axis represents Fabry-Perot solubility (mg/mL) and the right Y-axis represents impurity E content (%).
Claims (5)
1. A stable injection of famprivir contains famprivir as an active ingredient and sodium sulfobutyl ether-beta-cyclodextrin;
the concentration of the fampicin in the injection is 25-40 mg/mL, and the concentration of the sulfobutyl ether-beta-cyclodextrin sodium is 300-500 mg/mL;
the pH of the injection is 6.8 to 7.6.
2. The injection according to claim 1, wherein the concentration of fampicvir in the injection is 30mg/mL and the concentration of sodium sulfobutyl ether- β -cyclodextrin is 400mg/mL.
3. The injection according to claim 1, wherein the pH of the injection is 7.2.
4. The injection according to claim 1, wherein the injection further comprises a pH adjuster.
5. The method for preparing an injection according to any one of claims 1 to 4, wherein the sterilization is performed by a terminal sterilization method;
the method comprises the following steps:
(1) Taking water for injection with the prescription amount of 60-90%, heating to the temperature of 50-80 ℃, adding sulfobutyl ether-beta-cyclodextrin sodium, and stirring to dissolve; adding an alkaline regulator solution, and alkalizing a sulfobutyl ether-beta-cyclodextrin sodium solution;
(2) Adding fampicin, stirring for 0.25-2 h to obtain a clear solution, regulating the pH value of the solution to between 6.8 and 7.6 by using an acid-base regulator, supplementing water to the full amount, and filtering by using a 0.22 mu m filter membrane;
(3) Filling the filtrate into a penicillin bottle or an ampoule bottle, sealing, performing terminal damp-heat sterilization, sterilizing at 115-126 ℃ for 10-40 min, packaging and storing.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010161960.1A CN111249229B (en) | 2020-03-10 | 2020-03-10 | Stable fampicin injection and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010161960.1A CN111249229B (en) | 2020-03-10 | 2020-03-10 | Stable fampicin injection and preparation method thereof |
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| Publication Number | Publication Date |
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| CN111249229A CN111249229A (en) | 2020-06-09 |
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| CN103209966A (en) * | 2010-09-30 | 2013-07-17 | 富山化学工业株式会社 | Sodium salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide |
| CN105884827A (en) * | 2015-02-13 | 2016-08-24 | 山东轩竹医药科技有限公司 | Pyrimidine amide derivative and salt |
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| CN103209966A (en) * | 2010-09-30 | 2013-07-17 | 富山化学工业株式会社 | Sodium salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide |
| CN105884827A (en) * | 2015-02-13 | 2016-08-24 | 山东轩竹医药科技有限公司 | Pyrimidine amide derivative and salt |
| WO2016172205A1 (en) * | 2015-04-20 | 2016-10-27 | Emory University | Managing ebola viral infections |
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| 磺丁基醚-β- 环糊精的增溶机制及在难溶性药物制剂中的应用;胡裕迪等;《中国医药工业杂志》;20181231;第49卷(第3期);第292-300页 * |
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