Liraglutide Powder CAS 204656-20-2

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Liraglutide powder , molecular formula C172H265N43O51, CAS 204656-20-2, molecular weight 1209.40. It is an artificially synthesized acylated human glucagon like peptide-1 (GLP-1) analogue with over 97% sequence similarity compared to natural GLP-1. Can be dissolved in water, ethanol, and propylene glycol. The 34th lysine position of the natural GLP-1 molecule is replaced by arginine, which not only preserves and prolongs the binding time between acylation products and proteins, but also significantly overcomes the disadvantage of easy degradation of GLP. Under normal storage conditions, it exhibits good stability, and its aqueous solution can maintain physical and chemical stability for at least 2 years.

Genetic toxicity: The results of the Ames test for Liraglutide powder, the chromosomal aberration test for human peripheral blood lymphocytes, and the rat micronucleus test were all negative.

Reproductive toxicity:

1. Male rats were subcutaneously injected with 0.1, 0.25, and 1.0mg/kg/d of liraglutide 4 weeks before mating and during mating. At a dose of 1.0mg/kg/d, male animal fertility was not directly affected. According to plasma AUC calculations, the systemic exposure generated by this dose was approximately 11 times that of human exposure at the maximum recommended human dose (MRHD). Subcutaneous injection of 1.0mg/kg into female rats resulted in increased early embryonic death, visible weight gain, and decreased food intake.

2. From 2 weeks before mating to the 17th day of pregnancy in female rats, subcutaneous injections of 0.1, 0.25, and 1.0 mg/kg/d of Liraglutide were administered. According to plasma AUC calculations, the systemic exposure generated by these three doses was approximately 0.8, 3, and 11 times that of human exposure under MRHD, respectively. In the 1mg/kg/d dose group, there was a slight increase in the number of early embryonic deaths. At all doses, fetal abnormalities, renal and vascular variations, irregular ossification of the skull, and a complete state of excessive ossification were observed. At a dose of 1.0mg/kg/d, spotted liver and slight rib twisting were observed. The incidence of fetal malformations exceeding the same period and historical control is: oropharyngeal malformations and/or stenosis at the throat opening at a dose of 01mg/kg/d, and umbilical defects at doses of 0.1 and 0.25mg/kg/d.

On the 6th to 18th day of pregnancy, rabbits were subcutaneously injected with liraglutide at concentrations of 0.01, 0.025, and 0.05mg/kg/d. According to plasma AUC calculations, the systemic exposure of pregnant rabbits was lower than that of humans during MRHD. At all doses, fetal weight decreased and the overall incidence of severe fetal abnormalities increased in a dose-dependent manner. At doses of 0.01mg/kg/d (kidney, shoulder and spleen bones), ≥ 0.01mg/kg/d (eyes and forelimbs), 0.025mg/kg/d (brain, tail and vertebrae, large blood vessels and heart, umbilical cord), ≥ 0.025mg/kg/d (sternum), and 0.05mg/kg/d (parietal bone and large blood vessels), the incidence of malformations exceeded that of contemporaneous and historical controls. Irregular ossification and/or skeletal abnormalities are found in the skull and collar, vertebrae and ribs, sternum, pelvis, coccyx, and shoulder and spleen bones; There is also a slight dose dependent skeletal variation visible. Visceral abnormalities are found in blood vessels, lungs, liver, and esophagus. All treatment groups showed double lobes or bifurcations of the gallbladder, but no similar situation was observed in the control group.

4. During the period from day 6 of pregnancy to weaning or termination of lactation on day 24, female rats were subcutaneously injected with 0.1, 0.25, and 1.0 mg/kg/d of liraglutide. According to plasma AUC calculations, systemic exposure was approximately 0.8, 3, and 11 times that of human exposure during MRHD. The delivery period of most animals in the treatment group was slightly delayed. The average weight of newborns in the treatment group was lower than that in the control group. Female rats in the 1.0mg/kg/d dose group exhibited blood loss and excitement behavior during delivery. The average body weight of F2 offspring rats in the treatment group from birth to the 14th day after birth was lower than that of the control group, but the differences between the groups did not reach statistical significance.

