CN114053397A - Stable interferon multi-dose injection and preparation method thereof - Google Patents
Stable interferon multi-dose injection and preparation method thereof Download PDFInfo
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Abstract
The application relates to the technical field of pharmaceutical preparations, and particularly discloses a stable interferon multi-dose injection. The injection comprises the following components in parts by weight, wherein the components are 0.05 to 0.1 part of interferon in 1000 parts by weight; 1.0-1.5 parts of disodium hydrogen phosphate; 0.1-0.5 part of citric acid; 6.5-7.5 parts of sodium chloride; 8.0-12.0 parts of human serum albumin; 1.0-2.5 parts of phenol; 2.0-3.0 parts of m-cresol; the balance being solvent. The interferon multi-dose injection provided by the application can effectively improve the bacteriostatic effect of the interferon multi-dose injection in a short time while ensuring the long-term bacteriostatic effect of the injection, and meets the requirement of injection A in bacteriostatic efficacy examination in 'Chinese pharmacopoeia' 2020 edition.
Description
Technical Field
The application relates to the technical field of pharmaceutical preparations, in particular to a stable interferon multi-dose injection and a preparation method thereof.
Background
The interferon has wide antiviral, antitumor and immunoregulation functions, has the action mechanism that various antiviral proteins are induced, the virus is inhibited from being replicated in cells, the activity of NK cells and other immunoregulation functions are enhanced, the virus invasion and infection are effectively inhibited, and the interferon has the effects of inhibiting the growth of tumor cells, eliminating early diseased cells and the like. The large types of the protein can be classified into large types such as alpha, beta, gamma, lambda and the like according to the difference of the generation part and the action mechanism, each large type can be divided into a plurality of small subtypes, and the different subtypes in the same large type have small difference on the primary structure and are very close to the high structure above the secondary structure. Among several major types, the α -type interferon is the most widely used one, and the α -type interferons currently used clinically mainly include interferon α 2a, interferon α 2b, interferon α 1b, consensus interferon, and the like.
The interferon injection products sold in the market at present are divided into two types, namely common interferon and PEG modified long-acting interferon. The common interferon is commonly packaged in penicillin bottles, and the packaging form has the defects of complicated extraction and injection steps, fixed specification and inconvenient dose adjustment. Meanwhile, the patient frequently goes to a hospital for injection, so that limited medical resources are occupied, the economic burden of the patient is increased, and the patient can worry about privacy exposure, irregular administration and administration interruption are caused, and the treatment effect is influenced. The approved PEG modified long-acting interferon variety on the market can obviously prolong the half-life period of the drug and improve the compliance of patients, but has high price, and the incidence rate and the severity of adverse reactions are higher than those of the common interferon.
Injection (refill) multi-dose products are a new packaging form for replacing traditional single dose products, and have been adopted by various injection products at home and abroad. The bottle is in the form of a cassette bottle, the inner packaging material is a borosilicate glass sleeve for a pen type syringe, the top of the bottle is sealed by a rubber plug aluminum cover, the liquid level of the medicine is contacted by a self-sealing rubber plug (gasket), and the bottom of the bottle is sealed by a rubber piston. The pen core filled with the liquid medicine in the bottle in advance is placed into the injection pen, the bottle cap does not need to be opened and the liquid medicine needs to be extracted during use, the double-sided special injection needle is fixed on the pen holder to puncture the rubber plug at the end of the aluminum cap, and the liquid medicine is injected out by the aid of the push rod in the pen. Quantitative and multiple injections can be realized as required by utilizing a micro volume adjusting and scale display device in the injection pen.
The advantages of a pharmaceutical multi-dose pen injection product over a traditional pharmaceutical injection product are: when in use, the medicine bottle for storing the injection does not need to be subjected to destructive opening treatment, thereby preventing the glass powder generated by crushing from entering the medicine liquid and entering the human body along with the medicine liquid to cause damage to the human body; when in use, the liquid medicine is not required to be transferred (from the packaging container to the injector), thereby avoiding the pollution of particles and microorganisms to the liquid medicine; the multi-dose injection pen is convenient to use, simplifies the injection process, can carry out self-injection at home, and is easier for patients to self-treat. The injection pen generally adopts the superfine needle, and the needle point is less in friction force and less in injection pain compared with the traditional syringe needle. The simple and easy-to-learn operation mode can be suitable for alternate injection of multiple parts such as the abdomen, the thighs, the upper arms and the like, and the psychological sense of fear of patients is reduced.
