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CN118105339A - Composition of Shugansu sodium injection and preparation method thereof - Google Patents

Composition of Shugansu sodium injection and preparation method thereof Download PDF

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Publication number
CN118105339A
CN118105339A CN202310471683.8A CN202310471683A CN118105339A CN 118105339 A CN118105339 A CN 118105339A CN 202310471683 A CN202310471683 A CN 202310471683A CN 118105339 A CN118105339 A CN 118105339A
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China
Prior art keywords
sodium
injection
nklysin
peptide
preparation
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Inventor
徐成
郭倩倩
邢珍珍
刘欢欢
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NANJING ZEHENG PHARMACEUTICAL SCIENCE & TECHNOLOGY CO LTD
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NANJING ZEHENG PHARMACEUTICAL SCIENCE & TECHNOLOGY CO LTD
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes

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  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Biomedical Technology (AREA)
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  • Toxicology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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Abstract

The invention discloses a composition and a preparation method of a sodium sulmore injection, wherein the prescription consists of a sodium sulmore active entity (501+502), a pH regulator, lc-NKlysin-1a peptide and water for injection, wherein the dosage of the Lc-NKlysin-1a peptide is 0.5-1.5 mg/mL. The sodium suger injection disclosed by the invention has the advantages of simple composition, stable quality, simple and efficient preparation process, no need of special equipment, low impurity level of finished products obtained after the process, and good stability.

