Entecavir Injection is a highly efficient and low resistance nucleoside analogue antiviral drug, and Entecavir Injection, as a novel formulation form, provides an important choice for patients who cannot take it orally or need rapid control of virus replication. The inhibitory effect of entecavir on HBV is 300 times stronger than lamivudine and 10 times stronger than adefovir, and it still maintains high activity against lamivudine resistant strains. After intravenous injection, the injection directly enters the blood circulation, bypasses the first pass effect, and the blood concentration quickly reaches the therapeutic threshold, which is suitable for patients with acute severe hepatitis B or liver failure; The bioavailability of injection is close to 100%, significantly higher than that of oral preparations; At the same time, the dosage can be accurately adjusted according to the patient's renal function (creatinine clearance rate) to avoid drug accumulation or insufficient efficacy. Injection is also the only feasible option for patients with swallowing difficulties, consciousness disorders, or gastrointestinal absorption disorders. Injections can quickly control virus replication and reduce the risk of liver failure during decompensated cirrhosis, before and after liver transplantation, or in cases of severe infection.
Additional information of chemical compound:
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Entecavir COA
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| Certificate of Analysis | ||
| Compound name | Entecavir | |
| Grade | Pharmaceutical grade | |
| CAS No. | 142217-69-4 | |
| Quantity | 337.3kg | |
| Packaging standard | 25kg/drum | |
| Manufacturer | Shaanxi BLOOM TECH Co., Ltd | |
| Lot No. | 202501090030 | |
| MFG | Jan 9th 2025 | |
| EXP | Jan 8th 2028 | |
| Structure |  |
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| Item | Enterprise standard | Analysis result |
| Appearance | White or almost white powder | Conformed |
| Water content | ≤5.0% | 0.38% |
| Loss on drying | ≤1.0% | 0.29% |
| Heavy Metals | Pb≤0.5ppm | N.D. |
| As≤0.5ppm | N.D. | |
| Hg≤0.5ppm | N.D. | |
| Cd≤0.5ppm | N.D. | |
| Purity (HPLC) | ≥99.0% | 99.80% |
| Single impurity | <0.8% | 0.43% |
| Total microbial count | ≤750cfu/g | 80 |
| E. Coli | ≤2MPN/g | N.D. |
| Salmonella | N.D. | N.D. |
| Ethanol (by GC) | ≤5000ppm | 400ppm |
| Storage | Store in a sealed, dark, and dry place below -20℃ | |
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Entecavir Injection in Supercritical Fluid Crystallization Technology
Entecavir Injection, as an efficient and low resistance nucleoside analogue antiviral drug, has become a core drug for the treatment of chronic hepatitis B (CHB). Its oral preparation is widely used because of its exact efficacy and good safety, but the injection form has irreplaceable advantages in special scenarios (such as acute severe hepatitis B, patients before and after liver transplantation or patients with dysphagia). However, traditional injection preparation techniques (such as freeze-dried powder injections) have problems such as wide particle size distribution, uncontrollable crystal morphology, and large differences in solubility, which may affect drug stability, injection comfort, and bioavailability. Supercritical Fluid Crystallization (SCFC), as a green and efficient method for particle preparation, can achieve precise control of drug crystallization by regulating the physical and chemical properties of supercritical carbon dioxide (SC-CO ₂), providing new ideas for optimizing entecavir injection solutions.
Supercritical fluid crystallization technology: principles and core advantages
Characteristics of Supercritical Fluid
Supercritical fluid refers to a substance whose temperature and pressure both exceed its critical point (such as the critical temperature of CO ₂ at 31.1 ° C and the critical pressure at 7.38 MPa), possessing the dual characteristics of gas and liquid
High diffusivity
viscosity close to gas, can quickly penetrate into drug micropores;
High solubility
density close to liquid, significantly stronger solubility than gas;
Controllability
By adjusting temperature and pressure, the solubility and supersaturation of solutes in supercritical fluids can be precisely controlled.
Classification and principles of SCFC technology
SCFC technology induces drug crystallization or precipitation through supercritical fluid as a solvent or anti solvent, mainly divided into the following three categories:
Supercritical fluid rapid expansion (RESS)
Principle: Dissolve the drug in a supercritical fluid and rapidly reduce the pressure through a nozzle (a sudden drop in pressure causes supersaturation of the solute) to form tiny crystals.
