Send Message
Home >

FARMASINO PHARMACEUTICALS (ANHUI) CO.,LTD Company Blog & News

Blog & News
01

Semaglutide reduces heart failure–related symptoms and physical limitations

On 6 Aprile 2024, Novo Nordisk published the result of STEP HFpEF DM on the New England Journal of Medicine. The results demonstrated that among patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes, semaglutide led to larger reductions in heart failure–related symptoms and physical limitations and greater weight loss than placebo at 1 year.

02

Visit FarmaSino at API China 2024 Shanghai

  API China focuses on improving the overall level of production, research and development of pharmaceutical raw materials, intermediates and pharmaceutical excipient in China, representing new products and technologies in China's pharmaceutical industry. API China has become a brand event that brings together industry leaders, exhibits advanced product technologies, interprets policies and regulations for enterprises, improves industry production levels and reflects industry development trends. The exhibition is supported by more than 97% of China's top 100 pharmaceutical industry enterprises, providing pharmaceutical enterprises with decision-making, procurement, technology, research and development personnel to establish information exchange and business cooperation opportunities with target customers.   From May 15 to 17, 2024, FarmaSino will sincerely welcome you at Booth 1.2Y96, the National Exhibition and Convention Center (Shanghai). We will bring our latest products, the most professional service, the most competitive price, the most warm reception and the most sincere friendship to visitors from all over the world. We sincerely welcome your visit and look forward to further cooperation and development with you. We wish people all over the world the same : ‘Better health, better life.’   Contents: Pharmaceutical raw materials, pharmaceutical accessories, natural extracts, chemical reagents, intermediates, fine chemical raw materials, important raw materials, food raw materials and additives, veterinary raw materials, feed raw materials and additives, health care raw materials and additives, biotechnology, pharmaceutical research and development services, contract customized production services, registration and pharmaceutical services, training services

03

GLP-1: A Multifunctional Target

As an important class of hypoglycemic and weight loss drugs, GLP-1 drugs have attracted much attention and made significant development in recent years. Since GLP-1 drugs were found to have hypoglycemic effects, GLP-1 targets have been firmly in the hot track, especially after the approval of semaglutide for weight loss indications, the research and development of GLP-1 drugs has reached the peak. In 2023, the market value of Novo Nordisk and Eli Lilly skyrocketed, and the core factor driving the market value skyrocketed was the popular GLP-1 drugs. With the increasing number of diabetes and obesity patients worldwide, the demand for GLP-1 drugs has great potential, and the research and development momentum at home and abroad is strong. In the future, GLP-1 drugs are expected to play a therapeutic role in fields such as cardiovascular disease and fatty liver.   In 1985, a peptide chain composed of 31 amino acids, natural GLP-1 was first discovered, but its half-life is very short, about 2 minutes, and it is easy to be degraded by DPP-4 enzyme after secretion into the blood. The development of GLP-1 receptor agonists needs to solve the problem of short half-life.   The first short-acting GLP-1RA, exenatide (Astrazeneca), was approved by the FDA in 2005. It has a half-life of about 3 hours and requires twice daily subcutaneous injections. In 2009, the first long-acting GLP-1 RA, liraglutide (Novo Nordisk), was launched as a once-daily subcutaneous injection. Once-weekly injections of dulaglutide (Eli Lilly) and semaglutide (Novo Nordisk) were approved in 2014 and 2017, respectively. In 2022, the dual-target GLP-1/GIP telpotide (Eli Lilly) was approved for marketing, which kicked off the prologue of dual targets.   GIP-1 receptors are widely distributed, and multiple mechanisms of GLP-1RA act together. Glucagon like peptide-1 (GLP-1) : A hormone secreted by intestinal L-cells that promotes insulin secretion by pancreatic β cells in a glucose concentration-dependent manner, and its receptor (GLP-1R) is widely distributed in many organs and tissues such as the central nervous system, cardiovascular system, muscle, and gastrointestinal tract.   The receptor agonist of GLP-1 (GLP-1RA) stabilizes blood glucose and reduces body weight through various glucose-lowering mechanisms. If it acts on the stomach, it can delay gastric emptying by inhibiting gastrointestinal peristalsis; It acts on the central nervous system (especially the hypothalamus) to increase satiety and inhibit appetite; It acts on the liver and inhibits hepatic glucose output. Promoting insulin to stimulate glucose uptake in peripheral tissues (increasing insulin sensitivity).

04

Top 30 Anti-tumor Drugs in 2023 (In billion dollars)

Top 30 Anti-tumor Drugs in 2023 (In billion dollars)   No. Drug name Company Main indications Sales Growth rate 1 Keytruda (pembrolizumab) MSD Melanoma, NSCLC, Bladder cancer, HNC 25.01 19.5% 2 Opdivo (nivolumab) BMS/ONO Melanoma, NSCLC, HNC 10.04 9.0% 3 Darzalex (daratumumab) Johnson & Johnson Multiple myeloma, AL amyloidosis 9.74 22.2% 4 Imbruvica (ibrutinib) Abbvie/Joshnson CLL/SLL, MCL, GVHD 6.86 -17.9% 5 Revlimid (lenalidomide) BMS MM, MDS, MCL, FL 6.10 -39.0% 6 Tagrisso (osimertinib) Astrazeneca T790M NSCLC 5.80 7.0% 7 Xtandi (enzalutamide) Astellas Prostate cancer 5.07 4.3% 8 Ibrance (palbociclib) Pfizer Breast cancer 4.75 -6.0% 9 Jakafi (ruxolitinib) Incyte/Norvatis Myelofibrosis, PV 4.31 8.7% 10 Imfinzi (durvalumab) Astrazeneca Urothelial carcinoma,NSCLC, SCLC etc 4.24 52.0% 11 Perjeta (Pertuzumab) Roche HER2+ breast cancer 4.21 1.0% 12 Tecentriq (atezolizumab) Roche Urothelial carcinoma,NSCLC, TNBC 4.21 9.0% 13 Verzenio (abemaciclib) Eli Lilly Breast cancer 3.86 56.0% 14 Pomalyst (pomalidomide) BMS Multiple myeloma 3.44 -2.0% 15 Lynparza (olaparib) Astrazeneca/MSD Ovarian cancer, Breast cancer, Pancreatic cancer, Prostate cancer 2.81 7.0% 16 Enhertu (trastuzumab deruxtecan) Daiichi Sankyo/AZ HER2+ breast cancer, HER2-low brease cancer 2.57 104.8% 17 Calquence (acalabrutinib) Astrazeneca Mantle cell lymphoma, CLL/SLL 2.51 22.0% 18 Erleada (apalutamide) Johnson & Johnson Prostate cancer 2.39 26.9% 19 Venclexta (venetoclax) Abbvie CLL, AML 2.29 13.9% 20 Revolade/Promacta (eltrombopag) Norvatis Thrombocytopenia 2.27 10.0% 21 Yervoy (ipilimumab) BMS Melanoma, RCC, CRC 2.24 5.0% 22 Kadcyla (trastuzumab Emtansine) Roche HER2+ breast cancer 2.19 4.0% 23 Xgeva (denosumab) Amgen Solid tumor bone metastasis 2.11 5.0% 24 Kisqali (Ribociclib) Norvatis HR+ breast cancer 2.08 75.0% 25 Lenvima (lenvatinib) Eisai/MSD DTC, HCC, Endometrial carcinoma 2.01 8.4% 26 Sprycel (dasatinib) BMS ALL, CML 1.93 -11.0% 27 Tafinlar+Mekinist (dabrafenib+trametinib) Norvatis Melanoma, NSCLC, ATC 1.92 11.0% 28 Tasigna (nilotinib) Norvatis CML 1.85 -3.0% 29 Herceptin (trastuzumab) Roche HER2+ breast cancer 1.82 -16.0% 30 Avastin (bevacizumab) Roche CRC, Breast cancer, Lung cancer, Ovarian cancer etc 1.76 -19.0%    