Liraglutide powder is an artificially synthesized acylated human glucagon like peptide-1 (GLP-1) analogue with over 97% sequence similarity compared to natural GLP-1. The molecular structure of liraglutide includes the following main characteristics: the 34th lysine position of the natural GLP-1 molecule is replaced by arginine, which not only preserves and prolongs the binding time between acylation products and proteins, but also significantly overcomes the disadvantage of GLP's easy degradation; An additional fatty acid side chain was added to the 26th lysine, which helps to prolong the half-life of acylation products in vivo. These unique molecular changes have made delilaglutide show outstanding effects in clinical treatment, especially in diabetes and weight loss.

The chemical methods for synthesizing liraglutide mainly include the following steps:

1. Fragment synthesis

Firstly, divide the entire liraglutide into several segments, which can generally be divided into five segments: 1st to 4th amino acids, 5th to 10th amino acids, 11th to 16th amino acids, 17th to 24th amino acids, and 25th to 31st amino acids. Each fragment is synthesized separately, which can reduce the difficulty and cost of peptide synthesis and improve synthesis efficiency.

For the synthesis of each fragment, solid-phase synthesis or liquid-phase synthesis methods are generally used. The solid-phase synthesis method involves connecting the carboxyl groups of amino acids to the resin, then sequentially adding the amino acids to the resin in sequence, and finally cutting off the peptides from the resin. The liquid-phase synthesis method involves dissolving all amino acids in an organic solvent and then condensing them in sequence to form peptide fragments.

2. Coupling reaction

Perform coupling reaction on the 5 peptide fragments synthesized in step 1 to form a complete Liraglutide. The coupling reaction can be carried out using chemical or biological coupling agents, and the specific method can be selected according to actual needs.

In the coupling reaction, it is necessary to connect the amino group of each fragment with the carboxyl group of the next fragment. To achieve this, it is usually necessary to use condensation agents such as DIC or BOP. These condensation agents can promote the reaction between amino and carboxyl groups, forming peptide bonds. In the coupling reaction, attention should also be paid to controlling the reaction conditions, such as temperature, pH value, and reaction time, to ensure the smooth progress of the reaction.

3. Purification and identification

The synthesized liraglutide needs to be purified and identified to ensure the purity and quality of the product. Purification is usually carried out using methods such as high-performance liquid chromatography (HPLC) or electrophoresis, followed by identification using mass spectrometry, nuclear magnetic resonance, and other methods. Through these means, it can be ensured that the molecular weight and sequence of the synthesized product are consistent with expectations, and there are no impurities or by-product residues.

4. Other modifications

In addition to the above steps, sometimes other modifications are required, such as adding or removing protective groups. These steps are also essential as they can protect the active groups in peptides from being destroyed or side reactions occur, improving the quality and yield of synthesized Liraglutide powder.

The above are the main chemical methods for synthesizing liraglutide, but of course, some details and techniques need to be noted in practical operation. For example, selecting the appropriate solvent system, controlling temperature and pH, and using appropriate catalysts can all affect synthesis efficiency and product quality. Therefore, in practical operation, adjustments and optimizations need to be made according to specific circumstances.

Liraglutide (a long-acting GLP-1 receptor agonist) plays a significant role in the treatment of diabetes. To ensure its quality controllability, it is necessary to establish scientific and rigorous analytical methods, and conduct systematic validation to ensure the reliability of these methods. The following analysis is carried out from three aspects: validation items, validation methods, and key control points.

Core Verification Items and Technical Requirements

Specificity

Objective: To prove that the method can distinguish Liraglutide from impurities, degradation products, and excipients.

Implementation Strategy:

Chromatography: Use HPLC-UV or UPLC-MS. Through forced degradation tests (such as high temperature, light exposure, acid-base hydrolysis), generate degradation products and verify the separation degree of the main peak and the impurity peak (≥1.5). For example, in the study of the ApoE-/- mouse model, after Liraglutide is oxidized, the degradation products (such as formic acid adducts) need to be confirmed by chromatographic analysis to ensure the separation effect of the degradation products from the main peak.

