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Home » RADIOLABELLED » The USFDA has approved Navidea Biopharmaceuticals’ Supplemental New Drug Application (sNDA) for the expanded use of Lymphoseek (technetium Tc 99m tilmanocept) Injection

The USFDA has approved Navidea Biopharmaceuticals’ Supplemental New Drug Application (sNDA) for the expanded use of Lymphoseek (technetium Tc 99m tilmanocept) Injection

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Technetium (99mTc) tilmanocept……………….CAS1262984-82-6
Technetium-99m tilmanocept.svg[99mTc]-DTPA-mannosyl-dextran
Systematic (IUPAC) name
Dextran 3-[(2-aminoethyl)thio]propyl 17-carboxy-10,13,16-tris(carboxymethyl)-8-oxo-4-thia-7,10,13,16-tetraazaheptadec-1-yl 3-[[2-[[1-imino-2-(D-mannopyranosylthio)ethyl]amino]ethyl]thio]propyl ether technetium-99m complexes…………………………………………………..………………..OTHER NAME ………………Dextran 3-[(2-aminoethyl)thio]propyl 17-carboxy-10,13,16-tris(carboxymethyl)-8-oxo-4-thia-7,10,13,16-tetraazaheptadec-1-yl 3-[[2-[[1-imino-2-(D-mannopyranosylthio)ethyl]amino]ethyl]thio]propyl ether technetium-99Tc complexes
(1-6)-alpha-D-pyranoglucan partially etherified by 3-[(2-aminoethyl)sulfanyl]propyl 17-carboxy-10,13,16-tris(carboxymethyl)-8-oxo-4-thia-7,10,13,16-tetraazaheptadecyl and 3-[(2-{[2-(L-mannopyranosylsulfanyl)acetimidoyl]amino}ethyl)sulfanyl]propyl [99mTc]technetium coordination compound
[99mTc]-DTPA-mannosyl-dextran composed of a dextran backbone linked to multiple units of mannose and DTPA (diethylenetriamine pentaacetic acid) with an average molecular weight of 35800………………..LAUNCHED………….Launched – 2013
Clinical data
Trade names Lymphoseek
AHFS/Drugs.com entry
Pregnancy cat. C (US)
Legal status -only (US)
Routes Intradermal, subcutaneous
Pharmacokinetic data
Half-life 1.75 to 3.05 hours at injection site
Identifiers
ATC code V09IA09
Chemical data
Formula (C6H10O5)n(C19H28N4O9S99mTc)3–8(C13H24N2O5S2)12–20(C5H11NS)0–17
Mol. mass 15,281–23,454 g/mol[1]……………………..CODES1600
NEO3-06
TcDTPAmanDx
Tilmanocepthttp://chem.sis.nlm.nih.gov/chemidplus/rn/1262984-82-6NDA N202207 APPROVED

Mar 13, 2013

 

PATENT US 6409990, EXPMay 12, 2020

 

商品名:Lymphoseek  通用名:Technetium Tc 99m tilmanocept  中文名:未知
药企:Navidea Biopharmaceuticals, Inc.

FDA approves Navidea’s Lymphoseek for expanded use in head and neck cancer patients

The US Food and Drug Administration (FDA) has approved Navidea Biopharmaceuticals’ Supplemental New Drug Application (sNDA) for the expanded use of Lymphoseek (technetium Tc 99m tilmanocept) Injection indicated for guiding sentinel lymph node (SLN) biopsy in head and neck cancer patients with squamous cell carcinoma of the oral cavity.

http://drugdelivery.pharmaceutical-business-review.com/news/fda-approves-navideas-lymphoseek-for-expanded-use-in-head-and-neck-cancer-patients-160614-4294154

NCI: 99mTc-DTPA-mannosyl-dextran A radiolabeled macromolecule consisting of the chelating agent diethylenetriamine pentaacetic acid (DTPA) and mannose each attached to a dextran backbone and labeled with metastable technetiumTc-99 (Tc-99m), with mannose binding and radioisotopic activities. Upon injection, the mannose moiety of 99mTc-DTPA-mannosyl-dextran binds to mannose-binding protein (MBP). As MBPs reside on the surface of dendritic cells and macrophages, this gamma-emitting macromolecule tends to accumulate in lymphatic tissue where it may be imaged using gamma scintigraphy. This agent exhibits rapid clearance from the injection site, rapid uptake and high retention within the first draining lymph node, and low uptake by the remaining lymph nodes. MBP is a C-type lectin that binds mannose or fucose carbohydrate residues, such as those found on the surfaces of many pathiogens, and once bound activates the complement system.

 

The active ingredient in technetium Tc 99m tilmanocept is technetium Tc 99m tilmanocept. The active ingredient is formed when Technetium Tc 99m pertechnetate, sodium injection is added to the tilmanocept powder vial.

Technetium Tc 99m binds to the diethylenetriaminepentaacetic acid (DTPA) moieties of the tilmanocept molecule.

