TECHNOLOGY EXPLAINER
Peptide Therapeutics and GLP-1
— Making a two-minute molecule last a week with a single fatty-acid chain
Natural GLP-1 in blood1.5 to 2 minutesdecomposition. Once a week One amino acid replacement andone fatty acidIt was chemical modification. and oralizationAb erAnother material is to manufactureYeast fermentation and solid phaseThere are two ways:
Concept diagram of AI generation- Peptide and GLP-1 (3 lines)
- Receptors and agonists - "keyhole" and "key"
- Reasons to disappear in two minutes and two measures
- fatty acids – designed to ‘ride’ the bloodstream
- Calculation in this paper: How many times the half-life
- Material Technician Perspective 1: Fatty acid and PEG linker are “interface design”
- Oralization – Ab ent SNAC and stomach up
- Calculation: How many times the original medicine should be used for drinking medicine
- How to make yeast fermentation + chemical modification or solid phase
- Material Technician Perspective 2: Solid Phase Syn stacks “Pri Per Stage”
- Low GLP-1 receptor agonist
- Post-development and regulatory movements and issues that have not yet been determined
- Glossary/Reference Materials/Reference Table
Facts= Contents described in the publication material (with source link)
The calculation of this paper= The value calculated based on the specified premise
Undetermined / Future= Items that have not been confirmed as a plan and goal
In addition to this, it is possible to organize structures and read materials and process designs."Description"is distinguished.
About this articleDesign, formulation, and manufacture of peptides from the perspective of material technologyComment Weight reduction and blood sugar improvementNo efficacy or safety, we do not compare products.Not medical advice Dosage and conditions for attachmentsNumericals for determining the mechanism of original medicine and absorptionIt is not a description of how to use it. Please consult your medical institution for the use of GLP-1 receptor agonists.
Peptide and GLP-1 (3 lines)
- Peptides:It is a medicine of s with several to dozens of amino acids. US RulesOver 40 amino acidsdefined as proteinFactsFDAPolymerization consisting of 40 or less amino acids"Peptide"Facts
- GLP-1It is a hormone from the intestine depending on the diet. Victoza attachments are naturalHalf-life of GLP-1(7-37) 1.5-2 minutesDPP-4 and Neutral End Peptides (NEP)Decomposition by s anywhere in the bodyForFacts
- What is the core of technology:It is said that it is immediately dissolved, it is immediately discharged from the kidneys, and it is not absorbed by drinking from the mouth.Three weak points of peptideamino acid replacement, fatty acid modifier, and absorption promoterDesign of chemical and materialsIt is a history that solved one by one. Contents
semaglutide’s weekly dose is one fatty acid in the . Attachments"The main mechanism of semaglutide is albumin binding, promoted by modifying the 26th lysine with a hydrophilic spacer and C18 fatty acid."FactsHome PeptidesInverted to protein (albumin) in large quantities in the blood——As this is a 、 design,Interface and orption designIt is also (explanation by this article).
2. Receptors and agonists - "keyhole" and "key"
Contact UsIt is a protein that conveys signals in the cells when a specific molecule is combined with the cell surface. Agonist (operating agent)binds to the receptorWork as a natural substance
- OZEMPIC attachments are semaglutide"GLP-1 analogues with synergy between human GLP-1 and 94%"HOMESelectively join and activate the GLP-1 receptor, the target of natural GLP-1Facts
- MOUNJARO Attachments"GIP receptors and GLP-1 receptor agonists once a week"Working on two receptorsDesignFacts
- Kawai et al. GLP-1 receptor"G protein cooperative receptor of class B (GPCR)"Treated as one of the low actuator LY3502970"Partial Agonist"ReportFactsHome The degree of work of the receptor is called a partial agonist that is smaller than a natural substance (in this article)
3. Reasons to disappear in two minutes and two measures
GLP-1Cut in EnzymeHomeIt is discharged immediately from the kidney because it is smallThis is because the two are overlapping. The general theory of Knudsen and Lau aims for fatty acid modulation”Protecting peptides from both disassembly and renal filtration by DPP-IV”It explainsFacts。
(1) Counter to Enzymes: One Amino Acid
According to the general theory, we replaced the entire GLP-1 array with Alanin one by one, The stability of DPP-IV and the high affinity of the receptor were only introduced in the 8th place when the aminoisobutyric acid (Aib) was introduced.CommentFactsHome semaglutide"DPP-4 Qualifies 8th to stabilize the decomposition"FactsHome Aib is not used for natural proteinsNon-Code Amino AcidsHOME zepatide2nd and 13th AibIncludeFacts。
(2) Counter s against renal retion and disassembly – “Sy ” large protein
There is also a way to increase the peptide itself. CommentAlbiglutideHomedulaglutideas another method to suppress the renal clearanceFactsHome How to use Novo NordiskBind to albumin via fatty acids instead of increasing with shared bindingCommentFacts。
Designs that have been selected to ‘ride’ the buffer
| Bone | Position connecting fatty acids | Spacer | Fatty acid | Half-life (Attachment) | |
|---|---|---|---|---|---|
| liraglutide | GLP-1, compatibility 97% (34th Lys→Arg) | 26th place lysine | Glutamic Acid | C16 Fatty acid (Palmitate) | 13 hours |
| semaglutide | GLP-1, compatibility 94%) Aib, 34th Arg) | 26th place lysine | Hydrophilic Spacer | C18 Fat Diac Acid | About 1 week |
| tirzepatide | GIP array base · 39 residues (2nd and 13th Aib, C end amide) | 20th place lysine | γ-Glu+8-amino-3,6-dioxaoctanic acid×2 | 1,20-Acosan Diaccharide (C20) | 5 days |
AllFacts(VICTOZA・OZEMPIC・MOUNJARO attachment [Reference Material 4, 1, 5, andzezepatide linker configuration is a recent public review report [Reference Material 6]). About semaglutide spacer, Knudsen and Lau areγGlu-2xOEGIt is written as a linker [Reference Material 7].