Spectroscopy: Use a PDA detector to compare the UV spectra of the main peak and impurities, and confirm the purity of the peaks.

Blank Control: Verify the absence of false positive signals using samples without Liraglutide (such as excipient solutions).

 

Accuracy

Objective: To ensure that the measured results are close to the true value and the recovery rate is controlled within 98% - 102%.

Implementation Strategy:

Standard Addition Recovery Test: Add a known amount of reference substance to a sample with known Liraglutide content and measure the recovery rate. For example, in the analysis of the formulation, add 0.5 mg/mL, 1.0 mg/mL, and 1.5 mg/mL of Liraglutide to the blank excipient solution, repeat each concentration 3 times, and calculate the average recovery rate.

Comparison Method: Compare with classical methods (such as titration) or verified methods (such as pharmacopoeia methods), and the result deviation should be ≤ 2%.

 

Precision

Objective: To evaluate the degree of closeness of repeated measurement results, with RSD ≤ 2%.

Implementation Strategy:

Repeatability: Conduct 6 consecutive measurements of the same sample by the same analyst, the same instrument, and the same batch of samples, and calculate the RSD.

Intermediate Precision: Calculate the RSD by determining the same batch of samples by different analysts, different instruments, and different dates. For example, in the determination of Liraglutide content, the repeatability RSD should be ≤ 1.5%, and the intermediate precision RSD should be ≤ 2.0%.

Reproducibility: Collaborative verification by multiple laboratories (such as pharmacopoeia standard methods), RSD should comply with the guidance principles.

 

Detection Limit and Quantification Limit

Objective: To determine the minimum concentration that the method can detect and quantify Liraglutide.

Implementation Strategy:

Signal-to-Noise Ratio Method: Determine LOD with a 3:1 signal-to-noise ratio, and determine LOQ with a 10:1 signal-to-noise ratio. For example, in the HPLC-UV method, the LOD of Liraglutide can be as low as 0.01 μg/mL, and the LOQ is 0.05 μg/mL.

Standard Curve Method: Calculate LOD and LOQ using the response signals of low-concentration standard substances (such as 0.1 μg/mL - 1 μg/mL).

 

Linearity

Objective: To prove that the response signal is proportional to the concentration, with R² ≥ 0.999.

Implementation Strategy:

Gradient Concentration Test: Prepare 5-7 concentration gradients (such as 0.1 mg/mL - 2.0 mg/mL) of standard solutions, measure the peak area or response value, and draw the standard curve.

Residual Analysis: Check if the residuals are randomly distributed and there is no systematic deviation.

 

Range

Objective: To determine the applicable concentration range of the method, usually 120% of the LOQ to the upper limit of linearity.

Implementation Strategy:

Content Determination: The range is set at 80% - 120% of the labeled amount. For example, the content determination range of Liraglutide formulation should be 0.4 mg/mL - 1.2 mg/mL. Impurity control: According to the ICH Q3D guideline, set the limit range of impurities (e.g., single impurity ≤ 0.5%, total impurity ≤ 2.0%).

Validation Documents and Data Management

01

Validation plan and report

Clearly define the validation items, methods, acceptance standards, and abnormal handling procedures. For example, if the precision RSD exceeds the limit, it is necessary to investigate instrument faults or operational errors.

Record the original data (such as chromatograms, standard curves, recovery rate calculation tables) to ensure traceability.

02

Stability indication method development

For mandatory degradation tests, it should cover oxidation, light exposure, hydrolysis, etc., to simulate actual storage conditions. For example, Liraglutide placed at 60℃ for 48 hours, the degradation rate should be ≥ 10% to verify the method's ability to detect degradation products.

03

Regulatory compliance

Follow ICH Q2(R2), USP<1225>, and Chinese GMP guidelines to ensure that the validation items cover core indicators such as specificity and accuracy.

For elemental impurity analysis, it should comply with ICH Q3D and USP<233> requirements, controlling the limits of 1-class elements such as As, Cd, and Pb.

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