Chemically, technetium Tc 99m tilmanocept consists of technetium Tc 99m, dextran 3-[(2- aminoethyl)thio]propyl 17-carboxy-10,13,16- tris(carboxymethyl)-8-oxo-4-thia-7,10,13,16- tetraazaheptadec-1-yl 3-[[2-[[1-imino-2-(D- mannopyranosylthio) ethyl]amino]ethyl]thio]propyl ether complexes. Technetium Tc 99m tilmanocept has the following structural formula:

Empirical formula: [C6H10O5]n.(C19H28N4O9S99mTc)b.(C13H24N2O5S2)c.(C5H11NS)a

Calculated average molecular weight: 15,281 to 23,454 g/mol

It contains 3-8 conjugated DTPA (diethylenetriamine pentaacetic acid) molecules (b); 12-20 conjugated mannose molecules (c) with 0-17 amine side chains (a) remaining free.

The tilmanocept powder vial contains a sterile, non-pyrogenic, white to off-white powder that consists of a mixture of 250 mcg tilmanocept, 20 mg trehalose dihydrate, 0.5 mg glycine, 0.5 mg sodium ascorbate, and 0.075 mg stannous chloride dihydrate. The contents of the vial are lyophilized and are under nitrogen.

Technetium Tc 99m tilmanocept injection is supplied as a Kit. The Kit includes tilmanocept powder vials which contain the necessary non-radioactive ingredients needed to produce technetium Tc 99m tilmanocept. The Kit also contains DILUENT for technetium Tc 99m tilmanocept. The diluent contains a preservative and is specifically formulated for technetium Tc 99m tilmanocept. No other diluent should be used.

The DILUENT for technetium Tc 99m tilmanocept contains 4.5 mL sterile buffered saline consisting of 0.04% (w/v) potassium phosphate, 0.11% (w/v) sodium phosphate (heptahydrate), 0.5% (w/v) sodium chloride, and 0.4% (w/v) phenol. The pH is 6.8 – 7.2.http://www.druginformation.com/RxDrugs/T/Technetium%20Tc%2099m%20Tilmanocept%20Injection.html

 

Lymphoseek(TM) is a lymphatic tissue-targeting agent which was first launched in 2013 in the U.S. by Navidea Biopharmaceuticals (formerly known as Neoprobe) for lymphatic mapping with a hand-held gamma counter to assist in the localization of lymph nodes draining a primary tumor site in patients with breast cancer or melanoma. In 2014, a supplemental NDA was approved in the U.S. for its use as a sentinel lymph node tracing agent in patients with head and neck squamous cell carcinoma of the oral cavity. Although several tracing agents exist that are used in “off-label” capacities, Lymphoseek is the first tracing agent specifically labeled for lymph node detection.

In 2012, an MAA was filed in the E.U. for the detection of lymphatic tissue in patients with solid tumors, and in 2013, a supplemental MAA was filed in the E.U. for sentinel lymph node detection in patients with head and neck cancer. The products is also awaiting registration to support broader and more flexible use in imaging and lymphatic mapping procedures, including lymphoscintigraphy and other optimization capabilities.

Navidea holds an exclusive worldwide license of Lymphoseek(TM) through the University of California at San Diego (UCSD), and, in 2007, Lymphoseek(TM) was licensed to Cardinal Health by Navidea for marketing and distribution in the U.S.

Lymphoseek(TM), also known as [99mTc]DTPA-mannosyl-dextran, is a receptor-binding radiopharmaceutical designed specifically for the mapping of sentinel lymph nodes in connection with gamma detection devices in a surgical procedure known as intraoperative lymphatic mapping (ILM). It is made up of multiple DTPA and mannose units, each attached by a 5-carbon thioether spacer to a dextran backbone. The compound features subnanomolar affinity for the mannose binding protein receptor, and consequently shows low distal node accumulation. Additionally, its small molecular diameter of 7 nanometers allows for enhanced diffusion into lymphatic channels and capillaries.

 

1600
99mTc-tilmanocept
Tc-DTPA-mannosyl-dextran
Technetium Tc 99m Tilmanocept
Tilmanocept
UNII-8IHI69PQTC

 

Chemical structure of [99mTc]tilmanocept. [99mTc]Tilmanocept is composed of a dextran backbone (black) to which are attached multiple units of mannose (green) and DTPA (blue). The mannose units provide a molecular mechanism by which [99mTc]tilmanocept avidly binds to a receptor specific to reticuloendothelial cells (CD206), and the DTPA units provide a highly stable means to radiolabel tilmanocept with 99mtechnetium (red). The molecular weight of [99mTc]tilmanocept is approximately 19,000 g/mol; the molecular diameter is 7.1 nm

[(99m)Tc]Tilmanocept is a CD206 receptor-targeted radiopharmaceutical designed for sentinel lymph node (SLN) identification. Two nearly identical nonrandomized phase III trials compared [(99m)Tc]tilmanocept to vital blue dye.