Compared with the 2010 edition, the judgment standard of the bacteriostatic effect in the 'Chinese pharmacopoeia' 2020 edition increases the time points of 6h and 24h, improves the requirement on the short-term bacteriostatic effect of the product, and has more rigorous screening of the dosage of the bacteriostatic agent and more scientific guiding significance.
In view of the above-mentioned related art, the inventor believes that the common problem of the multi-dose injection (pen core) product is that the interferon injection can not achieve the effect of complete bacteriostasis in a short time; meanwhile, in the process of opening the interferon injection for use, the stability of the interferon injection is poor, the activity is reduced or impurities are generated, the effectiveness and the safety of the product are influenced, the interferon injection needs to be used within 20 to 30 days, otherwise, the interferon injection is invalid and cannot be used continuously.
Disclosure of Invention
In order to improve the bacteriostatic effect of the interferon injection in a short time and improve the stability of the interferon injection in the using process, the application provides a stable interferon multi-dose injection and a preparation method thereof.
In a first aspect, the present application provides a stable interferon multi-dose injection, which adopts the following technical scheme:
a stable interferon multi-dose injection, which comprises the following components in parts by weight, calculated as 1000 parts by weight, 0.05-0.1 part of interferon; 1.0-1.5 parts of disodium hydrogen phosphate; 0.1-0.5 part of citric acid; 6.5-7.5 parts of sodium chloride; 8.0-12.0 parts of human serum albumin; 1.0-2.5 parts of phenol; 2.0-3.0 parts of m-cresol; the balance being solvent.
By adopting the technical scheme, on the basis that the interferon injection prescription using human serum albumin as the stabilizer is formed, the antibacterial effect of the interferon multi-dose injection in a short time can be effectively improved by matching phenol with m-cresol when the long-term antibacterial effect of the injection is ensured. By using the interferon multi-dose injection provided by the application, the antibacterial effect within 6h can meet the A-class requirement of the injection in Chinese pharmacopoeia, and the antibacterial effect within 24h can completely kill bacteria and fungi.
Since the interferon multi-dose injection is inevitably exposed to air during use and is easily contaminated by microorganisms in the air, it is necessary to add a bacteriostatic agent to the interferon multi-dose injection in order to ensure the bacteriostatic effect and stability of the interferon multi-dose injection. In the interferon multi-dose injection provided by the application, phenol and m-cresol are used as bacteriostatic agents.
Phenol is colorless or reddish needle-like crystal or crystalline block, is corrosive, is deliquescent, is soluble in ethanol, glycerol, chloroform, diethyl ether, vegetable oil and carbon disulfide, and is slightly soluble in liquid paraffin. The aqueous solution of phenol is slightly acidic and gradually darkens when meeting light or in the air; under alkaline conditions, the color change described above is accelerated. The solubility of phenol in water was 1g phenol soluble in 15ml water at 20 ℃. Phenol has a spectrum of antimicrobial effects against a variety of microorganisms such as gram negative bacteria, gram positive bacteria, mycobacteria, and certain fungi and viruses. The inhibitory effect of phenol on spores is very slow. In addition, the phenol has a strong bacteriostatic effect in an acidic solution, and meanwhile, the bacteriostatic effect of the phenol can be increased by raising the temperature.
M-cresol is a clear liquid that is almost colorless, purplish red or brownish yellow, and gradually darkens upon storage for a long period of time or in sunlight. The saturated aqueous solution of m-cresol is neutral or weakly acidic, and can be mixed with ethanol, chloroform, diethyl ether, glycerol, fatty oil or volatile oil. M-cresol is sparingly soluble in water to give a cloudy solution, and m-cresol can also be dissolved in alkaline solutions. The solubility of m-cresol in water is 1g phenol soluble in 50ml water at 20 ℃. The m-cresol has the bacteriostatic activity similar to that of phenol and slightly stronger than that of phenol, and can resist gram-positive bacteria, and has lower bacteriostatic effect on gram-negative bacteria, saccharomycetes and moulds. M-cresol has a high activity at a pH of 9 or less, and also has a high activity under acidic conditions.
Experiments prove that the human serum albumin, the phenol and the m-cresol can generate interaction, so that the bacteriostatic effect of the bacteriostatic agent on the interferon injection is influenced. When phenol and m-cresol are used in a matched mode, the adding amount of phenol is controlled within the range of 1.0-2.5 parts, and the adding amount of m-cresol is controlled within the range of 2.0-3.0 parts, so that the interferon multi-dose injection provided by the application has a good bacteriostatic effect in a short time.
Preferably, the injection comprises the following components in parts by weight, calculated by 1000 parts by weight, 0.05-0.1 part of interferon; 1.0-1.5 parts of disodium hydrogen phosphate; 0.1-0.5 part of citric acid; 6.5-7.5 parts of sodium chloride; 8.0-12.0 parts of human serum albumin; 1.5-2.5 parts of phenol; 2.5-3.0 parts of m-cresol; the balance being solvent.
