CN112245388A - Sodium chloride injection containing peramivir and preparation method thereof - Google Patents
Sodium chloride injection containing peramivir and preparation method thereof Download PDFInfo
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- CN112245388A CN112245388A CN202011323810.2A CN202011323810A CN112245388A CN 112245388 A CN112245388 A CN 112245388A CN 202011323810 A CN202011323810 A CN 202011323810A CN 112245388 A CN112245388 A CN 112245388A
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- peramivir
- sodium chloride
- injection
- preparation
- chloride injection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
Abstract
The invention discloses a peramivir sodium chloride injection and a preparation method thereof, wherein the peramivir sodium chloride injection is composed of peramivir and pharmaceutic adjuvant, wherein the pharmaceutic adjuvant comprises an osmotic pressure regulator sodium chloride and a pH regulator such as hydrochloric acid or sodium hydroxide. The invention also provides a preparation method of the peramivir sodium chloride injection, which has the advantages of simple process, high sterility assurance level, low cost and suitability for commercial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a sodium chloride injection containing peramivir and a preparation method thereof.
Background
Peramivir (Peramivir), developed by american biological crystal drug products gmbh, is another novel Neuraminidase (NA) inhibitor anti-influenza virus drug after the successful development of zanamivir and oseltamivir and the marketing in 1999, and is used for the treatment and prevention of influenza a and b in adults and children.
Peramivir has been developed to date as an antiviral drug and in particular for use in influenza therapy. As neuraminidase inhibitors, peramivir is effective in inhibiting replication of all types of influenza viruses. Peramivir can be used by over-injection and is known to be well tolerated and cause only minor side effects. The peramivir is an influenza neuraminidase inhibitor, can kill highly pathogenic H5N1 avian influenza virus, and can effectively resist the H5N1 avian influenza virus. Results of preclinical studies show that it can effectively act on a variety of influenza viruses (including the H5N1 virus). It is a novel cyclopentane anti-influenza drug taking influenza virus surface glycoprotein neuraminidase as an action target. Laboratory tests have shown that peramivir is effective against each of the known H5N1 viruses and is extremely virulent and resistant to the virus.
Because of low oral availability of peramivir, the peramivir is mainly prepared into parenteral preparations such as injection, for example, CN101314579A discloses anhydrous peramivir crystals and pharmaceutical compositions thereof, including injection containing 200mg of peramivir crystals: 200mg of anhydrous peramivir crystal, mannitol, a proper amount of hydrochloric acid and water for injection are added to 100 mL. And freeze-dried powder injection: 200mg of anhydrous peramivir crystal, mannitol, a proper amount of hydrochloric acid and water for injection are added to 20mL for freeze-drying. The problems in the invention are that 1) the concentration of peramivir in the injection is small, about 2 mg/ml; 2) the freeze-drying needle separation preparation process adopts filtration sterilization, needs an aseptic production process, and has a lower aseptic guarantee level than a terminal sterilization process.
CN102058522A discloses a peramivir injection and a preparation method thereof, which comprises peramivir, a non-aqueous solvent, a cosolvent and water for injection. The weight volume ratio (g/ml) of the peramivir to the non-aqueous solvent is 1: 10-100, the dosage ratio of the non-aqueous solvent in the formula is 20-60% (v/v), the dosage of the cosolvent is 1-20% (w/v), the non-aqueous solvent is one or a mixed solvent of ethanol, propylene glycol, glycerol and polyethylene glycol, and the cosolvent is one or more of glucose, sorbitol, mannitol and inositol. Provides a peramivir injection which can be diluted by water for injection, sodium chloride or glucose infusion in any proportion and can keep the clarity of the solution, and a preparation method thereof. The injection can improve the solubility of the peramivir, can meet the reasonable preparation formula and preparation method of injection medication requirements, increases the solubility of the peramivir and maintains the stability of the solution by using a proper amount of non-aqueous solvent and cosolvent, avoids the problems of turbid solution, incapability of administration and the like during clinical dilution use, reduces the using amount of the non-aqueous solvent as far as possible, and improves the concentration of original drugs. The invention has the problems that a non-aqueous solvent and a cosolvent are required to be used for increasing the solubility of the peramivir and maintaining the stability of the solution, but the non-aqueous solvent such as ethanol, propylene glycol, glycerol and polyethylene glycol has certain vascular irritation, and the clinical medication is influenced.
