L-5-Methyltetrahydrofolate Calcium (5-MTHF-Ca), also known as active folate or (6S)-5-methyltetrahydrofolate calcium, is the naturally occurring bioactive form of folic acid. While folic acid was first isolated from spinach leaves in 1941, the stable form of L-5-MTHF-Ca wasn't successfully commercialized until 2000 when scientists developed the calcium salt crystal form, solving previous stability issues.
Unlike synthetic folic acid, L-5-MTHF-Ca can be directly absorbed and utilized by the human body without metabolic conversion. The United States approved it as a new folate source in 2001, followed by Europe in 2004, and China in 2017, marking the beginning of the "active folate era".
The manufacturing process of L-5-MTHF-Ca has undergone significant technological advancements. Early synthesis methods were complicated with limited yields. Researchers from Peking University developed a synthesis route starting from folic acid, achieving a total yield of 54%-59%.
Modern processes typically employ one-pot methods under weak alkaline conditions with optimized ratio of folic acid to sodium borohydride (1:24), reacting at 70°C to achieve yields up to 69.97%. The key breakthrough came with crystallization technology - the C-crystal technology not only solved product stability issues but also enhanced bioavailability. Lianyungang Jinkang Hexin Pharmaceutical made significant progress in dissolution rate and stability through patented crystal technology.
The core advantage of L-5-MTHF-Ca lies in its ability to bypass liver metabolism and directly participate in human physiological activities. It represents the main circulating form of folate in plasma and participates in two key metabolic pathways: methylation processes and DNA synthesis.
Clinical applications primarily include:
Preventing birth defects: Directly participates in fetal nervous system development, reducing the risk of neural tube defects
Improving anemia: Serves as hematopoietic raw material for treating megaloblastic anemia caused by folate deficiency
Regulating homocysteine: Reduces blood homocysteine concentration through methylation metabolism, lowering cardiovascular disease risk
Supporting neurological health: Participates in neurotransmitter synthesis, assisting in mood improvement and cognitive function
For populations with MTHFR gene mutations (relatively common in Chinese population), L-5-MTHF-Ca provides an effective folate supplementation solution, avoiding the metabolic challenges associated with regular folic acid.
China dominates the global folate market, accounting for over 90% of global folic acid raw material production, with 60% exported. As an emerging ingredient, L-5-MTHF-Ca has been sold in European and American markets for over 20 years, with a substantial market scale.
Application distribution:
Health products sector: 80% of total volume, mainly for maternal nutrition and daily health supplements
Food industry: As a nutritional fortifier in modulated dairy products, baked goods, etc.
Pharmaceutical industry: For treating megaloblastic anemia and related cardiovascular diseases
Regionally, East and South China are the main consumption markets, benefiting from higher economic development and health awareness. Since China's approval of naturalized folate as a new folate source in 2017, the domestic market has entered a period of rapid growth.
With deepening research on folate metabolism mechanisms and growing health awareness, L-5-MTHF-Ca faces promising market prospects. Future development trends include:
Technical optimization: Continuous improvement of fermentation technology and synthesis processes to enhance yield and purity
Application expansion: From current maternal and infant fields to broader areas like cardiovascular health and neurological support
Awareness popularization: Targeted use of active folate will become increasingly common with the popularization of MTHFR gene testing
Policy support: Government policies supporting folic acid fortification will provide sustained momentum for market growth
L-5-Methyltetrahydrofolate Calcium represents the future direction of folate supplementation. Its excellent bioavailability and extensive application value will play an increasingly important role in the global nutrition and health industry.
Vitamin K was first discovered in 1929 by Danish biochemist Henrik Dam, who named it "Koagulationsvitamin" for its essential role in blood clotting. The natural forms of Vitamin K include Vitamin K1 (phylloquinone) and Vitamin K2 (menaquinone). Vitamin K2 MK-7, characterized by its seven-isoprene-unit side chain, offers a superior half-life and higher bioavailability compared to other forms.