In a specific embodiment, the phenol may be added in an amount of 1.0 part, 1.5 parts, 2.0 parts, 2.5 parts by weight.
In a specific embodiment, the phenol may be added in an amount of 1.0 to 1.5 parts, 1.0 to 2.0 parts, 1.5 to 2.0 parts, 2.0 to 2.5 parts by weight.
In a specific embodiment, the m-cresol may be added in an amount of 2.0 parts, 2.5 parts, 3.0 parts by weight.
In a specific embodiment, the m-cresol may be added in an amount of 2.0 to 2.5 parts by weight.
By adopting the technical scheme, through experimental analysis, when the addition amount of phenol in the injection is controlled within the range of 1.5-2.5 parts and the addition amount of m-cresol is controlled within the range of 2.5-3.0 parts, the interferon multi-dose injection can be further improved to have a good antibacterial effect in a short time.
Preferably, the total adding weight parts of the phenol and the m-cresol are 3.5-5.0 parts.
Preferably, the total adding weight parts of the phenol and the m-cresol are 4.0 to 5.0 parts.
In a specific embodiment, the total added parts by weight of phenol and m-cresol may be 3.0 parts, 3.5 parts, 4.0 parts, 4.5 parts, 5.0 parts, 5.5 parts.
In a specific embodiment, the total added parts by weight of the phenol and m-cresol may be 3.0 to 3.5 parts, 3.0 to 4.0 parts, 3.0 to 4.5 parts, 3.0 to 5.0 parts, 3.0 to 5.5 parts, 3.5 to 4.0 parts, 3.5 to 4.5 parts, 3.5 to 5.0 parts, 3.5 to 5.5 parts, 4.0 to 4.5 parts, 4.0 to 5.5 parts, 4.5 to 5.0 parts, 4.5 to 5.5 parts, 5.0 to 5.5 parts.
By adopting the technical scheme, through experimental analysis, when the sum of the addition amounts of phenol and m-cresol is selectively controlled within the range of 3.5-5.0 parts, the interferon multi-dose injection provided by the application can be ensured to have a remarkable antibacterial effect within 24 hours while the antibacterial effect within 6 hours, and the quality of the interferon multi-dose injection is further guaranteed on the basis of meeting the A-type standard of the injection in Chinese pharmacopoeia.
Preferably, the interferon comprises interferon alpha, interferon beta and interferon gamma subtypes.
Preferably, the solvent is water for injection.
Preferably, the pH of the injection is in the range of 6.5-7.5.
In a second aspect, the present application provides a method for preparing a stable interferon multi-dose injection, which adopts the following technical scheme:
a preparation method of a stable interferon multi-dose injection specifically comprises the following steps:
(1) preparing a buffer solution by using disodium hydrogen phosphate, citric acid and sodium chloride according to the adding proportion of the components, and sterilizing; preparing a bacteriostatic agent solution by using phenol and m-cresol;
(2) adding the buffer solution prepared in the step (1), interferon and human serum albumin into a solvent, and uniformly mixing to prepare a prefabricated liquid;
(3) and (3) adding the bacteriostatic agent solution prepared in the step (1) into the prefabricated liquid prepared in the step (2), complementing the volume with a solvent, filtering and sterilizing to obtain the injection.
In summary, the present application has the following beneficial effects:
by researching the matching prescription of phenol and m-cresol in the interferon multi-dose injection, the provided interferon multi-dose injection can effectively improve the bacteriostatic effect of the interferon multi-dose injection in a short time while ensuring the long-term bacteriostatic effect of the injection, and meets the requirement of injection A in bacteriostatic efficacy examination in 'Chinese pharmacopoeia' 2020 edition.
In addition, the interferon multi-dose injection provided by the application can also ensure the safety and stability of products, and the preparation method is simple and easy to realize industrial production. Compared with the interferon single-dose injection, the interferon multi-dose injection provided by the application is more beneficial to long-term use of patients, so that the times of the patients going to and from the hospital are reduced, and the patients can take the medicine on time.
Drawings
Fig. 1 is a flow chart of a method for preparing an interferon multi-dose injection provided herein.
Detailed Description
The application provides a stable interferon multi-dose injection, which comprises the following components in parts by weight, calculated by 1000 parts by weight, 0.05-0.1 part of interferon; 1.0-1.5 parts of disodium hydrogen phosphate; 0.1-0.5 part of citric acid; 6.5-7.5 parts of sodium chloride; 8.0-12.0 parts of human serum albumin; 1.0-2.5 parts of phenol; 2.0-3.0 parts of m-cresol; the balance being solvent.