Description

Composition of Shugansu sodium injection and preparation method thereof
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a sodium gluconate injection and a preparation method thereof.
Background
Neuromuscular blocking drugs (NMBAs) are one of the three factors ensuring smooth performance of general anesthesia, but as long as neuromuscular blocking drugs are used, residual neuromuscular blocking effect after surgery may occur, causing serious hypoxia to the patient and even upper respiratory obstruction, which is an important factor causing complications and death of the patient in the perianesthesia period. Since conventional neuromuscular conduction monitoring is not developed clinically, the occurrence of post-operative neuromuscular blocking residuals is often not readily identifiable. To prevent the occurrence of post-operative residual neuromuscular blocking, anesthesiologists generally employ two methods: 1) Prolonging the stay time of the patient in the postoperative recovery room, and returning the patient to the ward after the neuromuscular blocking effect is completely eliminated; 2) Some doctors choose to use cholinesterase inhibitors (e.g. neostigmine) +anticholinergic agents (atropine) to indirectly exert neuromuscular block antagonism. However, both methods cannot ensure that the postoperative residual neuromuscular blocking effect is rapidly and completely eliminated, and the combination of anticholinergic agents causes heart rate increase, urinary retention and the like, and increases the risk of cardiovascular events and even death of patients after operation.
The structural formula of the sodium glycose (Sugammadex Sodium) is shown in figure 1. The sodium sugammadex injection is the first and only specific binding neuromuscular blocking antagonist in the world developed by MERCK SHARP & Dohme Limited (moesadong) in the united kingdom and is a structurally modified gamma-cyclodextrin. The earliest approval of the market by EMA at month 7 of 2008, which has been marketed in batches in more than 50 countries and regions worldwide, is clinically used to reverse the effects of commonly used neuromuscular blockers, including rocuronium or vecuronium, including two phases: 1) After intravenous injection, the medicine is distributed in extracellular fluid to wrap all rocuronium or vecuronium molecules; 2) The concentration of muscle relaxant in the tissue surrounding the neuromuscular junction is reduced, and a concentration difference is generated between the neuromuscular junction and the neuromuscular junction, and the muscle relaxant molecules are transferred to the surrounding tissue and immediately wrapped by sodium glucose. The molecular type selective and high-affinity coating rocuronium bromide or vecuronium bromide is used for one molecule to lose activity, sodium gluconate is water-soluble, is not combined with plasma protein, is not metabolized in vivo, is not easy to permeate blood brain barrier and placenta, and is not easy to discharge a compound formed by the rocuronium bromide and the vecuronium bromide through kidneys, so that the concentration of muscle relaxant in blood and tissues is rapidly reduced, the neuromuscular junction function is recovered to be normal, the clearance of the medicine is not influenced by sex, race and weight, the distribution volume is 11-14L, the elimination half-life is about 100min, the plasma clearance rate is 84-138 mL/min, and 90% of the compound is discharged through kidneys within 48 hours.
The chemical structural formula is shown in figure 1.
The molecular formula: c 72H104Na8O48S8
Molecular weight: 2177.97
The sodium sulmore glucose can be oxidized and degraded in an aerobic environment, and meanwhile, as the chemical structure of the sodium sulmore glucose is a cavity structure, metal ions (such as iron, arsenic, nickel, manganese and the like) derived from auxiliary materials, preparation production equipment, packaging materials and the like are extremely easy to chelate, and in the aerobic environment, trace metal ions can catalyze the oxidative degradation of the sodium sulmore glucose, so that the impurity of the sodium sulmore glucose injection is obviously increased, and the color of a liquid medicine is obviously changed.
The main oxidative degradation impurities of sodium sugammadex are shown in figure 2.
As the injection is used as a preparation which directly enters the human blood system, the impurities contained in the injection can bring serious adverse effects to human bodies and even endanger lives, so that the use risk of the injection can be effectively controlled by reducing the impurity content in the injection and the change of the properties of the injection as much as possible.
As known from the Shugansu sodium injection import registration standard JX20140183 developed by the moxadong of the original grinding manufacturer, the impurity level of the original grinding product is higher, the limit of the maximum known degradation product is 2.4%, the limit of other single unknown degradation products is 2.0%, and the total amount of degradation products is 7.5%; in addition, through quality research on the commercial raw ground products, the maximum limit of known degradation products is 1.1%, the limit of other single unknown degradation products is 0.6%, the total amount of degradation products is 4.3%, the impurity level of the products is high, and the high impurity level definitely brings great potential safety hazard to the medication of patients.
In this regard, patent CN110638751a provides a method for preparing a sodium sulmore injection, which can reduce the impurity growth of the product, reduce the color change of the product, and prolong the effective period of the product, and the prepared product has better stability than the original developer Bridion, but the sodium sulmore injection prepared based on the method still has the risks of high-temperature degradation of impurities and increase of oxidative degradation of impurities.
Patent CN111714459B provides a preparation method of sodium sugammadex powder injection, which can effectively reduce impurity level and improve safety and stability of sodium sugammadex product, but the preparation method needs reasonable control of process steps, especially effective control of freeze-drying process, and has high requirement on operators.
Therefore, an antioxidant auxiliary material which has good compatibility with sodium sulmore gluconate, can protect the stability of sodium sulmore gluconate in the preparation production and storage environment and has better safety than other similar antioxidants is needed to be found.
Disclosure of Invention
The invention mainly aims to overcome the defects of the prior technical scheme of the sodium sugammadex injection and provide an antioxidant with good antioxidant effect and good safety. The invention also provides a prescription of the injection and a specific process preparation method, and the process is simple and efficient and is easy for large-scale production.
The object of the invention is achieved by:
a sodium sugammadex injection is characterized in that the prescription composition contains Lc-NKlysin-1a peptide.
The prescription composition of the sodium sugammadex injection comprises: sodium supreme active entity (501+502) 1 (100 mg/ml), lc-NKlysin-1a peptide, pH regulator and water for injection.
Note 1: the active ingredients of the product comprise sodium sulmore gluconate (501) active entity and mono-hydroxy sodium sulmore gluconate (502) active entity. 1mg 501 of active entity corresponds to 1.088mg 501 sodium salt and 1mg 502 of active entity corresponds to 1.080mg 502 sodium salt.
The amount of Lc-NKlysin-1a peptide is preferably 0.5 to 1.5 mg/ml, more preferably 0.8 to 1.2 mg/ml, still more preferably 1 mg/ml.
The preparation method of the Shugansu sodium injection comprises the following steps:
The prescription amount of sodium active entity of greater glucose (501+502) and Lc-NKlysin-1a peptide are added into the water for injection with the prescription amount of about 90 percent in sequence, stirred until the solution is clear, filtered, and filled and sealed in ampoule.
The sodium sugammadex active entity (501+502), and the Lc-NKlysin-1a peptide described in the present invention are commercially available.
The antioxidant Lc-NKlysin-1a peptide is applied to the product, can effectively prevent sodium gluconate from being oxidized, improves the stability of the product, has antibacterial activity, can be directly filled and sealed after being added, does not need a sterilization process, and reduces the generation of high-temperature degradation impurities. It is worth mentioning that the preparation process related by the invention requires equipment which is common equipment for producing injection in the industry, and has high practicability.
The following briefly describes the idea of the invention:
In view of the problem that sodium sulmore glucose injection is easy to oxidize, an antioxidant is not used in the original preparation prescription of the product. Therefore, the injection is unstable, the impurity level content is higher, and the inventor considers four antioxidants of Lc-NKlysin-1a peptide, sodium metabisulfite, sodium bisulphite and butylhydroxytoluene, and compares the quality index with that of the original prescription.
The test results show that the addition of the antioxidant can slow down the oxidation of sodium suger. However, the sodium metabisulfite and the sodium bisulphite are degraded by about 40-70% after sterilization, the safety of degraded impurities is unknown, and the addition of the sodium metabisulfite and the sodium bisulphite is easy to cause high total impurity level; the butylhydroxytoluene is not mutually soluble with water, and is separated out after water is added, thus being not suitable for being used as a component of the sodium sugammadex injection. Therefore, the Lc-NKlysin-1a peptide is preferably used as the antioxidant of the scheme, and the impurity level and the safety of the sodium gluconate product are better improved.
Lc-NKlysin-1 is obtained from large yellow croaker (LARIMICHTHYS CROCEA). To study the structure-function relationship, the derivative Lc-NKlysin-1a (12N-terminal amino acid residues of Lc-NKysin-1) was designed and synthesized. Lc-NKlysin-1a showed DPPH and hydroxyl radical scavenging activity in a dose dependent manner. The IC50 of DPPH clearance was 0.46mM. DPPH scavenging of Lc-NKlysin-1a is stable under the influence of temperature, pH, salt concentration, food excipients and metal ions. Lc-NKlysin-1a at a concentration of no more than 73.37mM had no significant cytotoxic effect on 293FT cells. The viability of 293FT cells treated with 7.3 mM Lc-NKlysin-1a and 400 mM H2O2 was 20% higher than 293FT cells treated with 400 mM hydrogen peroxide alone. The results indicate that Lc-NKlysin-1a protects 293FT cells from H2O 2. Lc-NKlysin a exhibited a broad range of antibacterial activity against gram-positive and gram-negative strains, including staphylococcus aureus, bacillus subtilis, escherichia coli, pseudomonas aeruginosa, vibrio and streptomycin resistant escherichia coli. Lc-NKlysin-1a has high antibacterial activity against staphylococcus aureus, escherichia coli and streptomycin-resistant escherichia coli, and the Minimum Inhibitory Concentration (MIC) is 11.5 to 22.9 mM. Meanwhile, lc-NKlysin-1a showed weak hemolytic activity, and the hemolysis rate was 3.8% at MIC concentration. Lc-NKlysin-1a is highly stable under temperature, pH and salt conditions. The antimicrobial activity of preheated Lc-NKlysin-1a increases slightly at higher temperatures, even up to 100 ℃. After treatment with Lc-NKlysin-1a, the cell membrane shrank and collapsed, resulting in cell death, indicating that Lc-NKysin-1a targets the cell wall and membrane.
The Lc-NKysin-1a peptide is the best antioxidant embodied by the invention, has antioxidant effect and antibacterial activity, is safer to use in injection, is also commonly used in the food industry, and is used as a food additive. In order to obtain the most suitable amounts of Lc-NKysin-1a peptide, a number of protocols were further made and screened.
The test result shows that the Lc-NKysin-1a peptide adopts 0.5-1.5 mg/ml for the sodium suger injection, the dissolution time of the preparation solution is short, the antioxidant capacity of the sodium suger injection can be effectively improved, and the total impurity content is low. The preferred prescription is: sodium supreme active entity (501+502) 100 mg/ml, lc-NKysin-1a peptide 0.5-1.5 mg/ml; more preferably, the sodium active entity of supreme glucose (501+502) is 100 mg/ml, the Lc-NKysin-1a peptide is 0.8-1.2 mg/ml; most preferably, the sodium active entity of supreme glucose (501+502) is 100 mg/ml, and the peptide Lc-NKysin-1a is 1mg/ml.
Drawings
FIG. 1: sodium gluconate chemical structure
Fig. 2: impurity map of main oxidative degradation of sodium sugammadex
Detailed Description
The content of the invention is further elucidated by means of the examples of the invention given below, without however being limited to the examples of implementation.
Example 1
Sodium gluconate injection every 20 mL s:
Sequentially adding the sodium sugammadex active entity (501+502) and Lc-NKysin-1a peptide into water for injection, stirring for dissolving, adjusting pH to 7.0-8.0, adding water for injection to 20mL, filtering with 0.22 μm, filling into ampoule, and sealing.
Example 2
Sodium gluconate injection every 20 mL s:
Sequentially adding the sodium sugammadex active entity (501+502) and Lc-NKysin-1a peptide into water for injection, stirring for dissolving, adjusting pH to 7.0-8.0, adding water for injection to 20mL, filtering with 0.22 μm, filling into ampoule, and sealing.
Example 3
Sodium gluconate injection every 20 mL s:
Sequentially adding the sodium sugammadex active entity (501+502) and Lc-NKysin-1a peptide into water for injection, stirring for dissolving, adjusting pH to 7.0-8.0, adding water for injection to 20mL, filtering with 0.22 μm, filling into ampoule, and sealing.
Example 4
Sodium gluconate injection every 20 mL s:
Sequentially adding the sodium sugammadex active entity (501+502) and Lc-NKysin-1a peptide into water for injection, stirring for dissolving, adjusting pH to 7.0-8.0, adding water for injection to 20mL, filtering with 0.22 μm, filling into ampoule, and sealing.
Example 5
Sodium gluconate injection every 20 mL s:
Sequentially adding the sodium sugammadex active entity (501+502) and Lc-NKysin-1a peptide into water for injection, stirring for dissolving, adjusting pH to 7.0-8.0, adding water for injection to 20mL, filtering with 0.22 μm, filling into ampoule, and sealing.
Example 6
The quality indexes of the prepared products meet the regulations by adopting the prescription process of the technical scheme examples 1-5.
Example 7
According to the four appendices 9001 of the edition 2020 of Chinese pharmacopoeia, "the stability test guidelines for raw materials and preparations", the stability test investigation is carried out on the sample prepared in the example 3 of the optimal combination:
acceleration test: the samples were placed in a constant temperature and humidity cabinet at 40 ℃ and 75% relative humidity for 6 months, sampled at 1,2, 3, and 6 months, respectively, and tested according to the stability study and compared with the data for 0 month.
Long-term test: samples were placed under intermediate conditions of 30℃and 60% relative humidity, sampled at 6 and 12 months, respectively, and tested according to the study and compared with data for 0 month.
The stability test result shows that after 6 months of accelerated test and 12 months of long-term test, each quality meets the regulations, and the sodium sulmore injection prepared by the technical scheme of the invention has stable and controllable quality.