Japan pioneered the development and use of Vitamin K2, largely attributed to their traditional fermented food natto. In 2001, Japan became the first country to approve Vitamin K2 as a treatment for osteoporosis. The European Food Safety Authority also recognized MK-7's high bioavailability and benefits for bone and cardiovascular health in 2009.
Vitamin K2 MK-7 is primarily produced through microbial fermentation using strains such as Bacillus subtilis and Bacillus natto.
Production techniques have advanced significantly. For example, Jiangxi Agricultural University optimized the fermentation conditions for Bacillus subtilis DC-1, achieving an MK-7 yield of 94.66 mg/L—a 48.04% increase from initial conditions. Another study employed genetic engineering to enhance Bacillus natto, resulting in a 1.26-fold increase in MK-7 production.
China has emerged as a dominant player in the global supply chain, accounting for over 70% of the world's MK-7 production capacity.
The primary function of Vitamin K2 MK-7 is the precise regulation of calcium metabolism, which it achieves through two key mechanisms:
Activation of Osteocalcin: Osteocalcin, secreted by osteoblasts, requires Vitamin K2 for carboxylation. This process enables osteocalcin to bind calcium and incorporate it into the bone matrix, thereby enhancing bone density.
Activation of Matrix Gla Protein (MGP): When activated by Vitamin K2, MGP acts as a potent inhibitor of vascular calcification, thus supporting cardiovascular health.
Clinical studies have shown that daily supplementation with 180μg of MK-7 can significantly reduce the risk of vertebral fractures in postmenopausal women and slow the progression of carotid artery atherosclerosis. Additionally, MK-7 has demonstrated potential benefits in improving insulin sensitivity and supporting gum health.
The global Vitamin K2 market was valued at approximately $280 million in 2023, with the MK-7 segment accounting for 65% of the market share. Projections indicate that the market will grow to $520 million by 2028, reflecting a compound annual growth rate (CAGR) of 13.2%.
Regional market characteristics include:
Europe is the largest consumer market, holding a 42% share of the global market.
North America is experiencing rapid growth.
The Asia-Pacific region, particularly China, shows immense potential, with an annual growth rate exceeding 20%.
In terms of applications, bone health supplements dominate, comprising about 55% of the market, while cardiovascular health products account for 30%. The growing aging population worldwide is expected to sustain demand for MK-7 in osteoporosis and atherosclerosis prevention.
With accumulating clinical evidence and rising consumer health awareness, the applications of Vitamin K2 MK-7 are expected to expand into new areas, such as chronic kidney disease and neurodegenerative disorders.
Future developments will likely focus on advancements in fermentation technology to improve efficiency, alongside innovations in formulations and combination products (e.g., with Vitamin D) to meet diverse health needs. In summary, Vitamin K2 MK-7, with its proven dual benefits for bone and cardiovascular health, is poised to play an increasingly vital role in the global nutrition and health market.
Alpha-Lipoic Acid (ALA), chemically known as C₈H₁₄O₂S₂, is a unique dithiol compound distinguished by its dual hydrophilic and lipophilic properties, enabling blood-brain barrier penetration and systemic diffusion. Initially discovered in 1937, ALA was first isolated from pig liver by American scientists Reed et al. in 1951. The pioneering chemical synthesis achieved in 1952 by Homberger Jr et al. marked the commencement of industrial production.
Functioning as an essential cofactor in mitochondrial dehydrogenase complexes, ALA participates in pivotal oxidative decarboxylation reactions in cellular energy metabolism. Since the 1960s, ALA has been employed for treating diabetic neuropathy, gaining widespread recognition post-1990 as a "universal antioxidant" due to its exceptional antioxidant and anti-aging properties.
ALA exists as two enantiomers: bioactive R-ALA and inactive but non-toxic S-ALA, with commercial products typically comprising racemic mixtures. Traditional chemical synthesis required 9 steps with merely 50% theoretical yield.