The length of fatty acids and how to connect to peptides are determined by systematic search.
- C12 to C20 comparison:Knudsen and Lau"The combination of C18 fat biic acid and γGlu-2xOEG linker combined with the highest albumin affinity and the strong effect on the GLP-1 receptor"Facts
- Only one piece:CommentWhen two fatty acids are connected, the effect of the receptor decreasedFactsHome OZEMPIC Attachments, 34th replacement"To combine only one fat diacid"Facts
- Albumin side:The theory is crystal structure analysisFatty acids from C10 to C18 bind to 7 parts on albuminIt is indicated that albumin has a great ability to carry fatty acids by high blood concentration, multiple binding sites and long half-lifeFacts
- Price:The abstract of Lau’s 2015 paper is semaglutideGLP-1 receptor affinity (0.38 ± 0.06 M) fell to one third ofragraglutide, while albumin affinity was higherReportFacts。Designs that have been selected for longer than ‘stability’Read this article
5. Theulation of this paper: how many times the half-life is
Compare the half-life described in the attachment to the minuteThe calculation of this paper。
- Natural GLP-1:1.5 to 2 minutes (Ving VICTOZA attachment)
- liraglutide：13 hours = 780 minutes → 780 ÷ 2 ~ 780 ÷ 1.5 = 390 to 520 times
- tirzepatide：About 5 days = 7,200 minutes → Approx. 3,600 to 4,800 times(GLP-1 ratio instead of natural GIP)
- semaglutide：1 week = 10,080 minutes → 10,080 ÷ 2 ~ 10,080 ÷ 1.5 = Approx. 5,000 to 6,700 times
Premises and Limits:The value of natural GLP-1 is obtained by conditions such as intravenous, and the value of the affinoid is the value after subcutaneous administration,No measurement conditionsHome "1 week" and "5 days" are the number of attachments.Conversion to show digit differenceIt does not indicate the superiority of the drug.
6. Material Technician Perspective 1: Fatty acid and PEG linker are “interface design”
semaglutide and zezepatideStructure similar to the design of surfactants and coupling agents(This article explains).
- Hydrophobic Tail:C16・C18・C20 fat (dihydrate).Explore length in one carbon unitSelectedFacts
- Hydrophilic binder:zezepatide linker with γ-Glu8-Amino-3,6-dioxacic acid 2The report of this websiteA part is a linker similar to polyethyleneIt is expressedFacts。Hydrophilic spacer with oxide unitLet’s release fatty acids from peptides and read them as a role (in this article)
- Number control:When two are connected, the action of the receptor decreasesFactsHome SoRe、 34th lysine with arginine to make one reaction pointFacts
The last point is suggested for the material shop.React the sensitive structure that is not reacting from the array first.Comment Chemical Qualification of Post-processOnly one location selectivelyto make it happen. This isWhen you want to introduce only one surface treatment agent to a multifunctional substrate, other reaction points are crushed beforehandSame as the idea This article explains.
In addition, "ad」sion to albumin" isReversiblenot meaningless. If it is too strong, it will not reach the receptor, and if it is too weak, it will get out of the kidney. LauRecombinant affinity with a drop to one- rd of receptor affinityFactsHome Design problems of carriers and absorptions, where to put absorption and detachment equilibriumRead as a commentary.