Patent CN107281096A discloses a water injection containing peramivir and a preparation method thereof, which is characterized in that the water injection consists of the peramivir, pharmaceutic adjuvant and water for injection, wherein the pharmaceutic adjuvant contains nano-scale montmorillonite, the average particle size is 12nm-15nm, the water for injection is boiled and then cooled to 45 ℃ for liquid preparation, and the sterilization process is sterilization at 121 ℃ for 10 min. The invention has the problems that 1) the safety of the medicine has certain challenge when the nano-scale montmorillonite which is an unusual auxiliary material is added into the injection; 2) the injection water needs to be boiled and then cooled to 45 ℃ for liquid preparation, and the boiling of the injection water in the production process needs special production equipment for treatment, so that the production process is complex and is not beneficial to commercial production; 3) the sterilization process is sterilization at 121 ℃ for 10min, a residual probability method is adopted, and the sterility assurance level is not high as the terminal sterilization process.
Therefore, there is still a need to provide a stable peramivir sodium chloride injection and a preparation method thereof, so that the product has better stability, higher sterility assurance level, convenience for clinical medication, simple process, low production cost and suitability for commercial production.
Disclosure of Invention
The invention provides a sodium chloride injection containing peramivir and a preparation method thereof, and is characterized in that each ml of the formula contains 10mg of peramivir, 9mg of sodium chloride and a proper amount of hydrochloric acid or sodium hydroxide.
The peramivir-containing sodium chloride injection and the preparation method thereof are characterized in that the specification of the peramivir-containing sodium chloride injection is 150mg/15ml, namely each product contains 150mg of peramivir, 135mg of sodium chloride, and proper amount of hydrochloric acid and sodium hydroxide.
The sodium chloride injection containing peramivir and the preparation method thereof are characterized in that a pH regulator hydrochloric acid or sodium hydroxide is used for regulating the pH value of a solution to 5.0-8.5.
The invention relates to a peramivir-containing sodium chloride injection and a preparation method thereof, which are characterized in that a terminal sterilization process, namely a sterilization process at 121 ℃ for 12min, is adopted in the preparation process of the peramivir-containing sodium chloride injection.
The peramivir-containing sodium chloride injection and the preparation method thereof are characterized in that the prepared peramivir-containing sodium chloride injection is an isotonic solution.
The peramivir-containing sodium chloride injection and the preparation method thereof are characterized in that the osmotic pressure concentration range of the peramivir-containing sodium chloride injection is 270-330 mmol/L.
The sodium chloride injection of peramivir and the preparation method thereof are characterized in that the preparation method comprises the following steps:
a. weighing 90% of water for injection at room temperature, adding peramivir and sodium chloride, dissolving, uniformly mixing, and adjusting the pH value of the solution to 5.0-8.5 by using a pH regulator hydrochloric acid or sodium hydroxide;
b. adding water for injection into the solution to the amount of the prescription;
c. filtering with 0.22 μm PVDF filter core to obtain peramivir sodium chloride solution containing peramivir 10mg per 1 ml;
d. filling to obtain peramivir sodium chloride solution with concentration of 150mg/15mL containing peramivir in each bottle;
e. sterilizing the peramivir sodium chloride solution by adopting a terminal sterilization process, namely a sterilization process at 121 ℃ for 12 min.
The research of the inventor finds that the peramivir is slightly soluble in deionized water and a 0.9% sodium chloride injection, and the solubility of the peramivir is increased in solutions with different pH values of 1-13, and can reach 15-20 mg/ml. When the pH value is more than 8.5, the peramivir is susceptible to alkaline hydrolysis, so that the stability of the medicine is reduced, and when the pH value is less than 5, the peramivir is susceptible to acidic hydrolysis, so that the stability of the medicine is reduced. When the pH value of the peramivir is within the range of 5-8.5, the peramivir has good water solubility, and meanwhile, the peramivir has good solution stability within the pH range.
The research of the inventor finds that when the peramivir sodium chloride injection contains 150mg of peramivir, 135mg of sodium chloride, hydrochloric acid and sodium hydroxide to adjust the pH value of the solution to 5-8.5, and the injection water is constant volume to 15ml, the peramivir sodium chloride injection has good stability and can endure a terminal sterilization process, namely, impurities are not remarkably increased compared with the non-sterilization process after the sterilization process is carried out at 121 ℃ for 12 min.
According to the invention, the prepared peramivir sodium chloride injection has the advantages of good stability, simple production process, high sterility assurance level and suitability for commercial production.