Revolutionary progress emerged through chemoenzymatic synthesis developed by East China University of Science and Technology, reducing steps to 6 while increasing yield by 40%, lowering costs by 20%, and achieving 99% optical purity. Implementation by Fushilai Pharmaceutical boosted total yield from 25% to 55%.
Current industrial production favors routes using 6,8-dichloroethyl octanoate or cyclohexanone as starting materials for their shorter pathways and reduced environmental impact. China has established global production dominance, accounting for over 90% of worldwide capacity.
ALA's exceptional therapeutic value stems from its potent antioxidant capabilities, directly neutralizing free radicals while regenerating other antioxidants including vitamin C, vitamin E, and glutathione. Its multifaceted mechanisms encompass:
Participation in tricarboxylic acid cycle regulation
Glucose-dependent improvement of insulin sensitivity
Heavy metal chelation and detoxification
Neuroprotection against oxidative damage
Clinically, ALA demonstrates remarkable efficacy against diabetic neuropathy. The ALADIN trial confirmed that intravenous ALA administration significantly improved lower extremity sensitivity and reduced plasma lipid peroxidation in diabetic patients. Additional applications include radiation injury, cataracts, cardiovascular diseases, and growing cosmetic and nutraceutical uses for anti-aging and skin revitalization.
The global ALA market reached $166 million in 2023, with projections indicating growth to $1.236 billion by 2027 at a 6.3% CAGR (2021-2027). China's ALA injection sales in public hospitals surpassed 521 million RMB in 2023.
Regional characteristics demonstrate:
China: Global production leader and major exporter, with 80-90% output exported despite domestic consumption representing only ~12% of global total
North America: Highest regional growth rate
Europe: Long-standing medicinal applications with dual status as pharmaceutical and dietary supplement
Japan: Dominates 70% of global ALA patents in cosmetics and health foods
Pharmaceutical applications dominate market value, accounting for approximately $500 million globally, with 80% dedicated to diabetes management. The nutraceutical segment reached $377 million in 2020.
With rising global diabetes prevalence (projected 643 million patients by 2030) and increasing health consciousness, ALA demand will maintain steady growth. Product structure is upgrading toward high-value R-ALA, predicted to exceed $1 billion market by 2027.
Production innovations like enzymatic synthesis promise 25-30% cost reduction for R-ALA, enhancing accessibility. Novel applications in neurodegenerative diseases and NAFLD are expanding.
Chinese manufacturers like Fushilai are strengthening global competitiveness through technological innovation, with industry concentration increasing (CR2 reaching 80%). With ongoing advances in synthetic biology and application development, ALA's significance in the global health industry will continue to escalate.
Retatrutide (LY3437943), developed by Eli Lilly, represents a groundbreaking advancement in metabolic disease therapeutics as the first and only GLP-1R/GIPR/GCGR triple agonist currently in clinical development. This innovative molecule simultaneously targets three key incretin pathways, creating a synergistic effect that delivers superior outcomes in weight management and metabolic regulation.
Phase II clinical trials demonstrated unprecedented efficacy, with participants achieving average weight reduction of 24.2% over 48 weeks at the highest dose (12mg) - the most significant results observed with any pharmacological agent to date. Building on these robust findings, Eli Lilly has advanced Retatrutide into multiple Phase III clinical studies exploring indications including obesity, type 2 diabetes, cardiovascular event prevention, and obstructive sleep apnea. Notably, in 2025, the company registered the first Phase III trial (TRIUMPH-7) investigating a triple agonist for chronic low back pain, highlighting its potential therapeutic expansion beyond metabolic disorders.
As a synthetic peptide therapeutic, Retatrutide is produced using advanced solid-phase peptide synthesis technology. Recent patent applications have revealed continuous improvements in synthesis methodologies to enhance purity and yield.
Optimized manufacturing approaches employing Fmoc/tBu solid-phase synthesis combined with fragment condensation strategies successfully minimize byproduct formation, resulting in final product purity exceeding 99% with individual impurities below 0.10%. The utilization of Sieber resin as a solid-phase carrier with specifically designed octapeptide protected fragments for key sequence coupling has significantly improved synthesis efficiency.