7. Oralization – Ab ent SNAC and stomach up
It was hard to make peptides a drink. The abstracts of Buckley’s 2018 paper are: "The oral administration of the、eutic peptide is blocked by extensive decomposition by protein decomposition、s, which adversely affects the absorption of the gastrointestinal barriers."and writeFacts。
- Ab er SNAC (N-[8-(2-Hydroxyethyl) Amino] Sodium Caprylate)semaglutide"In contrast to normal intestinal absorption in low s, the absorption of semaglutide occurs in the stomach, limited to the area near the tablet, and requires co-formulation with SNAC."Facts
- SNAC protects against decomposition by local buffering and increases absorption temporarilyFacts
- “The mechanism of absorption is compound-specific and transcellular, and there is no evidence to indicate the impact on tight junction.”Facts
"Material design of preparation" read from attachment
| semaglutide content | Additive (Attachment) | Estimated absolute bioavailability | |
|---|---|---|---|
| OZEMPIC | — | Hydrogen phosphate, polyethylene, phenol, etc. | 89% (bottom) |
| RY SUS Tablets | 3・7・14 mg | magnesium stearate,Crystal cellulose, povidone、SNAC | Approx. 0.4 to 1% |
| OZEMPIC Tablets | 1.5・4・9 mg | Magnesium stearate, SNAC | Approx. 1 to 2% |
| WEGOVY Tablets | Maintenance dose 25 mg | Contains SNAC as an absorber | Approx. 1 to 2% |
AllFacts(Attachment of OZEMPIC injection, oral semaglutinized tablets, WEGOVY [Reference Material 1, 2, 3]) The attachment of oral semaglutinized tablets is absorbedMainly occurs in the stomachCommentAbsorption has changed depending on the amount of water during taking and the fasting time after takingResults of clinical pharmacological trialsFacts。
Attachments for oral semaglutin tabletsThere was no clinically meaningful difference between AUC and Cmax in steady state between RY SUS’s 3, 7 and 14 mg and OZEMPIC tabletsHOME Close“I can’t replace each other with a mg unit.”FactsHome 14 mg and 9 mg if exposedThe original medicine is about 36% lessulation (1 - 9 ÷ 14)The calculation of this paperHome The difference in the formulation that can be confirmed by the attachment is:Crystal cellulose and povidoneHomeFactsHome However,Is the difference in content only caused by this formulation change?Sorry, this entry is only available in Japanese.
8. Calculation: How many times the original drug should be used for drinking medicine
WEGOVYMaintenance dose of injection 2.4 mg once a weekHomeTablet maintenance dose 25 mg once per dayContact UsFactsHome This can affect the original dosage per weekThe calculation of this paper。
- Injection:2.4 mg/week
- Tablets:25 mg x 7 days = 175 mg/week
- Size:175 ÷ 2.4 ＝ Approx. 73 times
- With Ab ed Quantity:Injection 2.4 × 0.89 = about 2.1 mg, tablets 175 × 175 ~ 0.02 = about 1.8 to 3.5 mg.The amount to enter the body is the same digit
Premises and Limits:Bioavailability is an estimate of the attachment (injection 89%, tablets about 1 to 2%), and the actual exposure is different individually, and the attachment is expected to have a higher blood density of the tablet.Facts。 It does not indicate the therapeutic equivalent.Conversion to indicate the required amount of the original drug.
Chapter 8 calculation shows the essence of oral peptides.If the absorption rate is 1 to 2%, the amount to be consumed should be from dozens of injectionsContact Us Oralization is the ingenuity of preparation,Decision to push the volume of the original drug to more than one digitIt is also (explanation by this article).
In addition, the active ingredient per tablet is several mg to 25 mg, the rest isAdditives such as SNACComment Absorption as shown by BuckleyClose to tabletsFactsHOME How the tablet collapses in the stomach and how it melts—The design of the collapse and e tion depends on the absorption rate as it isIt is considered (explanation by this article). You can also tell that the attachment is “none, crush, or bite”.Factsindicates that the form of the tablet itself is part of the function.
Ab ent Accelerator"Non-acting Materials"notFunctional additivesComment Knudsen and Lau are used in food applications in the USGRASing to the status of"The mechanism of its absorption is not fully understood"As of 2019Facts。
9. How to make yeast fermentation + chemical modification or solid phase ?
The same GLP-1 peptide is divided into two ways.
| Manufacturing Law (Indication of Publication Materials) | ||
|---|---|---|
| liraglutide | Precursor Peptideed yeastSaccharomyces cerevisiaeRecombinant DNA expression in )Created in a process including 26th place lysinee C16 fatty acids through glutamine | VICTOZA Attachments |
| semaglutide | Peptide skeleton is yeast fermentationProduced in | OZEMPIC |
| tirzepatide | Standard Solid Phase Peptide Syn (SPPS)It is synthesized with the addition of the 20th lysine side chain.Remove the protective base of the side chain as it is cut out of resin、Reverse chromatographypurified, concentrated, solvent exchange, iso , dried and original medicine. Original medicineOne locationManufactured in | Annual Report |
AllFacts(VICTOZA・OZEMPIC Attachment [Reference Material 4・1], Mounjaro's Annual Public Examination Report [Reference Material 6])
Knudsen and Lau replaced 34th place lysine with arginine withragraglutide designAdditional BenefitsHome “We made peptide skeletons in recombinant, then added fatty acids with simple chemical reactions, and used for semi-recombinant processes.”Contact UsFacts。 The manufacturing method was decided at the stage of designThat is This article explains. On the other hand, like AibNon-Code Amino Acidscan not be made into cells. The 8th Aib of semaglutide was introduced in the process.