Detailed Description
In order to make those skilled in the art better understand the technical solution of the present invention, the following specific examples are given, but the present invention is not limited to the following examples.
Comparative example 1:
the preparation method of the formula 1 comprises the following steps: weighing 90% of water for injection at room temperature, adding peramivir and sodium chloride, dissolving, uniformly mixing, and adjusting the pH value of the solution to a target pH value of 4.0 by using a pH regulator hydrochloric acid or sodium hydroxide; adding water for injection into the solution to the amount of the prescription; filtering by a PVDF filter element with the diameter of 0.22 mu m; filling to obtain solution containing peramivir with concentration of 150mg/15ml in each bottle, and sterilizing by wet heat sterilization at 121 deg.C for 12 min.
The preparation method of the formula 2 comprises the following steps: weighing 90% of water for injection at room temperature, adding peramivir and sodium chloride, dissolving, uniformly mixing, and adjusting the pH value of the solution to 5.0 by using a pH regulator hydrochloric acid or sodium hydroxide; adding water for injection into the solution to the amount of the prescription; filtering by a PVDF filter element with the diameter of 0.22 mu m; filling to obtain solution containing peramivir with concentration of 150mg/15ml in each bottle, and sterilizing by wet heat sterilization at 121 deg.C for 12 min.
The preparation method of the formula 3 comprises the following steps: weighing 90% of water for injection at room temperature, adding peramivir and sodium chloride, dissolving, uniformly mixing, and adjusting the pH value of the solution to 6.5 by using a pH regulator hydrochloric acid or sodium hydroxide; adding water for injection into the solution to the amount of the prescription; filtering by a PVDF filter element with the diameter of 0.22 mu m; filling to obtain solution containing peramivir with concentration of 150mg/15ml in each bottle, and sterilizing by wet heat sterilization at 121 deg.C for 12 min.
The preparation method of the formula 4 comprises the following steps: weighing 90% of water for injection at room temperature, adding peramivir and sodium chloride, dissolving, uniformly mixing, and adjusting the pH value of the solution to a target pH value of 8.5 by using a pH regulator hydrochloric acid or sodium hydroxide; adding water for injection into the solution to the amount of the prescription; filtering by a PVDF filter element with the diameter of 0.22 mu m; filling to obtain solution containing peramivir with concentration of 150mg/15ml in each bottle, and sterilizing by wet heat sterilization at 121 deg.C for 12 min.
The preparation method of the formula 5 comprises the following steps: weighing 90% of water for injection at room temperature, adding peramivir and sodium chloride, dissolving, uniformly mixing, and adjusting the pH value of the solution to 9.5 by using a pH regulator hydrochloric acid or sodium hydroxide; adding water for injection into the solution to the amount of the prescription; filtering by a PVDF filter element with the diameter of 0.22 mu m; filling to obtain solution containing peramivir with concentration of 150mg/15ml in each bottle, and sterilizing by wet heat sterilization at 121 deg.C for 12 min.
The stability of each of recipe 1, recipe 2, recipe 3, recipe 4 and recipe 5 was examined under accelerated conditions (40 ℃ C., 75% RH), and the results of the examination are shown in Table 1.
Table 1: stability under accelerated conditions
And (4) analyzing results: the peramivir sodium chloride injection is stable at pH 5.0-8.5, and is unstable when the pH values are 4.0 and 9.5, and the total impurities are more than 0.2%.
Comparative example 2:
the preparation method of the formula 6 comprises the following steps: weighing 90% of water for injection at room temperature, adding peramivir and sodium chloride, dissolving, uniformly mixing, and adjusting the pH value of the solution to 6.5 by using a pH regulator hydrochloric acid or sodium hydroxide; adding water for injection into the solution to the amount of the prescription; filtering by a PVDF filter element with the diameter of 0.22 mu m; filling to obtain a solution containing peramivir with the concentration of 150mg/15ml in each bottle.
The preparation method of the formula 7 comprises the following steps: weighing 90% of water for injection at room temperature, adding peramivir and sodium chloride, dissolving, uniformly mixing, and adjusting the pH value of the solution to 6.5 by using a pH regulator hydrochloric acid or sodium hydroxide; adding water for injection into the solution to the amount of the prescription; filtering by a PVDF filter element with the diameter of 0.22 mu m; filling to obtain solution containing peramivir with concentration of 150mg/15ml in each bottle, and sterilizing by wet heat sterilization at 121 deg.C for 12 min.