05

FDA Approves First Treatment to Reduce Risk of Serious Heart Problems Specifically in Adults with Obesity or Overweight

On 8 March, the U.S. Food and Drug Administration approved a new indication for use for Wegovy (semaglutide) injection to reduce the risk of cardiovascular death, heart attack and stroke in adults with cardiovascular disease and either obesity or overweight.     The FDA decision is based on the results of the landmark SELECT phase III cardiovascular outcomes trial that examined the effect of adding Wegovy® 2.4 mg or placebo to cardiovascular standard of care in adults with overweight and obesity with established CVD and without diabetes. Wegovy® 2.4 mg significantly reduced the risk for first occurrence of a three-part composite MACE endpoint consisting of cardiovascular death, non-fatal heart attack, or non-fatal stroke. The primary composite outcome occurred in 6.5% of patients treated with Wegovy® and 8.0% with placebo. The estimated relative risk reduction of MACE was 20% vs placebo (HR 0.80 [95% CI: 0.72, 0.90] p

06

SNAC: A Stepping Stone to Oral Semaglutide

Salcaprozate sodium (SNAC) is the sodium salt form of salcaprozate. It is used in the treatment of gastrointestinal disorders, especially gastrointestinal disorders caused by the malabsorption of dicarbonate-phosphate compounds. SNAC can also promote the absorption of drugs in gastrointestinal epithelial cells, and effectively cope with the obstacles to the absorption of oral peptide drugs, for instance Semaglutide.   Absorption of oral dose peptides by intestine is challenging due to the physiological effects of the gastrointestinal tract. Ingested peptides or proteins are broken down into amino acids by ph-sensitive proteases, which are then transported to the mucosa by the translocater. Large molecules of carbohydrates or lipids are decomposed into small molecules to promote intestinal absorption. The intestinal epithelium has the function of recognizing and absorbing bacteria, viruses and other pathogens. So complex cellular and mucus barriers are formed to limit the entry of foreign or harmful substances. Therefore, unfortunately, exogenous peptides or protein drugs are restricted to penetrate the intestinal epithelium and enter the circulation. In this case, SNAC and its related compounds are used as Permeation enhancers to deal with this problem. The mechanism that SNAC promotes the absorption of Active pharmaceutical ingredient (API) is still not fully understood. It is generally believed that SNAC improves the membrane permeability of gastrointestinal epithelial cells may be related to membrane perturbation, membrane fluidization, and changes in API solubility. It also may improve transcellular permeability by increasing its hydrophobic role through non-covalent bond binding to API.   The successful preparation of semaglutide tablets depends on its co-formulation with SNAC. SNAC promotes the monosomy of semaglutide, making it more permeable. For semaglutide molecules, most semaglutide exists in the form of oligomers in the stomach; However, SNAC triggered a change in polarity of the solution containing the dissolved tablet, weakening the hydrophobic interaction necessary for oligomerization. Since SNAC is lipophilic, it efficiently inserts into the cell membrane of the gastric epithelium, altering the intrinsic integrity of cholesterol phospholipids and proteins, which in turn affect the fluidity of the cell membrane. It was confirmed that SNAC enhances the intracellular uptake of semaglutide by gastric epithelial cells, thus supporting the notion that SNAC promotes transcellular transport of semaglutide. SNAC can effectively increase the local pH value around the semaglutide molecule in the stomach, prevent the degradation of peptides by pepsin, and make semaglutide penetrate the gastric mucosa and be absorbed into blood by the concentration gradient on the surface of the cell membrane. The use of SNAC is of great significance for oral semaglutide tablets. FarmaSino can provide high purity and high quality SNAC together with Semaglutide API* and intermediates include semaglutide-related fragments, main chains, and side chains of different steps. Please check following links for more information.