10. Material Technician Perspective 2: Solid Phase Syn stacks “Pri Per Stage”
1984 Nobel Chemical Award Presentations on Traditional Solution Syn"The yield of each phase is 0.00 — this is a very good yield — but the overall yield after 100 stages is 0.003%.",ExplainFactsHome In solid phase"It is possible to increase the yield of each stage more than 99.5%"Total yield in the same example0.003% to 61%I want to go upFacts。
zepatide39 ResiduesHomeFactsHome 1After attaching the remaining base to the resin,38 bindingsSet when needed Adding and desecting side chains is countless simplified)The calculation of this paper。
- Each step 99.9% → 0.99938 ＝ about 96%
- Each step 99.5% → 0.99538 ＝ about 83%
- Each step 99% → 0.9938 ＝ about 68%
- Each step 98% → 0.9838 ＝ about 46%
- Each step 90% → 0.9038 ＝ about 1.8%
99% of each stageThe chain of about 32% is connected by a step of the Premises and Limits:Actual process conditions and yields are not published.Simple calculation to apply the assumption binding rateComment The distribution of the actual sub-product depends on the process, such as whether the chains that are connected are stretched or stopped in the middle.
The difficulty of solid phase is more than the yield itselfProperties of impuritiesContact Us a chain that has a single connection,The same size and composition as the desiredComment So to purifySeparation to identify the difference of residue (reverse-phase chromatography in reports)RequiredFactsHome In order to extend the chain by se tial reaction,Problems of the same type of polymer dealing with severe distribution and terminal defects(This article explains).
Anotherents and reagentsComment Isidro-Llobet et al. 2019 paper abstracts are the current state of peptide、“It’s mostly dependent on old technology and uses a large amount of highly harmful reagents and solvents, and it’s hardly pointed to green chemistry and engineering.”and In 2016, ACS Green Institute Pharmaceutical Roundtable has positioned the development of a lower environmental impact process for peptides as “definitely important unmet needs”Contact UsFactsHome Chapter 8Dozens more than the original amount by oralizationHomeThe use of solvents, resins, protective amino acids and purified carriers is also effective at the same ratioSorry, this entry is only available in Japanese. Solid-phase carriers, protective amino acids, alternative solvents, separation materials—Large area of improvement from material sideComment
11. Low GLP-1 receptor agonist
Instead of oralizing peptides,Move receptors with low s from the beginningThere is also an approach.
- Structure clue:Kawai et al. was a low-actuator in 2020 PNAS LY3502970（OWL833）About Us"The currently approved GLP-1 receptor agonist is a peptide-based and it was difficult to obtain a low-activator with optimal pharmaceutical characteristics."HOME From the high resolution structure of the complex with the receptor,Unique binding pocket of the upper bundle, surrounded by extracellular domain, extracellular loop 2, membrane penetration 1, 2, 3, 7ed toFactsHome The author of the paper includes researchers from Chugai Pharmaceutical and E-LilyFacts
- Application:LaiApril 1, 2026FDA FOUNDAYO（orforglipron）has been announced that it has been approved. orforglipron"Low) (non-peptide) oral GLP-1 receptor agonist"HOMEDrug Discovery by Chugai in 2018Facts
- Example of Disco ed Development:FazerApril 14, 2025Low GLP-1 receptor agonist, oral danuglipronAnnouncement One participant in the dose optimization testPossibility of pharmacological liver failureWe consider all information including what was taken (recovered after disco ation), and make decisions based on opinions from regulatory authorities.Facts
| Oral semaglutide (peptide + SNAC) | orforglipron | |
|---|---|---|
| Weight | 4113.58 g/mol | 902.0 g/) ()ium salt) |
| Ab er | SNAC | SNAC is not included in the list of additives for attachments |
| Estimated absolute bioavailability | 0.4 to 2% | 77% (with 0.8 mg) |
| Meal and water conditions | In the case of ry, a small amount of water is taken, and it is stated that it takes more than 30 minutes | The description of which you can take with or without meals |
| Half-Life | About 1 week | Approx. 29 to 49 hours |
| Solubility in Water | — | ium saltInsoluble in waterMoisture absorption |
AllFacts(Attachment of oral semaglutin tablets, WEGOVY and FOUNDAYO [Reference Materials 2, 3, 13]).The condition of taking is quoted to indicate the difference in the mechanism of absorption, not the explanation of how to use it.