Claims (6)

1. A composition of a sodium sugammadex injection and a preparation method thereof are characterized in that the prescription composition contains Lc-NKlysin-1a peptide.
2. The Lc-NKlysin-1a peptide according to claim 1, characterized in that it is used in an amount of 0.5-1.5 mg/ml.
3. The Lc-NKlysin-1a peptide according to claim 1, characterized in that it is used in an amount of 0.8-1.2 mg/ml.
4. The Lc-NKlysin-1a peptide according to claim 1, characterized in that it is used in an amount of 1 mg/ml.
5. The sodium sulmore injection according to claim 1, characterized by consisting of sodium sulmore active entity (501+502), pH regulator, lc-NKlysin-1a peptide and water for injection.
6. The sodium sugammadex injection according to claim 1, which is prepared in a complete process comprising the steps of: sequentially adding the prescription amount of sodium sugammadex active entity (501+502) and Lc-NKlysin-1a peptide into 90% of water for injection, stirring until dissolution and clarification are achieved, adjusting the pH to 7.0-8.0, adding the rest water for injection, filtering, filling ampoule and sealing.
CN202310471683.8A 2023-04-27 2023-04-27 Composition of Shugansu sodium injection and preparation method thereof Pending CN118105339A (en)

Priority Applications (1)

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CN202310471683.8A CN118105339A (en) 2023-04-27 2023-04-27 Composition of Shugansu sodium injection and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202310471683.8A CN118105339A (en) 2023-04-27 2023-04-27 Composition of Shugansu sodium injection and preparation method thereof

Publications (1)

Publication Number Publication Date
CN118105339A true CN118105339A (en) 2024-05-31

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