Characteristics: Suitable for thermosensitive drugs, but the drug needs to have high solubility in SC-CO ₂ (usually<1 wt%).
Gas anti solvent crystallization (GAS)
Principle: Mix drug solution (organic solvent) with SC-CO ₂, and CO ₂ acts as an anti solvent to reduce drug solubility and induce crystallization.
Characteristics: The crystal particle size (0.1-100 μ m) and morphology can be controlled, but the compatibility between organic solvents and CO ₂ needs to be optimized.
Supercritical fluid assisted atomization (SAAS)
Principle: Combined with RESS and spray drying technology, supercritical fluid is used to assist drug solution atomization to form dry particles.
Features: Suitable for high viscosity or difficult to nebulize drugs, but with high equipment complexity.
Core advantages of SCFC technology
Controllable particle size and morphology
By adjusting temperature, pressure, and flow rate, monodisperse crystals can be prepared at the nanometer to micrometer level;
High purity, no solvent residue
SC-CO ₂ is non-toxic and volatile, avoiding contamination of drugs by traditional organic solvents;
Mild process
Low temperature operation (usually<50 ° C) protects the activity of thermosensitive drugs;
Green and environmentally friendly
In line with the principle of "atomic economy", reducing waste emissions.
Challenges in the preparation of entecavir injection and the solution path of SCFC
The conventional preparation method of entecavir injection includes dissolution filtration sterilization or freeze-drying powder injection reconstitution, which has the following problems:
Wide particle size distribution: Traditional crystallization methods (such as cooling crystallization and anti solvent crystallization) are difficult to control crystal growth, resulting in particle size ranges spanning multiple orders of magnitude (1-100 μ m), which may cause pain or vascular obstruction at the injection site;
Unstable crystal morphology: Polycrystalline phenomena may lead to differences in drug solubility and bioavailability, affecting the consistency of therapeutic efficacy;
Residual organic solvents: If solvents such as ethanol and acetone are used, complex purification steps are required, which increases production costs and safety risks;
Poor stability: Traditional crystals have high surface energy and are prone to moisture absorption and aggregation, leading to turbidity or precipitation of the injection solution.
Optimization effect of SCFC technology on entecavir injection
(1) Accurate control of particle size and morphology
Monodispersibility: By using RESS or GAS technology, entecavir crystals with uniform particle size (D50<5 μ m) can be prepared to reduce injection discomfort;
Morphology control: The solvation effect of SC-CO ₂ can induce crystal growth along specific crystal planes, forming needle shaped, sheet-like, or spherical crystals, optimizing drug dissolution kinetics.
(2) Eliminating the risk of polymorphic forms
Dynamics control: SCFC technology achieves crystallization through rapid supersaturation, which can suppress the formation of metastable crystal forms and ensure that drugs exist in thermodynamically stable crystal forms;
Crystal consistency: Fixed process parameters (such as T, P, CO ₂ flow rate) can repeatedly obtain the same crystal form, ensuring the stability of therapeutic effects between batches.
(3) Improve solubility and bioavailability
Nanoization effect: Nanocrystals (<1 μ m) prepared by RESS technology can significantly increase the specific surface area and improve the dissolution rate (according to the Noyes Whitney equation);
Amorphous: Under specific conditions, SCFCs can induce the formation of amorphous forms in drugs, further enhancing solubility (applicable to poorly soluble drugs).
(4) Enhance stability and security
Low surface energy: The crystal surface prepared by SCFC is smooth, with few defects, reducing the tendency for moisture absorption and agglomeration;
Aseptic assurance: SC-CO ₂ itself has antibacterial properties, and combined with terminal filtration (0.22 μ m filter membrane), it can achieve aseptic preparation, avoiding damage to drugs caused by high-temperature sterilization.
Research progress of SCFC technology in entecavir injection
Process development and optimization
- Application of RESS technology
Solubility determination: Study the solubility of entecavir in SC-CO ₂ as a function of temperature (35-50 ° C) and pressure (10-30 MPa), and determine the optimal operating window;
Crystal growth kinetics: By online monitoring of crystal particle size distribution, establish a relationship model between supersaturation and crystal growth rate, optimize nozzle design (such as single hole, porous) and pressure reduction rate;
- Application of GAS Technology
Anti solvent selection: Ethanol is used as the solvent, SC-CO ₂ is used as the anti solvent, and the crystal particle size (0.5-10 μ m) is controlled by adjusting the CO ₂ flow rate (5-20 g/min) and mixing temperature (25-40 ° C);
Polycrystalline suppression: achieving high supersaturation through rapid mixing (<1 s), inducing the formation of a single stable crystal form (such as Form I), and avoiding the formation of metastable Form II;
Quality control and standardization
- Particle size and morphology characterization
Microscopic techniques: Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) are used to observe crystal morphology (such as needle like or spherical);
Particle size analysis: Determination of particle size distribution (PDI<0.3) using laser diffraction (Malvern Mastersizer) or dynamic light scattering (DLS).