77% of orforglipron and about 2% of oral semaglutideApprox. 40-80 times(77 ÷ 2 ~ ÷ 1)The calculation of this paper。 If you make a low-, you need a different organic process than a peptide instead of the need for "different material" as an absorber.——This is an example of the choice of material and manufacturing as it is (in this article). Because the dosage is different, this ratio is not the ratio of the original dosage.
12. Post-development and regulatory movements and issues that have not yet been determined
(1) Guideline of the first postpartum and the guideline for postpartum peptides
FDADecember 23, 2024Refer to VICTOZA (liraglutide injection 18 mg/3 mL)First PostpartumApproved Hikma Pharmaceuticals USAFactsHome MoreJuly 28, 2026peptide products17 itemsGuidance (PSG) Targets include ralaglutide, semaglutide, zezepatide, andiparatide. Recombinant, , and semi- peptides (anda), natural immune response testing, impurities threshold, high-order structure evaluation, bioactive evaluationIt indicates recommendations aboutFactsHome dance in May 2021“ANDA of highly purified DNA peptide pharmaceuticals referring to recombinant DNA-derived products”HomeFDA does not reflect the current scientific thinkingDropped asFacts。
Can be treated as the same active ingredient for "precedents made by yeast" and "after-pro」 products made by chemical」"——The difference between the manufacturing method is replaced by the problem of the evaluation of impurities and immunity (in this article). Revised PSGdraftthe stage and the final content is not confirmedUndetermined / Future。
(2) Problems and things that could not be confirmed
- Production conditions and yield:The conditions, yields, and solvent usage of each company's solid phase and fermentation are not disclosed in the primary information referenced by this article.
- SNAC action completeness:Knudsen and Lau as of 2019"It is not fully understood"FactsHome The primary information that indicates the arrival point of the understanding after that was not confirmed in the scope of this article
- Oral Peptide Spread:Buckley et al. where the same method can be used with peptides other than semaglutide"The mechanism of absorption is the compound specific"Facts、Undetermined whether it can be generalizedHomeUndetermined / Future
- Positioning of low : actuator:The approval has just started in 2026, and how to use peptides is not handled in this article. For medical decisions
- The half-life of natural GLP-1 is 1.5 to 2 minutes.Dissolved in Ds such as DPP-4Facts
- Aib in 8th place strengthens the。 and phases the albumin with 26 fatty acids.semaglutide is about a weekFacts
- Half-life extends to about 5,000-6,700 timesThe calculation of this paper
- The key of oralization is absorbent promoter SNAC.Absorption occurs near the tablet surface of the stomach, and the absolute bioavailability is about 1-2%Facts
- Injectables and tablets of the same product name, the amount of the original drug for a week is about 73 timesThe calculation of this paper
- The production is "Yeast fermentation + chemical modification" and "solid phase ".In solid phase , the difference of 1-stage 1% is greatly effective in 38 stepsThe calculation of this paper
13. Glossary
- Peptides
- Medi s with several to dozens of amino acids. In the United States, 40 amino acids or less are peptides.
- GLP-1
- G-protein-coupled peptide-1. Hormones secreted from the intestines according to the diet.
- GIP
- G-coupled hormone-dependent insulin stimulating polypeptide. Array mounting.
- Contact Us
- Protein that transmits signals to cells when a specific molecule is combined. GLP-1 receptor GPCR in class B.
- Agonist (operating agent)
- Molecules that combine to receptors to work in the same way as natural substances.
- partial agonist
- Smaller agonists than natural substances that work with receptors.
- DPP-4
- Dipeptide Zil Peptides 4. Enzyme that cuts the N end side of GLP-1 and in。ts them.
- Aib
- Aminosobutyric acid. Non-coded amino acids not used for natural proteins. Used for DPP-4 resistance.
- Albumin binding
- A method that binds and persists versibly through fatty acids to protein albumins in the blood.
- Fat Dioxide
- Both ends are carboxylic fat chains. semaglutide C18,zezepatide C20.
- SNAC
- Sarcaprozate sodium. Ab ent promoter used for oral semaglutide tablets.
- Bioavailability
- The rate of blood flow of the whole body of the dose.
- Solid Phase Peptide Syn (SPPS)
- Synthetic method that extends the peptide chain combined with resin one residual. Can be cleaned.
- Semi-recombinant process
- A manufacturing method that creates skeletal microorganisms and modifies them by chemical reactions.
- Reverse chromatography
- Purification method to separate s by hydrophobic difference. Used for purification of peptides.
- ANDA／PSG
- Application for approval of post-department drugs in the U.S. / FDA guidelines for post-department development.