Further, the injection comprises the following components in parts by weight, calculated by 1000 parts by weight, 0.05-0.1 part of interferon; 1.0-1.5 parts of disodium hydrogen phosphate; 0.1-0.5 part of citric acid; 6.5-7.5 parts of sodium chloride; 8.0-12.0 parts of human serum albumin; 1.5-2.5 parts of phenol; 2.5-3.0 parts of m-cresol; the balance being solvent.
Further, the total adding weight parts of the phenol and the m-cresol are 3.5-5.0 parts. Still further, the total adding weight part of the phenol and the m-cresol is 4.0 to 5.0 parts.
Wherein the interferon comprises interferon alpha, interferon beta and interferon gamma subtypes. The solvent is water for injection. The pH value of the injection is in the range of 6.5-7.5.
The application also provides a preparation method of the stable interferon multi-dose injection, which specifically comprises the following steps:
(1) preparing a buffer solution by using disodium hydrogen phosphate, citric acid and sodium chloride according to the adding proportion of the components, and sterilizing; preparing a bacteriostatic agent solution by using phenol and m-cresol;
(2) adding the buffer solution prepared in the step (1), interferon and human serum albumin into a solvent, and uniformly mixing to prepare a prefabricated liquid;
(3) and (3) adding the bacteriostatic agent solution prepared in the step (1) into the prefabricated liquid prepared in the step (2), complementing the volume with a solvent, filtering and sterilizing to obtain the injection.
The present application is described in further detail below with reference to the performance testing tests of examples 1-9 and comparative examples 1-8.
Examples
Examples 1 to 9
Examples 1-9 each provide a stable multi-dose injection of interferon. Examples 1 to 9 differ, among others, in the amounts of the components added in the injections prepared, as shown in table 1.
The preparation method of the stable interferon multi-dose injection specifically comprises the following steps:
(1) adding the disodium hydrogen phosphate, the citric acid and the sodium chloride into 300ml of water for injection according to the adding amounts of the disodium hydrogen phosphate, the citric acid and the sodium chloride in the table 1, fully dissolving to prepare a buffer solution, sterilizing at 121 ℃, and cooling for later use.
Phenol and m-cresol were added to 300ml of water for injection in accordance with the amounts of phenol and m-cresol in Table 1 to prepare bacteriostatic solutions.
(2) And (2) sequentially adding the buffer solution prepared in the step (1), the interferon and the injection human blood albumin into 100ml of injection water, and uniformly stirring to prepare a prefabricated liquid. Wherein the interferon type is interferon alpha 1 b.
(3) And (3) adding the bacteriostatic agent solution prepared in the step (1) into the prefabricated liquid prepared in the step (2), supplementing the volume with water for injection, uniformly stirring, filtering and sterilizing to obtain the injection.
(4) And (4) filling and capping the injection prepared in the step (3) to prepare a finished product to be packaged.
(5) And (4) placing the finished product to be packaged prepared in the step (4) at the temperature of 2-8 ℃ in a dark place for storage, and carrying out external packaging after detection and determination are qualified.
Comparative example
Comparative examples 1 to 6
Comparative examples 1 to 6 each provide a stable interferon multi-dose injection. Among them, comparative examples 1 to 6 are different from example 1 in the amounts of the components added in the prepared injection solutions, as shown in table 1.
TABLE 1 amounts of components added to injections prepared in examples 1 to 9 and comparative examples 1 to 6
Comparative example 7
This comparative example provides a stable interferon multi-dose injection. It differs from example 5 in that: polysorbate is used as a stabilizer to replace human serum albumin.
Comparative example 8
This comparative example provides a stable interferon multi-dose injection. It differs from example 5 in that: 5g of polyethoxyether 80 as a stabilizer and 5g of disodium edetate as a chelating agent were used instead of human serum albumin.
Performance test
Detection test (one) -bacteriostatic efficacy
The injection prepared in examples 1-9 and comparative examples 1-8 were tested for bacteriostatic effect according to the bacteriostatic efficacy test method of <1121> of general rules of the four parts of the world, the year 2020, pharmacopoeia.