Further refinement by Suzhou Mediff Biotech demonstrated that stepwise peptide fragment synthesis and combination strategies can enhance both purity and yield of Retatrutide, establishing a solid foundation for industrial-scale production.
Retatrutide's triple-agonist mechanism provides its exceptional therapeutic profile. Unlike single-target agents, it simultaneously activates GLP-1, GIP, and GCG receptors. GLP-1 receptor activation primarily reduces appetite and delays gastric emptying; GIP receptor agonism enhances insulin sensitivity and optimizes energy metabolism; while GCG receptor activation increases energy expenditure - creating a powerful synergistic effect for weight loss and glucose control.
Clinical research has also revealed significant benefits in metabolic dysfunction-associated steatotic liver disease. In obese patients with liver fat content ≥10%, 24-week treatment with Retatrutide resulted in dramatic reductions of hepatic fat content ranging from 57.0% to 82.4% across different doses, alongside notable improvements in liver fibrosis biomarkers.
Additionally, the medication significantly improves other cardiovascular risk factors including blood pressure and lipid profiles, demonstrating multiple metabolic benefits. In clinical practice, Retatrutide is administered as a once-weekly subcutaneous injection, supporting patient adherence to long-term therapy.
Although Retatrutide has not yet received regulatory approval for commercial distribution, financial markets have responded enthusiastically to its development. Eli Lilly's stock value surged dramatically in 2023, partially driven by excitement around its obesity pipeline including Retatrutide, temporarily making it the most valuable pharmaceutical company in the United States by market capitalization.
Industry analysts project that Retatrutide, along with Lilly's oral GLP-1 agent Orforglipron, could potentially launch around 2026/2027. While direct sales contribution from Retatrutide is initially estimated at only 2%-5% by 2030, this valuation may be revised upward as development progresses.
The obesity therapeutics market that Retatrutide will enter represents a potentially $100 billion opportunity, with additional disruption expected to the $76 billion traditional weight loss industry (including commercial diet programs and exercise regimens). With global obesity prevalence continuing to rise, Retatrutide's superior efficacy profile positions it for strong market penetration upon approval.
With the continuing increase in global obesity and related metabolic disorders, Retatrutide is positioned for rapid growth, supported by its exceptional efficacy and multi-system metabolic benefits. Researchers are actively exploring its potential in new indications including non-alcoholic steatohepatitis and Alzheimer's disease, which could substantially expand its therapeutic applications and market potential.
Long-term, Retatrutide's significance extends beyond providing another treatment option - it establishes a new paradigm for multi-targeted metabolic disease therapy. As additional clinical data accumulates and real-world experience grows, this innovative triple-agent approach is poised to benefit patients worldwide, representing a transformative advancement in metabolic disease management.
Tirzepatide, developed by Eli Lilly and Company, represents the world's first dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist. This innovative therapeutic agent emerged from extensive research on the incretin system, revealing that simultaneous activation of both GIP and GLP-1 pathways produces synergistic therapeutic effects. After years of preclinical research and optimization, Lilly successfully developed this landmark medication for metabolic disorders.
In May 2022, tirzepatide received FDA approval for treating type 2 diabetes, followed by approval for chronic weight management in adults in November 2022. These regulatory milestones marked the beginning of a new era in metabolic disease treatment. The development journey exemplifies the paradigm shift from single-target to multi-target therapies, paving the way for future innovations in metabolic drug development.
As a linear synthetic peptide comprising 39 amino acids, tirzepatide is manufactured using advanced solid-phase peptide synthesis technology. The production process involves multiple precise steps including amino acid protection, sequential coupling, side-chain deprotection, and cleavage from the resin. High-performance liquid chromatography purification ensures the final product achieves exceptional purity exceeding 99.5%, meeting all pharmaceutical standards.