14. Reference Materials
- DailyMed「OZEMPIC (semaglutide) injection」 — dailymed.nlm.nih.gov
- DailyMed"RY)SUS/OZEMPIC (semaglutide) tablets" (Revised January 2026) — dailymed.nlm.nih.gov
- DailyMed「WEGOVY (semaglutide) injection／tablets」 — dailymed.nlm.nih.gov
- DailyMed「VICTOZA (liraglutide) injection」 — dailymed.nlm.nih.gov
- DailyMed「MOUNJARO (tirzepatide) injection」 — dailymed.nlm.nih.gov
- European Medicines Agency (CHMP)「Mounjaro — Assessment report」EMA/791310/2022 — ema.europa.eu
- Knudsen, L.B., Lau, J.「The Discovery and Development of Liraglutide and Semaglutide」Frontiers in Endocrinology 10, 155 (2019). doi:10.3389/fendo.2019.00155 — pmc.ncbi.nlm.nih.gov
- Lau, J. etc.「Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide」Journal of Medicinal Chemistry 58(18), 7370–7380 (2015). doi:10.1021/acs.jmedchem.5b00726 — pubmed.ncbi.nlm.nih.gov
- Buckley, S.T.「Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist」Science Translational Medicine 10(467), eaar7047 (2018). doi:10.1126/scitranslmed.aar7047 — pubmed.ncbi.nlm.nih.gov
- The Royal Swedish Academy of Sciences「The Nobel Prize in Chemistry 1984 — Press release」 — nobelprize.org
- Isidro-Llobet「Sustainability Challenges in Peptide Synthesis and Purification: From R&D to Production」The Journal of Organic Chemistry 84(8), 4615–4628 (2019). doi:10.1021/acs.joc.8b03001 — pubmed.ncbi.nlm.nih.gov
- Kawai, T. etc.「Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist」PNAS 117(47), 29959–29967 (2020). doi:10.1073/pnas.2014879117 — pmc.ncbi.nlm.nih.gov
- DailyMed「FOUNDAYO (orforglipron) tablets」 — dailymed.nlm.nih.gov
- Eli Lilly and CompanyFDA approves Lilly's FoundayoTM (orforglipron)... prnewswire.com
- Pfizer"Pfizer Provides Update on Oral GLP-1 Receptor Agonist Danuglipron" April 14, 2025 — pfizer.com
- FDA"FDA Approves Firstricric of Once-Daily GLP-1 Injection to Lower Blood in Patients with Type 2 Diabetes" December 23, 2024 — fda.gov
- FDAFDA Publishes Revised Draft Product-Specificancedances for Certain ric Peptide Products fda.gov
- United States Federal Regulations (eCFR)「21 CFR 600.3 Definitions」 — ecfr.gov
- FDA「"Deemed to be a License" Provision of the BPCI Act」 — fda.gov
15. Response Table of Claim and Sources (Audit)
| Content | Home | |
|---|---|---|
| Selectively bind and activate semaglutide to GLP-1 receptors with GLP-1 and 94% synergistic. The main mechanism is the hydrophilic translocation of 26th lysine and the albumin binding that is promoted by modification of C18 fatty acids, the 34th binding against DPP-4 degradation, the 34th replacement binds only one fatty acid, the peptide skeleton is produced by yeast fermentation, the weight is 4113.58 g/gram, half-life is approximately 1 week, absolute bioavailability of subcutaneous administration is 89%, additives | OZEMPIC[Reference 1]https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=adec4fd2-6858-4c99-91d4-531f5f2a2d79 | Facts |
| Additives of oral semaglutinized tablets (RYSUSSUS 3, 7, 14 mg, OZEMPIC tablets 1.5, 4, 9 mg), communicating with SNAC, absorption mainly occurs in the stomach, RY absolute bioavailability (RY SUS about 0.4–1%, OZEMPIC tablets about 1–2%), no clinically meaningful difference between AUC and Cmax in steady state between both preparations, no replacement in mg units, no absorption in fasting time after taking with water, no inhibitors at least 30 minutes. | RY SUS/OZEMPIC[Reference 2]https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=27f15fac-7d98-4114-a2ec-92494a91da98 | Facts |
| The maintenance dose of WEGOVY injection is 2.4 mg once a week, the maintenance dose of the tablet is 25 mg once a day, the tablet is about 1% to 2% of the absolute bioavailability, which is SN as an absorber of SNAC, the injection is 89%, and the tablet has a high blood density variation. | WEGOVY[Reference 3]https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ee06186f-2aa3-4990-a760-757579d8f77b | Facts |
| The half-life of GLP-1 (7-37) is 1.5 to 2 minutes, and it is for decomposition by DPP-4 and NEP. The precursor peptides of glargine are created in processes that contain recombinant DNA expression in yeast cells, and are equivalent to natural GLP-1 and 97% by substituting lysine at the 34th position with arginine, binding C16 fatty acids (palmitic acids) via glutamate transserine, with a molecular weight of 3751.2, and a plasma half-life of 13 hours after subcutaneous administration. | VICTOZA Attachments[Reference 4]https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5a9ef4ea-c76a-4d34-a604-27c5b505f5a4 | Facts |
| zezepatide is a weekly GIP receptor and GLP-1 receptor agonist that binds Aib, C-ter amide, 20th place lysine via a linker, 48 weight 4813.53 Da, half-life about 5 days | MOUNJARO[Reference 5]https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0 | Facts |