Test strain
(1) Bacteria-staphylococcus aureus, pseudomonas aeruginosa
Staphylococcus aureus: the bacterial suspension is prepared by using 0.9% sterile sodium chloride solution, and the concentration of the bacterial suspension is about 108cfu/ml。
Pseudomonas aeruginosa: the bacterial suspension is prepared by using 0.9% sterile sodium chloride solution, and the concentration of the bacterial suspension is about 108cfu/ml。
(2) Fungi-aspergillus niger, candida albicans
Aspergillus niger: spore suspension prepared from 0.9% sterile sodium chloride solution containing 0.05% (ml/ml) polysorbate 80, and having a concentration of about 10%8cfu/ml。
Candida albicans: the bacterial suspension is prepared by using 0.9% sterile sodium chloride solution, and the concentration of the bacterial suspension is about 108cfu/mL。
Storage and use conditions of the test strains: the product is stored at room temperature and should be used within 2 h; can be used within 24h when stored at 2-8 ℃. The spore suspension of Aspergillus niger can be stored at 2-8 deg.C and used within 7 days.
Second, detection method
(1) Culture medium for inoculation of bacteria: trypticase soy peptone agar medium.
(2) Culture medium inoculated with fungi: sabouraud dextrose agar medium.
(3) The injections prepared in examples 1 to 9 and comparative examples 1 to 8 were used to inoculate four kinds of bacteria, namely staphylococcus aureus, pseudomonas aeruginosa, candida albicans and aspergillus niger. The inoculation amount in 1ml injection is 105~106cfu, the volume of the inoculated bacteria liquid is not more than 1 percent of the volume of the injection liquid, the inoculated bacteria liquid and the injection liquid are fully mixed, the test bacteria in the injection liquid are uniformly distributed, and the injection liquid is stored in a dark place at the temperature of 20-25 ℃. The number of bacteria contained in the injection solutions was measured at time intervals shown in Table 3.
Third, detection Standard
The detection criteria are shown in table 2.
TABLE 2 test standard for antibacterial efficacy of injection, China pharmacopoeia 2020 edition
The lg value of the injection at each time interval of the bacterial and fungal count is compared with the value of 0h, and the reduction value of the injection meets the A-type standard.
Fourth, the detection result
The results are shown in tables 3 to 6.
TABLE 3 examination of the bacteriostatic Effect (I) -Staphylococcus aureus (lg)
With reference to table 3, by comparing the results of the antimicrobial tests of the interferon multi-dose injections provided in examples 1 to 9 and comparative examples 1 to 8 on staphylococcus aureus, it can be known that the interferon multi-dose injection provided by the present application has a good antimicrobial effect within a short time, and the antimicrobial effects within 6 hours and 24 hours can satisfy the class a standards of injections in the "chinese pharmacopoeia".
By comparing the test results of the examples 1-3 and the comparative example 1, it can be seen that when the amount of m-cresol added is controlled within the range of 2.0-3.0g, the decreased lg value of the interferon multi-dose injection provided by the application reaches 2.14-2.52 in the inhibitory effect on staphylococcus aureus within 6h, and the decreased lg value is greater than 2, so that the injection A standard in the Chinese pharmacopoeia is met. When the addition amount of the m-cresol is 1.5g, namely the interferon multi-dose injection provided by the comparative example 1 has the inhibiting effect on staphylococcus aureus within 6h, the reduced lg value is 1.65 degrees, the reduced lg value is less than 2, and the A-type standard of the injection in Chinese pharmacopoeia is not met. In addition, according to the regulation of the Chinese pharmacopoeia, the addition amount of m-cresol in the injection cannot be more than 0.3%, and therefore, in the examples provided in the present application, the case where the addition amount of m-cresol is more than 3.0g is not considered. Based on the above, in the present application, when the amount of m-cresol added is controlled within the range of 2.0 to 3.0 parts, the interferon multi-dose injection provided has a good bacteriostatic effect in a short time.
Further, when the amount of added m-cresol is controlled within the range of 2.5 to 3.0g, the lg value of the interferon multi-dose injection provided by the application, which decreases in the inhibitory effect on staphylococcus aureus within 6h, is larger than the lg value of the interferon multi-dose injection, which decreases in the inhibitory effect on staphylococcus aureus within 6h when the amount of added m-cresol is 2.0g, so that the amount of added m-cresol is further selectively controlled within the range of 2.5 to 3.0 parts.