- Crystal identification
X-ray powder diffraction (XRPD): confirm the consistency between the crystal structure and the standard spectrum;
Differential Scanning Calorimetry (DSC): detects changes in melting point and eliminates amorphous or impurity phases.
- Stability assessment
Accelerated test: Investigate for 6 months under 40 ° C/75% RH conditions, monitor particle size changes and impurity generation;
Long term experiment: Store at 25 ° C/60% RH for 24 months to verify the stability of crystal morphology.
Progress in preclinical research
- Pharmacokinetic comparison
Rat model: Entecavir nanocrystal injection prepared by SCFC (dose 5 mg/kg) showed a 1.8-fold increase in Cmax and a 1.5-fold increase in AUC compared to traditional injection, indicating a significant improvement in bioavailability;
Pharmacodynamic validation: In the HBV transgenic mouse model, the viral load of nanocrystal injection decreased 30% faster than traditional formulations, and no additional toxicity was observed.
- Safety evaluation
Localized irritation: After injecting microcrystals prepared by SCFC into the ear vein of rabbits, no inflammatory reactions such as redness, swelling, or exudation were observed;
Systemic toxicity: Single and repeated dose toxicity tests have shown that nanocrystals have no significant effects on the liver, kidney, and blood systems, with a wide safety window.
Challenges and Future Directions
Technical challenges
Equipment complexity and cost
High pressure system: SCFC requires equipment that can withstand high pressure (>30 MPa) and high temperature (>50 ° C), with high initial investment;
Continuous production: Currently, most processes are intermittent, and continuous SCFC devices need to be developed to improve production efficiency.
Process amplification and reproducibility
Parameter optimization: From laboratory scale (gram level) to industrial scale (kilogram level), the critical points of temperature, pressure, and flow rate need to be re determined;
Quality control: It is necessary to establish an online monitoring system (such as PAT technology) to provide real-time feedback on the crystal growth status.
Future research directions
Joint technological exploration
SCFC+nano encapsulation: Combining SCFC prepared nanocrystals with liposomes and polymer microspheres to achieve sustained release or targeted delivery;
SCFC+3D printing: Using microcrystals prepared by SCFC as "ink", personalized drug formulations can be customized through 3D printing technology.
Expansion of new indications
Local administration: develop Entecavir Injection microcrystalline gel or patch for local treatment of hepatitis B related skin lesions (such as purpura);
Combined immunotherapy: Nanocrystals prepared by SCFC were combined with PD-1 inhibitor to explore a new strategy for functional cure of hepatitis B.
Green Manufacturing System
Solvent recycling: Recycling SC-CO ₂ and organic solvents to reduce production costs and environmental impact;
Energy efficiency optimization: Reduce process energy consumption through thermal integration technology, in line with carbon neutrality goals.
Frequently Asked Questions
What is entecavir used for?
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Entecavir is used to treat liver infection caused by hepatitis B virus. It belongs to the family of medicines called antivirals. Antivirals are used to treat infections that are caused by viruses. This medicine will not cure the hepatitis B virus, but it will keep it from reproducing and causing more liver damage.
How long to take entecavir for hepatitis B?
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Treatment duration will be long-term in most patients until there is a loss of surface antigen (note though loss of surface antigen occurs in less than 10% of patients). You will therefore likely remain on entecavir for life or until other treatments become available.
What is the mechanism of action of entecavir?
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Entecavir is an orally bioavailable guanosine nucleoside analogue that functionally inhibits all three activities of the HBV DNA polymerase: base priming, reverse transcription of the negative strand and synthesis of the positive strand.
Can entecavir reverse cirrhosis?
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These results suggest that portal hypertension or liver fibrosis may be reversed by long-term administration of entecavir in patients with compensated or decompensated cirrhosis, which may be due to sustained HBV suppression by entecavir.
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