07

Semaglutide APIs and Related Intermediates in Different Specifications

Semaglutide is an anti-diabetic drug which is used to treat type 2 diabetes and manage chronic weight. Semaglutide is a glucagon-like peptide-1(GLP-1) receptor agonist with 94% sequence homology with human GLP-1. It increases the production of insulin, which can lower the blood glucose level. Semaglutide also appears to enhance growth of β cells, sites of insulin production, in the pancreas. By lowering appetite and slowing down digestion in the stomach, Semaglutide also can reduce food intake to control body weight.   Semaglutide for injectable grade 99% is prepared for the formulation of Semaglutide injection. The purity of this product can reach 99.0% and the assay should reach 95%~105% with peptide content of Semaglutide 76%~100%. Semaglutide for oral grade 98% is suitable for the markets with high requirements of oral dose for the control of raw material impurities. The purity of this product should reach 98% with the same acceptance criteria of other standards with Semaglutide injectable grade 99%. Semaglutide for oral grade 96% is much more suitable for a price sensitive market where the tabbing process does not produce new impurities with its purity of 96%. The assay of this product should reach 90%~100%. Semaglutide crude product is prepared for the enterprises that have the production capacity and want to own the API approval. Semaglutide API can be obtained after purification by chromatography and freeze drying from Semaglutide crude product. The purity of this product should reach 50% and the assay over 35%.   Semaglutide secondary acylation intermediate is N-1 intermediate of Semaglutide. The protection group of this prodcut was deprotected to obtain Semaglutide crude product, which was purified by chromatography and freeze dried to obtain API. Secondary acylation intermediate is suitable for the enterprises that have the production capacity and want to own the API approval.   Semaglutide primary acylation intermediate and Semaglutide dipeptide are Semaglutide N-2 main chain intermediate and N-2 fragment. The primary acylation intermediate was acylated with Semaglutide dipeptide to obtain Semaglutide secondary acylation intermediate and further hydrolyzed to obtain Semaglutide crude product. Acylation, hydrolysis tank, high pressure chromatography system, drying equipment are required.   Semaglutide main chain P29 and Semaglutide side chain (tetrapeptide) are Semaglutide N-3 main chain intermediate and N-3 fragment. TheSemaglutide main chain P29 was acylated with Semaglutide side chain to obtain Semaglutide primary acylation intermediate. Further reaction was underwent to obtain the final API. These products are suitable for for the enterprises that have the production capacity and want to own the API approval. Acylation, hydrolysis tank, high pressure chromatography system, drying equipment are required. FarmaSino provides these the API with different grade and related intermediates of Semaglutide with reliable quality and competitive price.   Please get more information from following links: 910463-68-2: Semaglutide Semaglutide Starts the New Life with Type 2 Diabetes   *All APIs and intermediates for R&D use ONLY.

08

Maghreb Pharma Expo 2024

Farmasino adheres to the localization development of Algeria. It provides a one-stop solution for the local biopharmaceutical industry, from raw materials to registration documents, from production processes to pharmaceutical machinery. In 2023, its cumulative exports exceeded 20 million US dollars. Welcome to our booth for mutual benefit.  

09

Happy Chinese New Year ! ! !

At the beginning of the new year, everything is renewed, on the occasion of this new year, we sincerely thank our customers for their support and co-operation with us in the past year. In the new year, our company will work harder to provide you with better service, our Spring Festival holiday arrangements are as follows: from 9th February 2024 to 18th February 2024. We hope you could understand the inconvenience caused by the holiday. We will arrange a special person to reply the message and make the projects run normally. We wish you all a happy Chinese New Year and a happy family!

10

Ticagrelor: the World’s First Reversible Combination Orally-administered P2Y12 Adenosine Diphosphate Receptor Antagonist

Ticagrelor, a new platelet aggregation inhibitor, is the world’s first reversible combination orally-administered P2Y12 adenosine diphosphate receptor antagonist. It is used to reduce cardiovascular death and heart attacks in patients with acute coronary syndrome. Ticagrelor is white to off-white powder with hygroscopic, so low temperature storage and transport is required. Mechanism Ticagrelor has reversibly acts on the 2 purine receptor subtype P2Y12, of vascular smooth muscle cells (VSMC,) which does not require metabolic activation, and has a significant inhibitory effect on platelet aggregation induced by adenosine diphosphate. In this case, platelet function will recover rapidly after stopping the dose. Features Rapid onset of action Ticagrelor can be absorbed in approximately 1.5 hours and After about 2.5 hours, ticagrelor can rapidly transformed into circulating metabolite AR-C124910XX. The mean bioavailability of ticagrelor was approximately 36%. Powerful drug Without increasing major bleeding, ticagrelor treatment for 12 months significantly reduced the risk of cardiovascular death by 21% compared with clopidogrel. Ticagrelor is already a first recommended drug for cardiovascular disease in Europe. Platelet function recovered quickly The interaction between ticagrelor and platelet P2Y12 ADP receptor is reversible, without conformational change and signal transmission, and platelet function in blood recovers rapidly after drug withdrawal. Sythesis Ticagrelor is mainly composed of three major fragments: a five-membered ring, a thioether pyrimidine, and a three-membered ring. At present, a variety of synthesis routes have been reported, and the common point is that there is no construction of chiral centers in the synthesis process, and all the six chiral centers are introduced by starting materials. In this synthetic route, starting materials S1 and S2 were coupled, then the ring was diazosed off under the conditions of sodium nitrite and acetic acid, and then coupled with starting material S3. Finally, the finished product of ticagrelor was obtained by removing the forkone protection. Usage and dosage Oral administration. This product can be taken before or after meals. The initial dose was a single dose of 180 mg, followed by 90 mg twice a day. It should be used in combination with aspirin unless clearly contraindicated. After the initial loading dose of aspirin, aspirin was maintained at a dose of 75 to 100mg once daily. Ticagrelor can be started in ACS patients who have already received a loading dose of clopidogrel. Treatment may be given for up to 12 months unless there is a clinical indication to discontinue treatment. Cautions The most frequently reported adverse effects were dyspnea, contusion, and epistaxis in patients who received ticagrelor, which occurred more frequently than in patients who received clopidogrel. Among patients with acute coronary syndromes who are treated with ticagrelor combined with aspirin, there is an increased risk of bleeding. Therefore, the increase of bleeding risk should be balanced against the benefit of preventing atherothrombotic events. Interruptions of ticagrelor tablets should be avoided. If ticagrelor must be temporarily discontinued, treatment should be restarted as soon. The risks of myocardial infarction, thrombosis, even death would increase if ticagrelor is discontinued.

11

Fosfomycin Tromethamine, a Broad-Spectrum Bactericidal, Especially for Lower Urinary Tract Infections.

