Introduction
With the development of semaglutide, people suffering from type 2 diabetes and obesity have a wider range of options for medication.
With the development of semaglutide, people suffering from type 2 diabetes and obesity have a wider range of options for medication. There are three brands under semaglutide: Ozempic, which treats type 2 diabetes; Rybelsus, which treats type 2 diabetes; and Wegovy, which treats obesity.
Ozempic and Rybelsus come in injection pens, while Rybelsus comes in pill format. Semaglutide, a GLP-1 receptor agonist, mimics GLP-1, which triggers insulin release when blood sugar levels rise. It aids weight loss by delaying digestion, helping patients feel full longer, and reducing their appetite.
Research suggests it may benefit cardiovascular health by reducing heart attack, stroke, and death risks. Examining semaglutide’s manufacturing reveals how pharmaceutical companies make anti-diabetic drugs and what strict quality controls they use.
Overview of Semaglutide
Semaglutide is a kind of GLP-1 receptor agonist or GLP-1 Ra. It copies the functionalities of naturally occurring GLP-1 receptors, which are typically in the pancreas’ beta cells and alpha cells. Beta cells produce insulin, while alpha cells inhibit the production of glucagon.
If insulin prevents blood sugar levels from getting too high, glucagon, on the other hand, prevents blood sugar levels from getting too low.
Semaglutide and its mechanism of action
‘Mechanism of action’ in pharmacology describes the biochemical process drugs follow to create effects in the body.
Semaglutide stimulates GLP-1 receptors, enabling incretins to function correctly and reduce blood sugar levels. This process delays gastric emptying, curbs appetite, reduces food intake, inhibits glucagon secretion, and lowers hepatic glucose production.
Hepatic glucose production also goes by the name of hepatic gluconeogenesis. This is a process wherein the body stores glycogen or excess energy for later use.
When necessary, the liver breaks down the glycogen in storage into glucose and distributes this throughout the body.
Therapeutic applications
Various studies and trials have had promising results investigating semaglutide’s therapeutic applications.
Studies show that it may help in protecting the liver from disease or injury, reducing liver fat content, liver inflammation, as well as fibrosis or tissue scarring, all common characteristics of the liver disease non-alcoholic steatohepatitis (NASH).
Semaglutide may potentially also be beneficial to obese women suffering from polycystic ovary syndrome or PCOS.
Research found that semaglutide injections once a week helped a majority of participants improve their body weight. Semaglutide also reduced their insulin levels and regulated fasting blood glucose levels.
Semaglutide and its manufacturing process
While there is little information on the specific manufacturing process of semaglutide, peptide drugs typically follow a standard production process.
Collection of raw materials and initial preparation
Selection of ingredients
Drugmakers select the necessary raw materials necessary in the manufacture of the drug.
These ingredients include amino acids and reagents that peptide synthesis requires, or the process by which these form semaglutide’s peptide chain.
Quality control measures for raw materials
The raw materials must be of the highest quality and undergo strict quality control measures before they are ready for the next stage of the manufacturing process.
Solid-Phase Peptide Synthesis (SPPS)
For manufacturers to produce a peptide drug like semaglutide, they first need to create a peptide chain. Semaglutide, in particular, consists of a linear arrangement of 31 amino acids that share peptide bonds, making it a polypeptide.
Solid-phase peptide synthesis uses a systematic approach to build chains of amino acids. To produce semaglutide, scientists add amino acids one by one in a specific order to create the peptide chain. They remove protecting groups from the peptide chain during deprotection and elongation.
By allowing scientists to create a specific sequence of amino acids, they can develop synthetic peptides, such as those in medication.
Step 1: First, scientists add amino acids individually in a particular order to a supporting pillar until they build the peptide chain. Protecting groups then temporarily cover certain reactive functional groups in amino acids during synthesis to avoid changing the peptide sequence.
Once protecting groups shield the specific functional groups, the synthesis progresses, with specific alterations to improve its stability and efficacy.
Step 2: Next, scientists add amino acids individually in the proper sequence, starting from the peptide chain’s C-terminus to the N-terminus.
The C-terminus also goes by the names carboxy-terminus, carboxyl-terminus, C-terminal tail, carboxy tail, or COOH-terminus. These names refer to the last part of a peptide chain. N-terminus, meanwhile, refers to the beginning of the peptide chain.
Step 3: Coupling, or the chemical reaction wherein an amino acid connects to a growing peptide chain, takes place.
Step 4: Scientists remove the protecting groups in step 1 as the peptide chain grows, part of the deprotection and elongation process.