| Zezepatide is a peptide of 39 amino acids, and the linker is made of two gamma-Glu and 8-amino-3,6-dioxaoctanoic acids, some of which are similar to poly l, and standard solid-phase peptide synthesis (including 20-residue chain additions). | Public Examination Report (Mounjaro, /791310/2022)[Reference Material 6]https://www.ema.europa.eu/en/documents/assessment-report/mounjaro-epar-public-assessment-report_en.pdf | Facts |
| The aim of fatty acid modulation is to protect from both DPP-IV decomposition and renal filtration by reversible binding to albumin. Only 8th Aib was the result of the Alanin scan that combined DPP-IV stability and high receptor affinity. albiglutide and dulaglutide Two fatty acids reduce the effect of receptors. The systematic testing of C12 to C20 combines the highest albumin affinity and the effect of receptors with C18 fat diac acids and γGlu-2xOEG linkers. C10 to C18 fatty acids should be combined into 7 sites on albumin. By subst。ting 34th to Arginine, it was possible to recombinant the skeleton. SNAC has gained GRAS status in food applications, and the absorption SN mechanism is not fully understood (as of 2019) | Knudsen and Lau(2019)[Reference Material 7]https://pmc.ncbi.nlm.nih.gov/articles/PMC6474072/ | Facts |
| semaglutide’s GLP-1 receptor affinity (0.38 ± 0.06 M) drops to one- rd ofragraglutide, resulting in increased albumin affinity | Lau et al (2015)[Reference 8]https://pubmed.ncbi.nlm.nih.gov/26308095/ | Facts |
| Oral administration of the eutectic peptide is blocked by gastrointestinal barriers and decomposition. The absorption of semaglutide, co-formed with SNAC, requires SNAC in the stomach and close to the tablet surface, SNAC temporarily increases protection from decomposition by local buffering, and the absorption mechanism has no evidence of the effects on compound-specific, transcellular, and tight junction. | Buckley et al (2018) abstract[Reference 9]https://pubmed.ncbi.nlm.nih.gov/30429357/ | Facts |
| The overall yield after 100 stages is 0.003% at each stage, and solid-phase synthesis enables more than 99.5% at each stage, increasing the overall yield to 61%. | Nobel Prize 1984 Press Release[Reference Materials 10]https://www.nobelprize.org/prizes/chemistry/1984/press-release/ | Facts |
| Peptide mainly rely on anti technology, using large amounts of harmful reagents and solvents, and in 2016, ACS GCI Pharmaceutical Roundtable has been determining the development of a lower environmentally-friendly peptide drug process. | Isidro-Llobet et al (2019)[Reference Materials 11]https://pubmed.ncbi.nlm.nih.gov/30900880/ | Facts |
| The approved GLP-1 receptor agonist was peptide-based and difficult to obtain a low quality of optimal properties, and the LY3502970 (OWL833) is a partial agonist that is biased towards G protein activation, which is selective for other class B GPCRs, combined with the upper binding pocket that is enclosed by the receptor cellular domain, cell loop 2, membrane penetration 1, 2, 3, and 7. The author includes researchers from Chugai and Eli Lilly. | Kawai et al (2020)[Reference Material 12]https://pmc.ncbi.nlm.nih.gov/articles/PMC7703558/ | Facts |
| orforglipron weight of calcium salt 902.0 g/ , insoluble in water, absolute bioavailability at 0.8 mg, can be taken with or without meals, loss half-life about 29 to 49 hours, list of additives | FOUNDAYO[Reference 13]https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8ac446c5-feba-474f-a103-23facb9b5c62 | Facts |
| On April 1, 2026, the FDA approved FOUNDAYO (orforglipron), which is a low-) (non-peptide) oral GLP-1 receptor actuator per day, was created by Chugai and introduced by Lily in 2018. | Announcement of E-Lily[Reference 14]https://www.prnewswire.com/news-releases/fda-approves-lillys-foundayo-orforglipron-the-only-glp-1-pill-for-weight-loss-that-can-be-taken-any-time-of-day-without-food-or-water-restrictions-302731485.html | Facts |
| On April 14, 2025, one participant of the dose optimization test has the possibility of pharmacotic liver failure and recovery after disco ation, and the decision based on the opinions of all information and regulatory authorities. | Presentation of fazers (Facts about our products)[Reference Materials 15]https://www.pfizer.com/news/press-release/press-release-detail/pfizer-provides-update-oral-glp-1-receptor-agonist | Facts |
| On December 23, 2024, the FDA approved Hikma Pharmaceuticals USA the first postpartum to refer to VICTOZA (liraglutide 18 mg/3 mL) | FDA Press Release[Reference 16]https://www.fda.gov/news-events/press-announcements/fda-approves-first-generic-once-daily-glp-1-injection-lower-blood-sugar-patients-type-2-diabetes | Facts |