Fosfomycin is a broad-spectrum bactericidal for human and animals purposes, which inhibits the growth of E. coli, S. aureus, Serratia, Klebsiella, Citrobacter, Enterococcus, and Enterobacter etc.. Fosfomycin tromethamine is a phosphonic acidepoxide derivative, which expands the therapeutic utility of fosfomycin salt because its water solubility increased enough to allow oral administration. This compound is a white to off-white powder with great hygroscopic and solubility in water.   Mechanism Fosfomycin tromethamine, is a derivate of fosfomycin, which was initially isolated from fermentationsof streptomyces spp and been used as human medicine and veterinary medicine for over 50 years. Fosfomycin can inactivate the first enzyme in the bacterial cell wall biosynthesis pathway, which occurs through nucleophilic opening of the epoxide ring. Fosfomycin tromethamine only acts on the bacterial cell wall, human cells do not have this target site and is not affected. In this case this compound can be used in pregnant women, children and elderly patients.   Features Broad spectrum antibiotic Fosfomycin sodium is a broad-spectrum antibiotic of Gram-positive and Gram-negative bacteria, for instance E. coli, S. aureus, Serratia, Klebsiella, Citrobacter, Enterococcus, and Enterobacter etc. and is particularly suitable for the treatment of acute cystitis   Rapid sterilization After oral administration, fosfomycin tromethamine is rapidly decomposed into fosfomycin and tromethamine in the body. With the characteristics of low molecular weight and high hydrophilicity, fosfomycin tromethamine appears good distribution in fluid and strong penetration. So this medicine can widely distribute in body fluid and tissue to increase curative effect. Tromethamine is a weakly osmotic diuretic, which can alkalinize urine and effectively reduces the symptom of urinary tract irritation.   Low toxicityand residue of Fosfomycin tromethamine Bioavailability of Fosfomycin tromethamine by oral administration is from 34% to 41% in healthy adults, 37% in fasting and 30% after eating. It shows little irritation on the body, no acute toxicity and adverse reactions. The maximum plasma concentration was reached within 2 to 2.5 hours after dose, and will be excreted mainly in its original form in urine and feces in 48h.   Sythesis The synthesis of fosfomycin tromethamine use fosfomycin sodium as an intermediate. Prepare a certain concentration tromethamine-sulfuric acid solution and then it was added to fosfomycin sodium aqueous solution by drop. After that the sodium sulfate solid is precipitated with methanol and the filtrate is crystallized at low temperature with n-butanol to obtain fosfomycin tromethamine.   Fosfomycin Tromethamine Clinical Application Fosfomycin tromethamine is used for the treatment of acute uncomplicated lower urinary tract infections caused by sensitive bacteria (such as acute cystitis, acute onset of chronic cystitis, acute urethrovesical syndrome, non-specific urethritis, asymptomatic bacteriuria during pregnancy, and urinary tract infections after surgery) and for the prevention of urinary tract infections during surgery and infections caused by diagnostic procedures of the urinary tract.   Usage and dosage Adults: single-dose treatment, 3g active ingredient per course; Clinical symptoms usually resolve 2 to 3 days after treatment. For preventing infections caused by surgical procedures and urinary tract care: 6g active ingredient per dose, with first dose taken 3 hours before surgery and second dose taken 24 hours after surgery.   Cautions The main symptoms of fosfomycin tromethamine were are diarrhea and soft stools, occasional rash and nausea, which will disappear after drug withdrawal. It is not known whether fosfomycin tromethamine is excreted in human milk, but given the potential for serious adverse effects of fosmycin tromethamine in lactating infants, it should not be administered to lactating women. The efficacy and safety of fosfomycin tromethamine in children aged 12 years and younger are lack of sufficient and well-designed clinical verification.

12

Baloxavir Marboxil a New Drug against Influenza with Noval Mechanism

Baloxavir Marboxil is a new anti-influenza drug developed by Shionogi Pharmaceutical from Japan and Roche from Switzerland. The drug was first approved for use in Japan in February 2018 and later by the FDA in October for the treatment of acute uncomplicated influenza in patients 12 years of age and older who have been symptomatic for no more than 48 hours. Baloxavir marboxil is a cap-endonuclease inhibitor, which has a unique mechanism of action to Inhibit the proliferation of influenza virus. Mechanism Baloxavir marboxil is a prodrug that enters the body and is hydrolyzed to the active substance baloxavir, which plays an anti-influenza virus activity. Baloxavir is a selective inhibitor of influenza cap-endonuclease, an enzyme required for viral gene transcription and replication, which prevents polymerase function and influenza virus mRNA replication. It has therapeutic activity against both influenza A and B virus infections, even strains resistant to current antiviral drugs. Baloxavir marboxil inhibits an enzyme of viral replication, thus the flu virus infection can be rapidly treated and the symptoms will be alleviated. Features New antiviral influenza drug Baloxavir marboxil is the first anti-influenza virus drug with a new mechanism in the past 20 years. Cpmpared with traditional anti-influenza drugs, Baloxavir Marboxil selectively inhibits the CAP-endonuclease of influenza virus, thereby preventing polymerase function and influenza virus mRNA replication.This unique mechanism gives Baloxavir Marboxil a unique advantage against influenza viruses. Excellent activity of anti influenzavirus Baloxavir marboxil has excellent anti-virus performance against influenza, including influenza A virus (IAV) and influenza B virus (IBV). A single dose of Baloxavir marboxil was shown to be superior to placebo in relieving influenza symptoms and superior to both oseltamivir and placebo drug in virologic outcomes (marked by decreased viral load). Highly effective and long acting drug Baloxavir marboxil is a prodrug. By oral administration, almost all baloxavir marboxil is converted to the active constituent baloxavir. The tmax of Baloxavir to reach the Cmax in vivo is about 4 hours on average. The average half-life of bacalovirda in vivo is approximately 80 hours, so only one dose is needed for most patients. These make Baloxavir marboxil a highly effective and long acting drug. Synthesis The synthesis of Baloxavir marboxil mainly divided into two parts. In each part, a main intermediate is synthesized separately. In the synthesis of intermediate A (1985607-83-7), 7-(Benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (intermediate A-2, 1370250-39-7) yields the intermediate A by cyclization and reduction reactions. The coupling of the intermediate A and intermediate B was carried out under dehydration conditions of 1-propanephosphonic anhydride (T3P) and methanesulfonic acid at 70℃ to obtain protected Baloxavir N-2. Compound N-2 was then reacted with 0.6 equivalents of PhBr and K2CO3. Debenzylation was then carried out using LiCl in CH3CONMe2 to give Baloxavir acid in 94% yield. In the final step, Baloxavir acid was reacted with chloromethyl methyl carbonate in dimethylacetamide in 93% yield to form Baloxavir marboxyl. Usage and dosage The Baloxavir Marboxil is used for the treatment of acute uncomplicated influenza in patients (adults and pediatric patients 5 years of age and older) who have been symptomatic for no more than 48 hours. Baloxavir marboxil should be taken as a single dose as soon as possible and within 48 hours of influenza symptom onset for treatment of acute uncomplicated influenza. The specific dose should be adjusted according to the patient’s weight as follow: 20 kg to less than 80 kg: 40mg At least 80 kg: 80mg Cautions Hypersensitivity such as anaphylaxis, angioedema, urticaria, and erythema multiforme may occur or be suspected. Increased incidence of treatment-emergent resistance in patients less than 5 years of age. Baloxavir Marboxil has not been shown to prevent serious bacterial infections, which may begin with influenza-like symptoms or may coexist with, or occur as, a complication of influenza.