The stability of each of the formulations 6, 7 and 7 was examined under accelerated conditions (40 ℃ C., 75% RH), and the results are shown in Table 2.
Table 2: stability under accelerated conditions
| 40℃、75％RH | Prescription 6 | Prescription 7 |
| Total impurities of 0 month | 0.03％ | 0.03％ |
| Accelerate total impurities for 6 months | 0.12％ | 0.13％ |
And (4) analyzing results: the peramivir sodium chloride injection is subjected to filtration sterilization and moist heat sterilization respectively at 121 ℃ for 12min, and no significant difference is found in total impurities in 0 month and 6 months accelerated, so that the peramivir sodium chloride injection can tolerate a terminal sterilization process.
In the description herein, reference to the description of the terms "one embodiment/mode," "some embodiments/modes," "example," "specific example," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment/mode or example is included in at least one embodiment/mode or example of the application. In this specification, the schematic representations of the terms used above are not necessarily intended to be the same embodiment/mode or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments/modes or examples. Furthermore, the various embodiments/aspects or examples and features of the various embodiments/aspects or examples described in this specification can be combined and combined by one skilled in the art without conflicting therewith.
Furthermore, the terms "first", "second" and "first" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one such feature. In the description of the present application, "plurality" means at least two, e.g., two, three, etc., unless specifically limited otherwise.
It will be understood by those skilled in the art that the foregoing embodiments are merely for clarity of illustration of the disclosure and are not intended to limit the scope of the disclosure. Other variations or modifications may occur to those skilled in the art, based on the foregoing disclosure, and are still within the scope of the present disclosure.
Claims (7)
1. The sodium chloride injection containing peramivir and the preparation method thereof are characterized in that each ml of the prescription contains 10mg of peramivir, 9mg of sodium chloride and proper amount of hydrochloric acid or sodium hydroxide.
2. The peramivir sodium chloride injection and the preparation method thereof as claimed in claim 1, wherein the peramivir sodium chloride injection is 150mg/15ml in specification, that is, each product contains 150mg of peramivir, 135mg of sodium chloride, and appropriate amounts of hydrochloric acid and sodium hydroxide.
3. The peramivir-containing sodium chloride injection as claimed in claim 1, wherein the pH of the solution is adjusted to 5.0-8.5 by using hydrochloric acid or sodium hydroxide as a pH regulator.
4. The peramivir-containing sodium chloride injection as claimed in claim 1, wherein a terminal sterilization process, namely a sterilization process at 121 ℃ for 12min, is adopted in the preparation of the peramivir-containing sodium chloride injection.
5. The peramivir-containing sodium chloride injection and the preparation method thereof according to claim 1, wherein the prepared peramivir sodium chloride injection is an isotonic solution.
6. The peramivir-containing sodium chloride injection and the preparation method thereof as claimed in claim 5, wherein the osmotic pressure concentration of the peramivir-sodium chloride injection is 270-330 mmol/L.
7. The peramivir sodium chloride injection and the preparation method thereof according to claim 1, wherein the preparation method comprises the following steps:
a. weighing 90% of water for injection at room temperature, adding peramivir and sodium chloride, dissolving, uniformly mixing, and adjusting the pH value of the solution to 5.0-8.5 by using a pH regulator hydrochloric acid or sodium hydroxide;
b. adding water for injection into the solution to the amount of the prescription;
c. filtering with 0.22 μm PVDF filter core to obtain peramivir sodium chloride solution containing peramivir 10mg per 1 ml;
d. filling to obtain peramivir sodium chloride solution with concentration of 150mg/15mL containing peramivir in each bottle;
e. sterilizing the peramivir sodium chloride solution by adopting a terminal sterilization process, namely a sterilization process at 121 ℃ for 12 min.
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| CN202011323810.2A CN112245388A (en) | 2020-11-23 | 2020-11-23 | Sodium chloride injection containing peramivir and preparation method thereof |
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| CN202011323810.2A CN112245388A (en) | 2020-11-23 | 2020-11-23 | Sodium chloride injection containing peramivir and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113398068A (en) * | 2021-08-05 | 2021-09-17 | 广州市桐晖药业有限公司 | Injection and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113398068A (en) * | 2021-08-05 | 2021-09-17 | 广州市桐晖药业有限公司 | Injection and preparation method thereof |
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