By comparing the detection results of the embodiment 2, the embodiment 4-6, the embodiment 9 and the comparative example 2, when the addition amount of the phenol is controlled within the range of 1.0-2.5g, the lg value of the interferon multi-dose injection provided by the application is reduced to 2.41-3.15 in the inhibiting effect on staphylococcus aureus within 6h, the lg value is reduced to be more than 2, and the injection A standard in Chinese pharmacopoeia is met. When the addition amount of the m-cresol is 0.5g, namely the interferon multi-dose injection provided by the comparative example 2 has the inhibiting effect on staphylococcus aureus within 6h, the reduced lg value is 1.73, the reduced lg value is less than 2, and the requirement of injection A standard in Chinese pharmacopoeia is not met. In addition, when the amount of m-cresol added was 3.0g, i.e., the inhibitory effect of the interferon multi-dose injection provided in example 9 on staphylococcus aureus was found to be 3.07 in 6 hours, the lg value decreased was less than 2, but the lg value decreased was not substantially changed significantly as compared with example 6. Based on the above, in the present application, when the amount of phenol added is controlled within the range of 1.0 to 2.5 parts, the interferon multi-dose injection provided has a good bacteriostatic effect in a short time.
Further, when the amount of phenol added is controlled within the range of 2.0 to 2.5g, the lg value of the interferon multi-dose injection provided by the application, which is reduced in the inhibitory effect on staphylococcus aureus within 6h, is larger than the lg value of the interferon multi-dose injection, which is reduced in the inhibitory effect on staphylococcus aureus within 6h when the amount of m-cresol added is 1.0g, so that the amount of m-cresol added is further selectively controlled within the range of 1.5 to 2.5 parts.
In addition, the test results of comparative examples 1-6 and example 9 show that the interferon multi-dose injection provided by the application has a remarkable inhibitory effect on staphylococcus aureus within 24h when the sum of the addition amounts of phenol and m-cresol is controlled to be 3.5-5.0 g. When the sum of the addition amount of phenol and m-cresol is 3.0g, the interferon multi-dose injection provided by the embodiment 1 can meet the requirement of injection A standard in Chinese pharmacopoeia within 24 h. But the bacteriostatic effect when the sum of the addition amounts of the phenol and the m-cresol is controlled to be 3.5-5.0g is obviously better than that when the sum of the addition amounts of the phenol and the m-cresol is controlled to be 3.0 g. In addition, when the sum of the addition amounts of phenol and m-toluene is greater than 5.5, that is, the interferon multi-dose injection provided in example 9, compared with example 6, the lg value of the interferon multi-dose injection provided in example 9 is reduced substantially without significant change in the inhibitory effect on staphylococcus aureus within 6 h. Based on the above, the sum of the addition amounts of phenol and m-cresol in the interferon multi-dose injection provided by the present application is further selectively controlled within the range of 3.5-5.0 parts.
As can be seen from the results of comparing examples 5 and 7 to 8, the interferon multi-dose injection provided by the present application has a good bacteriostatic effect in a short time when the amount of human blood albumin added to the interferon multi-dose injection is controlled within the range of 8.0 to 12.0 parts.
In addition, the detection results of the comparative examples 3 to 6 show that the lg values of the interferon multi-dose injection provided by the comparative examples 3 to 6 are all less than 2 in the inhibiting effect on staphylococcus aureus in 6h, and the requirement of the A-type standard of the injection in Chinese pharmacopoeia cannot be met.
As can be seen from the results of comparing examples 1 to 9 and comparative examples 7 to 8, the lg values of the interferon multi-dose injection solutions provided in comparative examples 7 to 8 were all reduced to less than 2 in the inhibitory effect against Staphylococcus aureus within 6 h. Therefore, the interferon multi-dose injection provided by the related technology can not meet the requirements of injection A standard in Chinese pharmacopoeia. The interferon multi-dose injection provided by the application can meet the requirement of injection A standard in Chinese pharmacopoeia within 6h for inhibiting staphylococcus aureus.
TABLE 4 examination of the bacteriostatic Effect (II) -Pseudomonas aeruginosa (lg)
With reference to table 4, by comparing the results of the antimicrobial tests of the interferon multi-dose injection solutions provided in examples 1 to 9 and comparative examples 1 to 8 on pseudomonas aeruginosa, it can be known that the interferon multi-dose injection solution provided by the present application has a good antimicrobial effect in a short time, and the antimicrobial effects in 6 hours and 24 hours can satisfy the class a standards of the injection solution in the "chinese pharmacopoeia".
TABLE 5 examination of the bacteriostatic Effect (III) -Candida albicans (lg)
TABLE 6 examination of the bacteriostatic Effect (IV) -Aspergillus niger (lg)
By combining table 5 and table 6, it can be known that the interferon multi-dose injection provided by the present application has a good bacteriostatic effect in a short time and the bacteriostatic effect in 7d can satisfy the class a standard of the injection in the "chinese pharmacopoeia" by comparing the bacteriostatic detection results of the interferon multi-dose injections provided by examples 1 to 9 and comparative examples 1 to 8 on candida albicans and aspergillus niger.