01

Semaglutide reduces heart failure–related symptoms and physical limitations

On 6 Aprile 2024, Novo Nordisk published the result of STEP HFpEF DM on the New England Journal of Medicine. The results demonstrated that among patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes, semaglutide led to larger reductions in heart failure–related symptoms and physical limitations and greater weight loss than placebo at 1 year.

02

Visit FarmaSino at API China 2024 Shanghai

  API China focuses on improving the overall level of production, research and development of pharmaceutical raw materials, intermediates and pharmaceutical excipient in China, representing new products and technologies in China's pharmaceutical industry. API China has become a brand event that brings together industry leaders, exhibits advanced product technologies, interprets policies and regulations for enterprises, improves industry production levels and reflects industry development trends. The exhibition is supported by more than 97% of China's top 100 pharmaceutical industry enterprises, providing pharmaceutical enterprises with decision-making, procurement, technology, research and development personnel to establish information exchange and business cooperation opportunities with target customers.   From May 15 to 17, 2024, FarmaSino will sincerely welcome you at Booth 1.2Y96, the National Exhibition and Convention Center (Shanghai). We will bring our latest products, the most professional service, the most competitive price, the most warm reception and the most sincere friendship to visitors from all over the world. We sincerely welcome your visit and look forward to further cooperation and development with you. We wish people all over the world the same : ‘Better health, better life.’   Contents: Pharmaceutical raw materials, pharmaceutical accessories, natural extracts, chemical reagents, intermediates, fine chemical raw materials, important raw materials, food raw materials and additives, veterinary raw materials, feed raw materials and additives, health care raw materials and additives, biotechnology, pharmaceutical research and development services, contract customized production services, registration and pharmaceutical services, training services

03

GLP-1: A Multifunctional Target

As an important class of hypoglycemic and weight loss drugs, GLP-1 drugs have attracted much attention and made significant development in recent years. Since GLP-1 drugs were found to have hypoglycemic effects, GLP-1 targets have been firmly in the hot track, especially after the approval of semaglutide for weight loss indications, the research and development of GLP-1 drugs has reached the peak. In 2023, the market value of Novo Nordisk and Eli Lilly skyrocketed, and the core factor driving the market value skyrocketed was the popular GLP-1 drugs. With the increasing number of diabetes and obesity patients worldwide, the demand for GLP-1 drugs has great potential, and the research and development momentum at home and abroad is strong. In the future, GLP-1 drugs are expected to play a therapeutic role in fields such as cardiovascular disease and fatty liver.   In 1985, a peptide chain composed of 31 amino acids, natural GLP-1 was first discovered, but its half-life is very short, about 2 minutes, and it is easy to be degraded by DPP-4 enzyme after secretion into the blood. The development of GLP-1 receptor agonists needs to solve the problem of short half-life.   The first short-acting GLP-1RA, exenatide (Astrazeneca), was approved by the FDA in 2005. It has a half-life of about 3 hours and requires twice daily subcutaneous injections. In 2009, the first long-acting GLP-1 RA, liraglutide (Novo Nordisk), was launched as a once-daily subcutaneous injection. Once-weekly injections of dulaglutide (Eli Lilly) and semaglutide (Novo Nordisk) were approved in 2014 and 2017, respectively. In 2022, the dual-target GLP-1/GIP telpotide (Eli Lilly) was approved for marketing, which kicked off the prologue of dual targets.   GIP-1 receptors are widely distributed, and multiple mechanisms of GLP-1RA act together. Glucagon like peptide-1 (GLP-1) : A hormone secreted by intestinal L-cells that promotes insulin secretion by pancreatic β cells in a glucose concentration-dependent manner, and its receptor (GLP-1R) is widely distributed in many organs and tissues such as the central nervous system, cardiovascular system, muscle, and gastrointestinal tract.   The receptor agonist of GLP-1 (GLP-1RA) stabilizes blood glucose and reduces body weight through various glucose-lowering mechanisms. If it acts on the stomach, it can delay gastric emptying by inhibiting gastrointestinal peristalsis; It acts on the central nervous system (especially the hypothalamus) to increase satiety and inhibit appetite; It acts on the liver and inhibits hepatic glucose output. Promoting insulin to stimulate glucose uptake in peripheral tissues (increasing insulin sensitivity).

04

Top 30 Anti-tumor Drugs in 2023 (In billion dollars)

Top 30 Anti-tumor Drugs in 2023 (In billion dollars)   No. Drug name Company Main indications Sales Growth rate 1 Keytruda (pembrolizumab) MSD Melanoma, NSCLC, Bladder cancer, HNC 25.01 19.5% 2 Opdivo (nivolumab) BMS/ONO Melanoma, NSCLC, HNC 10.04 9.0% 3 Darzalex (daratumumab) Johnson & Johnson Multiple myeloma, AL amyloidosis 9.74 22.2% 4 Imbruvica (ibrutinib) Abbvie/Joshnson CLL/SLL, MCL, GVHD 6.86 -17.9% 5 Revlimid (lenalidomide) BMS MM, MDS, MCL, FL 6.10 -39.0% 6 Tagrisso (osimertinib) Astrazeneca T790M NSCLC 5.80 7.0% 7 Xtandi (enzalutamide) Astellas Prostate cancer 5.07 4.3% 8 Ibrance (palbociclib) Pfizer Breast cancer 4.75 -6.0% 9 Jakafi (ruxolitinib) Incyte/Norvatis Myelofibrosis, PV 4.31 8.7% 10 Imfinzi (durvalumab) Astrazeneca Urothelial carcinoma,NSCLC, SCLC etc 4.24 52.0% 11 Perjeta (Pertuzumab) Roche HER2+ breast cancer 4.21 1.0% 12 Tecentriq (atezolizumab) Roche Urothelial carcinoma,NSCLC, TNBC 4.21 9.0% 13 Verzenio (abemaciclib) Eli Lilly Breast cancer 3.86 56.0% 14 Pomalyst (pomalidomide) BMS Multiple myeloma 3.44 -2.0% 15 Lynparza (olaparib) Astrazeneca/MSD Ovarian cancer, Breast cancer, Pancreatic cancer, Prostate cancer 2.81 7.0% 16 Enhertu (trastuzumab deruxtecan) Daiichi Sankyo/AZ HER2+ breast cancer, HER2-low brease cancer 2.57 104.8% 17 Calquence (acalabrutinib) Astrazeneca Mantle cell lymphoma, CLL/SLL 2.51 22.0% 18 Erleada (apalutamide) Johnson & Johnson Prostate cancer 2.39 26.9% 19 Venclexta (venetoclax) Abbvie CLL, AML 2.29 13.9% 20 Revolade/Promacta (eltrombopag) Norvatis Thrombocytopenia 2.27 10.0% 21 Yervoy (ipilimumab) BMS Melanoma, RCC, CRC 2.24 5.0% 22 Kadcyla (trastuzumab Emtansine) Roche HER2+ breast cancer 2.19 4.0% 23 Xgeva (denosumab) Amgen Solid tumor bone metastasis 2.11 5.0% 24 Kisqali (Ribociclib) Norvatis HR+ breast cancer 2.08 75.0% 25 Lenvima (lenvatinib) Eisai/MSD DTC, HCC, Endometrial carcinoma 2.01 8.4% 26 Sprycel (dasatinib) BMS ALL, CML 1.93 -11.0% 27 Tafinlar+Mekinist (dabrafenib+trametinib) Norvatis Melanoma, NSCLC, ATC 1.92 11.0% 28 Tasigna (nilotinib) Norvatis CML 1.85 -3.0% 29 Herceptin (trastuzumab) Roche HER2+ breast cancer 1.82 -16.0% 30 Avastin (bevacizumab) Roche CRC, Breast cancer, Lung cancer, Ovarian cancer etc 1.76 -19.0%    