A comprehensive quality control system is implemented throughout the manufacturing process. From raw material procurement to final product release, each batch undergoes rigorous testing including peptide content determination, related substances analysis, and biological activity assessment. This all-encompassing quality assurance system guarantees excellent batch-to-batch consistency and stability, ensuring reliable clinical safety.
The dual agonist mechanism forms the scientific basis for tirzepatide's outstanding efficacy. GIP receptor activation not only enhances the glucose-lowering effects of GLP-1 but also significantly improves insulin sensitivity while reducing adverse effects. This unique dual mechanism provides distinct therapeutic advantages across multiple parameters.
In the SURPASS clinical trial program, tirzepatide demonstrated exceptional therapeutic performance. Study data revealed that the highest dose (15mg) administered weekly achieved up to 20.9% weight reduction and over 2.4% HbA1c decrease after 72 weeks of treatment. Additionally, the medication significantly improved lipid profiles, reduced blood pressure, and showed potential cardiovascular benefits. These comprehensive metabolic improvements position it as an ideal choice for managing metabolic syndrome.
Since its launch, tirzepatide has demonstrated remarkable market performance. Achieving $2.5 billion in first-year sales, the drug is projected to reach global sales exceeding $10 billion by 2025. Currently holding 18% market share in US diabetes medications and 32% in obesity therapeutics, it demonstrates strong market competitiveness.
Geographically, North America accounts for 65% of total sales, with Europe and Asia contributing 20% and 15% respectively. Particularly noteworthy is the accelerating growth rate in the Asia-Pacific region, driven by improving diagnostic rates and growing treatment awareness for metabolic diseases. This global market performance solidifies its important position and widespread acceptance in metabolic disease treatment.
With the continuing global rise in obesity and diabetes prevalence, tirzepatide is expected to maintain its rapid growth trajectory in coming years, supported by its outstanding efficacy and safety profile. Researchers are actively conducting clinical studies exploring new indications including non-alcoholic steatohepatitis (NASH) and Alzheimer's disease, which may further expand its therapeutic applications.
Long-term, tirzepatide's success not only provides new treatment options for metabolic disease patients but more importantly establishes a new paradigm for multi-targeted metabolic disease therapy. As more clinical data accumulates and application experience grows, this innovative medication is poised to benefit more patients worldwide, making significant contributions to metabolic disease treatment.
Semaglutide, developed by Novo Nordisk, is a breakthrough long-acting GLP-1 analog. With 94% sequence homology to native GLP-1 and structural modifications, it achieves extended half-life allowing once-weekly dosing.
The injectable form received FDA approval in 2017, entering China's market in 2021. The groundbreaking oral formulation, approved in 2019, overcame peptide drug delivery challenges.
Manufacturing combines solid-phase and liquid-phase synthesis. Initial methods used solid-phase synthesis for the linear peptide chain.
Jiangnan University developed an efficient native chemical ligation method, simplifying production. Lanzhou University introduced fragment condensation with pseudoproline strategy, reducing byproducts and costs. These advances resolved key industrial production challenges.
Semaglutide activates GLP-1 receptors, regulating blood glucose levels while delaying gastric emptying to enhance satiety. Clinical trials demonstrated 17.4% weight reduction after 68 weeks and significant cardiovascular risk reduction.
Available as weekly injection and daily oral tablet, the oral form uses Eligen® technology, showing superior efficacy to conventional diabetes medications at 7mg and 14mg doses.
Global sales reached $10.6 billion in 2021. Projections indicate injectable and oral formulations will reach $5.28B and $3.23B respectively by 2024.
The global GLP-1 drug market valued at 56B RMB in 2023, with China accounting for 6.2B RMB. Expected to grow to 107.5B RMB by 2029, the market shows a 10.44% CAGR. North America leads growth while Asia-Pacific shows strong potential.
Rising prevalence of metabolic diseases ensures continued demand. Post-patent competition will drive process optimization and cost reduction, expanding patient access. Semaglutide represents a milestone in metabolic disease treatment through its innovative design and proven efficacy.
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