Addition of a fatty acid chain
As semaglutide, a GLP-1 receptor agonist, is an analogue or a compound so close in chemical composition to an actual GLP-1 molecule, there are only three main differences in its molecular composition versus that of GLP-1:
- Alpha-aminoisobutyric acid replaces the amino acid Alanine in position 8,
- A C-18 fatty acid joins Lys in position 26, and
- Arginine replaces the amino acid Lysine in position 34.
Adding the C-18 fatty acid gives semaglutide a longer half-life in plasma, which enhances its effectiveness.
The half-life refers to the time necessary for a drug’s amount of concentration in the blood to diminish by 50 percent.
Purification and isolation of semaglutide
Manufacturers purify the synthesized peptide to remove impurities or byproducts. These impurities may come in fragments from incomplete peptide sequences, unwanted side products from chemical reactions, residual chemicals like reagents or solvents, and stereoisomers of compounds. Stereoisomers refer to two or more compounds that only differ in the spatial arrangement of their atoms.
They use High-Performance Liquid Chromatography (HPLC) to separate impurities from the peptide. they purify the peptide, they then isolate semaglutide as a pure compound.
Formulation and finalization
Dosage form: Specific processes are used to formulate peptide drugs to achieve their stability, efficacy, and safety.
After synthesis and purification, manufacturers formulate semaglutide into dosage forms like solutions, tablets, syrups, or sprays.
Ozempic comes in three doses: 0.5 milligrams, 1 milligram, and 2 milligrams, while Wegovy comes in 2.4 milligram doses.
Rybelsus, on the other hand, comes in either 7 milligram or 14 milligram tablets.
As previously mentioned, both Ozempic and Wegovy come in pre-filled injectable pens, whereas Rybelsus comes in pill format.
Stabilization: Because peptides may be subject to degradation, the dosage forms also play a crucial role in helping maintain the peptide’s structural integrity.
Some methods such as freeze-drying or lyophilization make use of stabilizing agents to support the peptide’s stability.
In some cases, increasing the solubility of a peptide may ensure they are dissolved in the right manner when administered.
Excipient selection: Pharmaceutical excipients are substances other than the active ingredient that is used in a medicine. In the case of semaglutide, semaglutide is the active ingredient in Ozempic, Wegovy, and Rybelsus.
Ozempic’s excipients are disodium phosphate dihydrate, propylene glycol, phenol, and water for injections, while that of Rybelsus are magnesium stearate, microcrystalline cellulose, povidone, and salcaprozate sodium.
Wegovy, meanwhile, has the following inactive ingredients: disodium phosphate dihydrate, sodium chloride, hydrochloric acid, sodium hydroxide, and water for injection.
Compatibility testing: Next, they conduct compatibility testing (DECS) to ensure excipients work effectively with the active ingredient.
The intention is to arrive at a stable and effective formulation.
Manufacturing and quality control: Peptide drugs undergo strict formulation conditions and meticulous testing to ensure purity, quality, efficacy, and safety.
Packaging, storage, and usage of semaglutide
Manufacturers place the medicines in appropriate containers to prevent contamination or degradation. These are then stored in proper facilities under controlled conditions such as humidity and temperature to maintain their quality and potency.
Once the peptide drugs have been distributed to pharmacies and other healthcare providers, these are now available for purchase and the use of eligible consumers.
Semaglutide requires a prescription before it can be bought and administered using the correct dosage.
Challenges in making semaglutide
While solid-phase peptide synthesis has been a standard practice in the manufacture of peptide-based drugs, it does come with its share of difficulties that affect the manufacturing process.
Amino acids, for instance, can become erratic and cause unwanted chemical reactions in the peptide chain being built.
The removal of protection groups on functional groups of amino acids can also accidentally alter the structure of the peptide chain.
As a peptide chain grows, so is it more likely to have errors in its structure. This affects not just the purity of the drug but the efficacy as well.
SPPS requires time and incurs high costs for drugmakers due to the combined expenses of equipment, raw materials, and reagents.
In spite of these potential setbacks, semaglutide remains a key player, if not the forerunner, in the anti-diabetes and weight management space. More innovations are expected in 2024 with the conclusion of six clinical trials on obesity.
Conclusion
The manufacturing process for peptide-based drugs such as semaglutide is complex and tedious, relying on the successful implementation of solid-phase peptide synthesis. As many factors can affect the potency and safety of the medicine, pharmaceutical companies take extra care in preparing and using only the highest quality raw materials.
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