05

FDA Approves First Treatment to Reduce Risk of Serious Heart Problems Specifically in Adults with Obesity or Overweight

On 8 March, the U.S. Food and Drug Administration approved a new indication for use for Wegovy (semaglutide) injection to reduce the risk of cardiovascular death, heart attack and stroke in adults with cardiovascular disease and either obesity or overweight.     The FDA decision is based on the results of the landmark SELECT phase III cardiovascular outcomes trial that examined the effect of adding Wegovy® 2.4 mg or placebo to cardiovascular standard of care in adults with overweight and obesity with established CVD and without diabetes. Wegovy® 2.4 mg significantly reduced the risk for first occurrence of a three-part composite MACE endpoint consisting of cardiovascular death, non-fatal heart attack, or non-fatal stroke. The primary composite outcome occurred in 6.5% of patients treated with Wegovy® and 8.0% with placebo. The estimated relative risk reduction of MACE was 20% vs placebo (HR 0.80 [95% CI: 0.72, 0.90] p

06

SNAC: A Stepping Stone to Oral Semaglutide

Salcaprozate sodium (SNAC) is the sodium salt form of salcaprozate. It is used in the treatment of gastrointestinal disorders, especially gastrointestinal disorders caused by the malabsorption of dicarbonate-phosphate compounds. SNAC can also promote the absorption of drugs in gastrointestinal epithelial cells, and effectively cope with the obstacles to the absorption of oral peptide drugs, for instance Semaglutide.   Absorption of oral dose peptides by intestine is challenging due to the physiological effects of the gastrointestinal tract. Ingested peptides or proteins are broken down into amino acids by ph-sensitive proteases, which are then transported to the mucosa by the translocater. Large molecules of carbohydrates or lipids are decomposed into small molecules to promote intestinal absorption. The intestinal epithelium has the function of recognizing and absorbing bacteria, viruses and other pathogens. So complex cellular and mucus barriers are formed to limit the entry of foreign or harmful substances. Therefore, unfortunately, exogenous peptides or protein drugs are restricted to penetrate the intestinal epithelium and enter the circulation. In this case, SNAC and its related compounds are used as Permeation enhancers to deal with this problem. The mechanism that SNAC promotes the absorption of Active pharmaceutical ingredient (API) is still not fully understood. It is generally believed that SNAC improves the membrane permeability of gastrointestinal epithelial cells may be related to membrane perturbation, membrane fluidization, and changes in API solubility. It also may improve transcellular permeability by increasing its hydrophobic role through non-covalent bond binding to API.   The successful preparation of semaglutide tablets depends on its co-formulation with SNAC. SNAC promotes the monosomy of semaglutide, making it more permeable. For semaglutide molecules, most semaglutide exists in the form of oligomers in the stomach; However, SNAC triggered a change in polarity of the solution containing the dissolved tablet, weakening the hydrophobic interaction necessary for oligomerization. Since SNAC is lipophilic, it efficiently inserts into the cell membrane of the gastric epithelium, altering the intrinsic integrity of cholesterol phospholipids and proteins, which in turn affect the fluidity of the cell membrane. It was confirmed that SNAC enhances the intracellular uptake of semaglutide by gastric epithelial cells, thus supporting the notion that SNAC promotes transcellular transport of semaglutide. SNAC can effectively increase the local pH value around the semaglutide molecule in the stomach, prevent the degradation of peptides by pepsin, and make semaglutide penetrate the gastric mucosa and be absorbed into blood by the concentration gradient on the surface of the cell membrane. The use of SNAC is of great significance for oral semaglutide tablets. FarmaSino can provide high purity and high quality SNAC together with Semaglutide API* and intermediates include semaglutide-related fragments, main chains, and side chains of different steps. Please check following links for more information.

