Description

Technical Parameters

Introduction

peptides

product-1400-1400

Products Description

#### **1. Overview of Semaglutide**

Semaglutide is a long-acting **glucagon-like peptide-1 (GLP-1) receptor agonist** developed by Novo Nordisk of Denmark. As a GLP-1 analog, it enhances insulin secretion, inhibits glucagon release, delays gastric emptying and reduces appetite by mimicking the mechanism of action of natural GLP-1. Its indications include **type 2 diabetes (T2DM)** and **obesity**, and it has become one of the most popular peptide drugs in recent years due to its significant weight loss effect.

#### **2. Classification and structural characteristics of Semaglutide**

The molecular design of Semaglutide is based on the structural optimization of natural GLP-1, and chemical modification is used to improve stability and half-life. According to the differences in chemical modification and dosage form, it can be divided into the following categories:

##### **1. Structural classification**

- **Natural GLP-1 analogs**

Natural GLP-1 consists of 30 amino acids, but is easily degraded by dipeptidyl peptidase-4 (DPP-4), with a half-life of only 2 minutes.

- **Chemically modified Semaglutide**

- **Amino acid substitution**: Alanine at position 8 is replaced with α-aminoisobutyric acid (Aib) to enhance DPP-4 resistance.

- **Fatty acid side chain modification**: Lysine at position 26 is connected to C18 fatty acid diacid (stearic acid derivative) through a spacer to promote binding to albumin and extend the half-life to 7 days.

- **Polyethylene glycol (PEG) (only in some studies)**: Further improve solubility and stability.

##### **2. Dosage form classification**

- **Injection (Ozempic®/Wegovy®)**: Subcutaneous injection, once a week, with a bioavailability of up to 89%.

- **Oral preparation (Rybelsus®)**: Adopts SNAC (sodium N-(8-[2-hydroxybenzoyl]-aminooctanoate) technology to protect the drug from gastric acid destruction, with a bioavailability of about 0.4-1%.

#### **3. Core advantages of Semaglutide**

##### **1. Efficacy advantage**

- **Glycemic control**: Significantly reduces HbA1c (1.5-1.8%), which is better than traditional glucose-lowering drugs (such as sitagliptin).

- **Weight loss effect**: In the STEP clinical trial, obese patients lost an average of 15-20% weight, which is close to the effect of bariatric surgery.

- **Cardiovascular protection**: The SUSTAIN-6 trial showed a 26% reduction in the risk of major cardiovascular events.

##### **2. Pharmacokinetic advantages**

- **Long-term effect**: Half-life is about 7 days, supporting once-weekly dosing.

- **Targeting**: Specific activation of GLP-1 receptors to reduce off-target effects.

##### **3. Safety**

- **Low risk of hypoglycemia**: Promotes insulin secretion only when blood sugar is elevated.

- **Gastrointestinal tolerance**: Common side effects (nausea, diarrhea) are mostly mild and alleviated with medication time.

#### **4. Physical and chemical properties of Semaglutide**

##### **1. Basic physical and chemical parameters**

- **Molecular formula**: C₁₈₇H₂₉₁N₄₅O₅₉

- **Molecular weight**: 4113.58 Da

- **Isoelectric point (pI)**: About 5.5 (because the fatty acid side chain is negatively charged)

- **Solubility**

- **Injection**: Easily soluble in neutral buffer (pH 7.4), solubility>50 mg/mL.

- **Oral**: Requires SNAC to assist in dissolving in gastric juice, and has high pH sensitivity.

##### **2. Stability**

- **Temperature sensitivity**: APIs need to be stored at -20°C for a long time, and preparations (lyophilized powder or solution) can be stably stored at 2-8°C.

- **Light sensitivity**: Need to be stored away from light, ultraviolet radiation may cause peptide chain breakage.

- **pH stability**: Optimum pH 7.0-8.0, acidic environment (such as gastric juice) is prone to conformational changes.

##### **3. Preparation characteristics**

- **Injection**: Colorless to slightly yellowish clear liquid (prefilled pen), lyophilized powder is white loose block.

- **Oral tablets**: White to off-white film-coated tablets, the coating contains SNAC and enteric materials.

#### **5. Color and appearance characteristics**

- **API**: White to off-white powder (lyophilized form).

- **Injection**: Colorless and transparent solution (may be light yellow due to concentration differences).

- **Oral tablets**: White coating, tablet core is white or light yellow.

- **Degradation indication**: Darkening of color (e.g., yellow or brown) may indicate oxidation or polymerization.

#### **6. Production process and quality control**

##### **1. Synthesis process**

- **Solid phase peptide synthesis (SPPS)**: 34 amino acid backbones are synthesized stepwise using Fmoc chemistry.

- **Fatty acid modification**: C18 side chains are attached by click chemistry or amide bonds.

- **Purification**: Reverse phase high performance liquid chromatography (RP-HPLC) purification to >99%.

##### **2. Key quality indicators**

- **Purity**: HPLC detection of main peak area ≥95%.

- **Impurity control**: Including oxidation products (Met14 oxidation), deamidation (Asn28) and aggregates.

- **Biological activity**: Potency is verified by in vitro GLP-1 receptor activation assay.

#### **7. Application and market prospects**

- **Diabetes treatment**: Among the more than 460 million diabetics in the world, Semaglutide accounts for 40% of the GLP-1 market.

- **Obesity**: Wegovy® sales exceeded $1 billion in the first year after its launch.

- **Expanded indications**: Research on non-alcoholic steatohepatitis (NASH), Alzheimer's disease (improvement of insulin resistance), etc. is underway.

#### **8. Challenges and future directions**

- **Cost issues**: The complex synthesis process leads to high prices (about $1,300/month).

- **Oral dosage form optimization**: New carrier technology to improve bioavailability (such as lipid nanoparticles).

- **Long-term upgrade**: Develop monthly or quarterly dosage forms (such as implantable microspheres).

#### **9. Conclusion**

Semaglutide has become a model for peptide drug development by balancing efficacy and safety through clever molecular design. Its physicochemical properties (such as fatty acid modification, high solubility) and innovative dosage form (oral SNAC technology) provide important references for subsequent drug development. With the optimization of production processes and the expansion of indications, Semaglutide is expected to continue to lead the revolution in the field of metabolic diseases.