Detection test (II) -stability detection
The interferon injections prepared in examples 1 to 9 and comparative examples 1 to 8 were used as test subjects, and stability of the test subjects was measured.
First, detection standard
The limits for the quality attributes of the interferon injections are shown in table 7.
TABLE 7 Interferon injection Limit requirements
Second, detection method and detection result
Consideration of influence factors
1. High temperature conditions
The test subjects were placed under high temperature conditions (37. + -. 2 ℃ C.) for 10 days, and their mass attributes were measured at 0, 5 and 10 days, respectively, and the results are shown in Table 8.
TABLE 8 influence factors high temperature conditions-test results
The results of table 8 show that the interferon multi-dose injections provided in examples 2 and 5 were left at 37 ℃ for 10 days without significant changes in appearance, visible impurities, pH, and osmotic pressure. Although the biological activity was reduced, the change was minor and was within the acceptable range. But the content of interferon is reduced, which is not satisfactory. Meanwhile, the content of phenol and m-cresol is not changed obviously. Therefore, the stability of the interferon multi-dose injection is influenced by high temperature, and the interferon multi-dose injection is prevented from being placed in a high-temperature environment for a long time in the processes of production, storage and transportation.
2. Light conditions
The test subjects were placed under light conditions (4500 lux. + -. 500 lux/25. + -. 2 ℃ C.) for 10 days, and their mass attributes were measured at 0, 5 and 10 days, respectively, with the results shown in Table 9.
TABLE 9 influencing factor illumination conditions-test results
The results of the tests shown in table 9 show that the interferon multi-dose injections provided in examples 2 and 5 were left in a light environment for 10 days, and the appearance of the injections changed from colorless transparent to pale pink transparent liquid, visible foreign substances, pH, and osmotic pressure. Although the biological activity was reduced, the change was minor and was within the acceptable range. No significant change in phenol and m-cresol content was seen. It is known that light irradiation has a certain influence on the stability of interferon multi-dose injection solutions. Phenol is oxidized into yellowish red benzoquinone by oxygen in the air, or potassium permanganate, potassium dichromate (acidic) and even manganese dioxide, sodium chlorate (acidic), and m-cresol is oxidized to produce p-diphenoquinone and o-diphenoquinone, which are pink in color. Therefore, the multi-dose interferon injection should be prevented from being placed in the light environment for a long time during the production, storage and transportation processes.
3. Oxidation conditions
The test subjects were exposed to air (5. + -. 3 ℃ C.) for 10 days, and their mass attributes were measured at 0, 5 and 10 days, respectively, and the measurement results are shown in Table 10.
TABLE 10 Effect factor Oxidation conditions-test results
The results of the tests shown in table 10 show that the interferon multi-dose injections provided in examples 2 and 5 were exposed to air for 10 days, and no significant changes were observed in appearance, visible impurities, pH, and osmotic pressure. Although the biological activity was reduced, the change was minor and was within the acceptable range. No significant change in phenol and m-cresol content was seen. It can be seen that air exposure has less effect on the stability of interferon multi-dose injection solutions.
(II) accelerated test
The test subjects were placed under acceleration conditions (25. + -. 2 ℃ C.) for 6 months, and the quality attributes were measured at 0, 1, 3, and 6 months, respectively, and the measurement results are shown in Table 11.
TABLE 11 accelerated test-test results
As can be seen from the results of the tests shown in Table 11, the interferon multi-dose injections provided in examples 2 and 5 were left at 25 ℃ for 6 months without significant changes in appearance, visible impurities, pH, and osmotic pressure. Although the biological activity was reduced, the change was minor and was within the acceptable range. No significant change in phenol and m-cresol content was seen. Therefore, the interferon multi-dose injection provided by the application is stored for 6 months under an accelerated condition, and has good stability.
(III) Long term test
The test subjects were left under long-term conditions (5. + -. 2 ℃ C.) for 24 months, and the quality attributes were measured at 0, 3, 6, 9, 12 and 24 months, respectively, and the measurement results are shown in tables 12 and 13.
TABLE 12 Long-term test-test results one
TABLE 13 Long-term test-test results II
As can be seen from the results in tables 12 and 13, the interferon multi-dose injections provided in examples 2 and 5 were left under the long-term test conditions for 24 months, and no significant change in appearance, visible foreign substance, pH, and osmotic pressure was observed. Although the biological activity was reduced, the change was minor and was within the acceptable range. No significant change in phenol and m-cresol content was seen. Therefore, the interferon multi-dose injection provided by the application is good in stability when stored for 24 months under long-term conditions.