07

Semaglutide APIs and Related Intermediates in Different Specifications

Semaglutide is an anti-diabetic drug which is used to treat type 2 diabetes and manage chronic weight. Semaglutide is a glucagon-like peptide-1(GLP-1) receptor agonist with 94% sequence homology with human GLP-1. It increases the production of insulin, which can lower the blood glucose level. Semaglutide also appears to enhance growth of β cells, sites of insulin production, in the pancreas. By lowering appetite and slowing down digestion in the stomach, Semaglutide also can reduce food intake to control body weight.   Semaglutide for injectable grade 99% is prepared for the formulation of Semaglutide injection. The purity of this product can reach 99.0% and the assay should reach 95%~105% with peptide content of Semaglutide 76%~100%. Semaglutide for oral grade 98% is suitable for the markets with high requirements of oral dose for the control of raw material impurities. The purity of this product should reach 98% with the same acceptance criteria of other standards with Semaglutide injectable grade 99%. Semaglutide for oral grade 96% is much more suitable for a price sensitive market where the tabbing process does not produce new impurities with its purity of 96%. The assay of this product should reach 90%~100%. Semaglutide crude product is prepared for the enterprises that have the production capacity and want to own the API approval. Semaglutide API can be obtained after purification by chromatography and freeze drying from Semaglutide crude product. The purity of this product should reach 50% and the assay over 35%.   Semaglutide secondary acylation intermediate is N-1 intermediate of Semaglutide. The protection group of this prodcut was deprotected to obtain Semaglutide crude product, which was purified by chromatography and freeze dried to obtain API. Secondary acylation intermediate is suitable for the enterprises that have the production capacity and want to own the API approval.   Semaglutide primary acylation intermediate and Semaglutide dipeptide are Semaglutide N-2 main chain intermediate and N-2 fragment. The primary acylation intermediate was acylated with Semaglutide dipeptide to obtain Semaglutide secondary acylation intermediate and further hydrolyzed to obtain Semaglutide crude product. Acylation, hydrolysis tank, high pressure chromatography system, drying equipment are required.   Semaglutide main chain P29 and Semaglutide side chain (tetrapeptide) are Semaglutide N-3 main chain intermediate and N-3 fragment. TheSemaglutide main chain P29 was acylated with Semaglutide side chain to obtain Semaglutide primary acylation intermediate. Further reaction was underwent to obtain the final API. These products are suitable for for the enterprises that have the production capacity and want to own the API approval. Acylation, hydrolysis tank, high pressure chromatography system, drying equipment are required. FarmaSino provides these the API with different grade and related intermediates of Semaglutide with reliable quality and competitive price.   Please get more information from following links: 910463-68-2: Semaglutide Semaglutide Starts the New Life with Type 2 Diabetes   *All APIs and intermediates for R&D use ONLY.

08

Maghreb Pharma Expo 2024

Farmasino adheres to the localization development of Algeria. It provides a one-stop solution for the local biopharmaceutical industry, from raw materials to registration documents, from production processes to pharmaceutical machinery. In 2023, its cumulative exports exceeded 20 million US dollars. Welcome to our booth for mutual benefit.  

09

Happy Chinese New Year ! ! !

At the beginning of the new year, everything is renewed, on the occasion of this new year, we sincerely thank our customers for their support and co-operation with us in the past year. In the new year, our company will work harder to provide you with better service, our Spring Festival holiday arrangements are as follows: from 9th February 2024 to 18th February 2024. We hope you could understand the inconvenience caused by the holiday. We will arrange a special person to reply the message and make the projects run normally. We wish you all a happy Chinese New Year and a happy family!

10

Ticagrelor: the World’s First Reversible Combination Orally-administered P2Y12 Adenosine Diphosphate Receptor Antagonist

Ticagrelor, a new platelet aggregation inhibitor, is the world’s first reversible combination orally-administered P2Y12 adenosine diphosphate receptor antagonist. It is used to reduce cardiovascular death and heart attacks in patients with acute coronary syndrome. Ticagrelor is white to off-white powder with hygroscopic, so low temperature storage and transport is required. Mechanism Ticagrelor has reversibly acts on the 2 purine receptor subtype P2Y12, of vascular smooth muscle cells (VSMC,) which does not require metabolic activation, and has a significant inhibitory effect on platelet aggregation induced by adenosine diphosphate. In this case, platelet function will recover rapidly after stopping the dose. Features Rapid onset of action Ticagrelor can be absorbed in approximately 1.5 hours and After about 2.5 hours, ticagrelor can rapidly transformed into circulating metabolite AR-C124910XX. The mean bioavailability of ticagrelor was approximately 36%. Powerful drug Without increasing major bleeding, ticagrelor treatment for 12 months significantly reduced the risk of cardiovascular death by 21% compared with clopidogrel. Ticagrelor is already a first recommended drug for cardiovascular disease in Europe. Platelet function recovered quickly The interaction between ticagrelor and platelet P2Y12 ADP receptor is reversible, without conformational change and signal transmission, and platelet function in blood recovers rapidly after drug withdrawal. Sythesis Ticagrelor is mainly composed of three major fragments: a five-membered ring, a thioether pyrimidine, and a three-membered ring. At present, a variety of synthesis routes have been reported, and the common point is that there is no construction of chiral centers in the synthesis process, and all the six chiral centers are introduced by starting materials. In this synthetic route, starting materials S1 and S2 were coupled, then the ring was diazosed off under the conditions of sodium nitrite and acetic acid, and then coupled with starting material S3. Finally, the finished product of ticagrelor was obtained by removing the forkone protection. Usage and dosage Oral administration. This product can be taken before or after meals. The initial dose was a single dose of 180 mg, followed by 90 mg twice a day. It should be used in combination with aspirin unless clearly contraindicated. After the initial loading dose of aspirin, aspirin was maintained at a dose of 75 to 100mg once daily. Ticagrelor can be started in ACS patients who have already received a loading dose of clopidogrel. Treatment may be given for up to 12 months unless there is a clinical indication to discontinue treatment. Cautions The most frequently reported adverse effects were dyspnea, contusion, and epistaxis in patients who received ticagrelor, which occurred more frequently than in patients who received clopidogrel. Among patients with acute coronary syndromes who are treated with ticagrelor combined with aspirin, there is an increased risk of bleeding. Therefore, the increase of bleeding risk should be balanced against the benefit of preventing atherothrombotic events. Interruptions of ticagrelor tablets should be avoided. If ticagrelor must be temporarily discontinued, treatment should be restarted as soon. The risks of myocardial infarction, thrombosis, even death would increase if ticagrelor is discontinued.

11

Fosfomycin Tromethamine, a Broad-Spectrum Bactericidal, Especially for Lower Urinary Tract Infections.