| On July 28, 2026, the FDA announced the revised PSRs of 17 peptide products, suggesting the ANDA for recombinant and peptide peptides, natural immune response tests, impurity thresholds, high-order structures, and bioactivity assessments, as well as the peptide ANDA guidance in May 2021. | FDA Publication[Reference Materials 17]https://www.fda.gov/drugs/drug-alerts-and-statements/fda-publishes-revised-draft-product-specific-guidances-certain-generic-peptide-products | Facts |
| Proteins are defined as alpha-amino acid polymers that exceed 40 amino acids | 21 CFR 600.3(h)(6)[Reference Materials 18]https://www.ecfr.gov/current/title-21/chapter-I/subchapter-F/part-600/subpart-A/section-600.3 | Facts |
| The FDA is a polymer composed of less than 40 amino acids as “peptide” and is not eligible for “no approval” in 2020. | FDA "Unauthorized" clause[Reference Materials 19]https://www.fda.gov/drugs/guidance-compliance-regulatory-information/deemed-be-license-provision-bpci-act | Facts |
| Half-life ratio (liraglutide about 390 to 520 times, zezepatide about 3,600 to 4,800 times, semaglutide about 5,000 to 6,700 times) RYSUSSUS 14 mg and OZEMPIC tablets that have about 36% of original drugs from the ratio of 9 mg. Original dosage per week of WEGOVY (injectable 2.4 mg, tablets 175 mg, about 73 times) and absorption (about 2.1 mg, about 1.8–3.5 mg). The cumulative ratio of 38 bonds (approx. 96%, 83%, 68%, 46%, and 1.8。, resulting in a loss of about 32% in each stage. Ratio of orforglipron and oral semaglutide bioavailability (about 40-80 times) | Calculation in this article. Simple conversion of the attached document (dose, half-life, bioavailability), and no measurement conditions or individual differences. The binding rate of each stage is assumed to have this article, not actual manufacturing conditions and yields. Neither indicates the therapeutic equivalence or superiority. | The calculation of this paper |
| Final content of the revised PSG. How oralization methods can be generalized to peptides other than semaglutide | PSG is the stage of draft, and the primary information of the compound specific paper was not confirmed at the time of the investigation of this article (September 2026). | Undetermined / Future |
| Conditions of solid phase and fermentation, yield, and solvent usage. The process of in semaglutide’s 8th Aib. Is the difference in the content of OZEMPIC tablets only due to prescription changes? After the understanding of the action of SNAC. SNAC | The first information referenced in this article cannot be confirmed, so it is not stated | |
| The three weak points of peptide (decomposition, renal excretion, absorption) have been solved by the design of chemical and material. The design of a fatty acid and PEG-like linker is based on the design of a surfactant and a coupling agent, and the idea of removing the reaction point from the array has been assembled on surface treatment, reading the albumin bond as a design of the adsorption equilibrium of adsorption and detachment. Read that oralization is also a decision to push up the original dosage, and the disintegration and dissolution of tablets affect the absorption rate. Read that the impurities of solid-phase are flawed by serial polymerization, and the usage of solvents and resins by oralization. Read that the difference between manufacturing methods is replaced by the evaluation of impurities and immunity. | Also commentary of this article based on the publication content. It is not the opinion of authors, regulators and companies of each paper. | |
| Effectiveness of each product (weight reduction, improvement of blood sugar, etc.), comparison of products, usage | [This article] is an explanation of materials and manufacturing technologies, and does not evaluate or compare the efficacy and safety. Dosage and dosage conditions are quoted to determine the original dosage and absorption mechanism, not a description of how to use. | |
| Fig. 1 - Fig. 6 is a drawing for explanation, not actual structure, device and any. Hero image and figure 7 must be an AI generation image. | Notes by this article |
Last Updated: September 26, 2026/Source is limited to primary information (FDA approved document [DailyMed], recent public review report, FDA published material, U.S. federal rule, Nobel Foundation announcement, corporate official announcement, and research review paper). They are distinguished from the facts by being labeled as "explanation" because they include readings in design, preparation, and process. The production conditions, yields, solvent usage, SNAC content, semaglutide's Aib implementation process, and the final mark of the revised PSG are not listed because it cannot be confirmed with the primary information published. This article explains materials and manufacturing technologies.It does not evaluate and compare efficacy and safety, but it is not medical advice. All diagrams are illustrations for explanation. Fig. 1 - Fig. 6 is a vector drawing, and Fig. 7 is an AI-generated image.We do not show actual s, devices, and products.