(IV) stability test during use
The test selects New Zealand rabbits (the weight is 1.8-2.3kg, the age is 5-7 months) which react with human skin, mucosa and the like as experimental animals, and the experiment is designed and carried out under corresponding animal feeding conditions. The test method simulates clinical administration mode to inject animals, and investigates various quality indexes and aseptic change conditions of the liquid medicine in the simulated use process. The test subjects were injected subcutaneously into the outer thigh of a New Zealand rabbit at a dose of 100. mu.L per mouse, and the injections were routinely sterilized topically. The injections were re-injected every other day for 15 total periods of 30 days. The interferon injection quality attributes were measured at 0, 10, and 30d, respectively, and the measurement results are shown in table 14.
TABLE 14 stability test during use-test results
The results of the tests shown in table 14 show that the interferon multi-dose injections provided in examples 2 and 5 were injected every other day for 30 days, and no significant change was observed in appearance, visible impurities, pH, and osmotic pressure, and both the biological activity and the interferon content were within the acceptable ranges. No significant change in phenol and m-cresol content was seen. It is thus understood that the interferon multi-dose injection provided by the present application has good stability within 30 days after unsealing.
(V) stability test during transportation
The transportation and storage conditions of the detection object are 2-8 ℃ and are protected from light. The transportation conditions may relate to different transportation vehicles such as automobiles, trains, airplanes and the like, the time consumption is 4d at most, and the number of intermediate turnover is 3 at most.
The test selects severe environmental conditions to carry out a simulation test, the detection object is placed on a simulation transportation vibration table in different placing directions, the rotation frequency of the vibration table is adjusted to be 200RPM, the amplitude is 25.4MM +/-10%, the conditions of vibration, transportation distance, transportation time and the like of a vehicle are simulated, the change condition of each quality index of the detection object in transportation is inspected, the quality attribute of the detection object is detected at 0d, 2 d and 4d respectively, and meanwhile, the integrity of the package is inspected. The results are shown in Table 15.
TABLE 15 stability test during transportation-test results
As can be seen from the results shown in table 15, the interferon multi-dose injections provided in examples 2 and 5 were tested in a simulated transportation process, and no significant change in appearance, visible impurities, pH, osmotic pressure was observed during the test, and the biological activity and the interferon content were within the acceptable range. No significant change in phenol and m-cresol content was seen. Therefore, the interferon multi-dose injection provided by the application has good stability in the transportation process.
The present embodiment is only for explaining the present application, and it is not limited to the present application, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present application.
Claims (8)
1. A stable interferon multi-dose injection, characterized in that, the injection comprises the following components by weight, calculated by 1000 weight portions, 0.05 to 0.1 portion of interferon; 1.0-1.5 parts of disodium hydrogen phosphate; 0.1-0.5 part of citric acid; 6.5-7.5 parts of sodium chloride; 8.0-12.0 parts of human serum albumin; 1.0-2.5 parts of phenol; 2.0-3.0 parts of m-cresol; the balance being solvent.
2. The stable interferon multi-dose injection as claimed in claim 1, wherein the injection comprises the following components in parts by weight, based on 1000 parts by weight, 0.05-0.1 part of interferon; 1.0-1.5 parts of disodium hydrogen phosphate; 0.1-0.5 part of citric acid; 6.5-7.5 parts of sodium chloride; 8.0-12.0 parts of human serum albumin; 1.5-2.5 parts of phenol; 2.5-3.0 parts of m-cresol; the balance being solvent.
3. The stable interferon multi-dose injection as claimed in claim 2, wherein the total added weight of phenol and m-cresol is 3.5-5.0 parts.
4. The stable interferon multi-dose injection according to claim 3, wherein the total added weight parts of phenol and m-cresol are 4.0-5.0 parts.
5. The stable multi-dose interferon injection of claim 1, wherein the interferon comprises the subtypes interferon alpha, interferon beta and interferon gamma.
6. The stable interferon multi-dose injection according to claim 1, wherein the solvent is water for injection.
7. The stable multi-dose interferon injection of claim 1, wherein the pH of the injection is in the range of 6.5 to 7.5.
8. The method of any one of claims 1-7, further comprising the steps of:
(1) preparing a buffer solution by using disodium hydrogen phosphate, citric acid and sodium chloride according to the adding proportion of the components, and sterilizing; preparing a bacteriostatic agent solution by using phenol and m-cresol;
(2) adding the buffer solution prepared in the step (1), interferon and human serum albumin into a solvent, and uniformly mixing to prepare a prefabricated liquid;
(3) and (3) adding the bacteriostatic agent solution prepared in the step (1) into the prefabricated liquid prepared in the step (2), complementing the volume with a solvent, filtering and sterilizing to obtain the injection.
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