Fosfomycin is a broad-spectrum bactericidal for human and animals purposes, which inhibits the growth of E. coli, S. aureus, Serratia, Klebsiella, Citrobacter, Enterococcus, and Enterobacter etc.. Fosfomycin tromethamine is a phosphonic acidepoxide derivative, which expands the therapeutic utility of fosfomycin salt because its water solubility increased enough to allow oral administration. This compound is a white to off-white powder with great hygroscopic and solubility in water.   Mechanism Fosfomycin tromethamine, is a derivate of fosfomycin, which was initially isolated from fermentationsof streptomyces spp and been used as human medicine and veterinary medicine for over 50 years. Fosfomycin can inactivate the first enzyme in the bacterial cell wall biosynthesis pathway, which occurs through nucleophilic opening of the epoxide ring. Fosfomycin tromethamine only acts on the bacterial cell wall, human cells do not have this target site and is not affected. In this case this compound can be used in pregnant women, children and elderly patients.   Features Broad spectrum antibiotic Fosfomycin sodium is a broad-spectrum antibiotic of Gram-positive and Gram-negative bacteria, for instance E. coli, S. aureus, Serratia, Klebsiella, Citrobacter, Enterococcus, and Enterobacter etc. and is particularly suitable for the treatment of acute cystitis   Rapid sterilization After oral administration, fosfomycin tromethamine is rapidly decomposed into fosfomycin and tromethamine in the body. With the characteristics of low molecular weight and high hydrophilicity, fosfomycin tromethamine appears good distribution in fluid and strong penetration. So this medicine can widely distribute in body fluid and tissue to increase curative effect. Tromethamine is a weakly osmotic diuretic, which can alkalinize urine and effectively reduces the symptom of urinary tract irritation.   Low toxicityand residue of Fosfomycin tromethamine Bioavailability of Fosfomycin tromethamine by oral administration is from 34% to 41% in healthy adults, 37% in fasting and 30% after eating. It shows little irritation on the body, no acute toxicity and adverse reactions. The maximum plasma concentration was reached within 2 to 2.5 hours after dose, and will be excreted mainly in its original form in urine and feces in 48h.   Sythesis The synthesis of fosfomycin tromethamine use fosfomycin sodium as an intermediate. Prepare a certain concentration tromethamine-sulfuric acid solution and then it was added to fosfomycin sodium aqueous solution by drop. After that the sodium sulfate solid is precipitated with methanol and the filtrate is crystallized at low temperature with n-butanol to obtain fosfomycin tromethamine.   Fosfomycin Tromethamine Clinical Application Fosfomycin tromethamine is used for the treatment of acute uncomplicated lower urinary tract infections caused by sensitive bacteria (such as acute cystitis, acute onset of chronic cystitis, acute urethrovesical syndrome, non-specific urethritis, asymptomatic bacteriuria during pregnancy, and urinary tract infections after surgery) and for the prevention of urinary tract infections during surgery and infections caused by diagnostic procedures of the urinary tract.   Usage and dosage Adults: single-dose treatment, 3g active ingredient per course; Clinical symptoms usually resolve 2 to 3 days after treatment. For preventing infections caused by surgical procedures and urinary tract care: 6g active ingredient per dose, with first dose taken 3 hours before surgery and second dose taken 24 hours after surgery.   Cautions The main symptoms of fosfomycin tromethamine were are diarrhea and soft stools, occasional rash and nausea, which will disappear after drug withdrawal. It is not known whether fosfomycin tromethamine is excreted in human milk, but given the potential for serious adverse effects of fosmycin tromethamine in lactating infants, it should not be administered to lactating women. The efficacy and safety of fosfomycin tromethamine in children aged 12 years and younger are lack of sufficient and well-designed clinical verification.

12

Baloxavir Marboxil a New Drug against Influenza with Noval Mechanism

Baloxavir Marboxil is a new anti-influenza drug developed by Shionogi Pharmaceutical from Japan and Roche from Switzerland. The drug was first approved for use in Japan in February 2018 and later by the FDA in October for the treatment of acute uncomplicated influenza in patients 12 years of age and older who have been symptomatic for no more than 48 hours. Baloxavir marboxil is a cap-endonuclease inhibitor, which has a unique mechanism of action to Inhibit the proliferation of influenza virus. Mechanism Baloxavir marboxil is a prodrug that enters the body and is hydrolyzed to the active substance baloxavir, which plays an anti-influenza virus activity. Baloxavir is a selective inhibitor of influenza cap-endonuclease, an enzyme required for viral gene transcription and replication, which prevents polymerase function and influenza virus mRNA replication. It has therapeutic activity against both influenza A and B virus infections, even strains resistant to current antiviral drugs. Baloxavir marboxil inhibits an enzyme of viral replication, thus the flu virus infection can be rapidly treated and the symptoms will be alleviated. Features New antiviral influenza drug Baloxavir marboxil is the first anti-influenza virus drug with a new mechanism in the past 20 years. Cpmpared with traditional anti-influenza drugs, Baloxavir Marboxil selectively inhibits the CAP-endonuclease of influenza virus, thereby preventing polymerase function and influenza virus mRNA replication.This unique mechanism gives Baloxavir Marboxil a unique advantage against influenza viruses. Excellent activity of anti influenzavirus Baloxavir marboxil has excellent anti-virus performance against influenza, including influenza A virus (IAV) and influenza B virus (IBV). A single dose of Baloxavir marboxil was shown to be superior to placebo in relieving influenza symptoms and superior to both oseltamivir and placebo drug in virologic outcomes (marked by decreased viral load). Highly effective and long acting drug Baloxavir marboxil is a prodrug. By oral administration, almost all baloxavir marboxil is converted to the active constituent baloxavir. The tmax of Baloxavir to reach the Cmax in vivo is about 4 hours on average. The average half-life of bacalovirda in vivo is approximately 80 hours, so only one dose is needed for most patients. These make Baloxavir marboxil a highly effective and long acting drug. Synthesis The synthesis of Baloxavir marboxil mainly divided into two parts. In each part, a main intermediate is synthesized separately. In the synthesis of intermediate A (1985607-83-7), 7-(Benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (intermediate A-2, 1370250-39-7) yields the intermediate A by cyclization and reduction reactions. The coupling of the intermediate A and intermediate B was carried out under dehydration conditions of 1-propanephosphonic anhydride (T3P) and methanesulfonic acid at 70℃ to obtain protected Baloxavir N-2. Compound N-2 was then reacted with 0.6 equivalents of PhBr and K2CO3. Debenzylation was then carried out using LiCl in CH3CONMe2 to give Baloxavir acid in 94% yield. In the final step, Baloxavir acid was reacted with chloromethyl methyl carbonate in dimethylacetamide in 93% yield to form Baloxavir marboxyl. Usage and dosage The Baloxavir Marboxil is used for the treatment of acute uncomplicated influenza in patients (adults and pediatric patients 5 years of age and older) who have been symptomatic for no more than 48 hours. Baloxavir marboxil should be taken as a single dose as soon as possible and within 48 hours of influenza symptom onset for treatment of acute uncomplicated influenza. The specific dose should be adjusted according to the patient’s weight as follow: 20 kg to less than 80 kg: 40mg At least 80 kg: 80mg Cautions Hypersensitivity such as anaphylaxis, angioedema, urticaria, and erythema multiforme may occur or be suspected. Increased incidence of treatment-emergent resistance in patients less than 5 years of age. Baloxavir Marboxil has not been shown to prevent serious bacterial infections, which may begin with influenza-like symptoms or may coexist with, or occur as, a complication of influenza.

1 2