Technetium (99mTc) tilmanocept, trade name Lymphoseek, is a radiopharmaceutical diagnostic imaging agent approved by the U.S. Food and Drug Administration (FDA) for the imaging of lymph nodes.[1][2] It is used to locate those lymph nodes which may be draining from tumors, and assist doctors in locating those lymph nodes for removal during surgery.[3]

http://blog.sina.com.cn/u/1242475203

…………………….

WO 2000069473

http://www.google.com/patents/EP1178838A2?cl=en

…………………………………………..

US 6409990

 http://www.google.co.in/patents/US6409990

References

  1. FDA Professional Drug Information
  2. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm343525.htm
  3. Marcinow, A. M.; Hall, N.; Byrum, E.; Teknos, T. N.; Old, M. O.; Agrawal, A. (2013). “Use of a novel receptor-targeted (CD206) radiotracer, 99mTc-tilmanocept, and SPECT/CT for sentinel lymph node detection in oral cavity squamous cell carcinoma: Initial institutional report in an ongoing phase 3 study”. JAMA otolaryngology– head & neck surgery 139 (9): 895–902. doi:10.1001/jamaoto.2013.4239. PMID 24051744.

http://www.google.com/patents/US8247538

Radiopharmaceuticals for use in therapy employ radionuclides which are generally longer in half-life and weaker in penetration capability, but emit stronger radiation, sufficient to kill cells, in relation to that for use in diagnosis. Alpha ray-emitting radionuclides are excluded from radiopharmaceuticals for the reason that they are highly radioactive and difficult to purchase and to attach to other compounds. All of the radionuclides currently used in pharmaceuticals are species that emit beta rays.

As mentioned above, radiopharmaceuticals, whether for use in therapy or diagnosis, are prepared by labeling pharmaceuticals with specific radionuclides. Technetium-99m (99mTc) is known as the radioisotope most widely used to label radiopharmaceuticals. Technetium-99m has a half life of as short as 6 hours and emits gamma rays at 140 KeV, and thus it is not so toxic to the body. In addition, gamma radiation from the radioisotope is highly penetrative enough to obtain images. Thanks to these advantages, technetium-99m finds a broad spectrum of therapeutic and diagnostic applications in the nuclear medicine field (Sivia, S. J., John, D. L., Potential technetium small molecule radiopharmaceuticals. Chem. Rev. 99, 2205-2218, 1999; Shuang, L., Edwards, D. S., 99mTc-Labeled small peptides as diagnostic radiopharmaceuticals. Chem. Rev. 99, 2235-2268, 1999).

Methods of labeling 99mTc-2,6-diisopropylacetanilidoiminodiacetic acid are well known in the art (Callery, P. S., Faith, W. C., et al., 1976. Tissue distribution of technetium-99m and carbon-labeled N-(2,6)-dimetylphenylcarbamoylmethyl iminodiacetic acid. J. Med. Chem. 19, 962-964; Motter, M. and Kloss, G., 1981. Properties of various IDA derivatives. J. Label. Compounds Padiopharm. 18, 56-58; Cao, Y. and Suresh, M. R. 1998. A Simple And Efficient Method For Radiolabeling Of Preformed Liposomes. J Pharm Pharmaceut Sci. 1 (1), 31-37).

Basically, the conventional methods are based on the following reaction formula. In practice, a solution of SnCl2.2H2O, serving as a reducing agent of technetium-99m, in 0.1 N HCl and 0.1 ml (10 mCi) of sodium pertechnetium were added to lyophilized 2,6-diisopropylacetanilidoiminodiacetic acid in a vial, followed by stirring at room temperature for 30 min to prepare 99mTc-2,6-diisopropylacetanilidoiminodiacetic acid. The preparation of 99mTc-2,6-diisopropylacetanilidoiminodiacetic acid may be realized according to the following reaction formula.

 

 

Such conventional processes of preparing radiopharmaceuticals labeled with technetium-99m can be divided into reactions between the radioisotope and a physiologically active material to be labeled and the separation of labeled compounds from unlabeled compounds.

M. Molter, et al., Properties of Various IDA Derivatives, J. Label. Compounds Padiopharm., vol. 18, pp. 56-58, 1981.
2 Patrick S. Callery, et al., Tissue Distribution of Technetium-99m and Carbon . . . , J. Med. Chem., vol. 19, pp. 962-964, 1976.
3 * Sang Hyun Park et al. Synthesis and Radiochemical Labeling of N-(2,6-diisopropylacetanilido)-Iminodiacetic acid and it s analogues under microwave irradiation: A hepatobiliary imaging agent, QSAR Comb. Sci. 2004, 23, 868-874.
4 Shuang Liu, et al., 99mTc-Labeled Small Peptides as Diagnostic . . . , Chem. Rev., vol. 99, pp. 2235-2268, 1999.
5 Shuang Liu, et al., 99mTc—Labeled Small Peptides as Diagnostic . . . , Chem. Rev., vol. 99, pp. 2235-2268, 1999.
6 Silvia S. Jurisson, et al., Potential Technetium Small Molecule . . . , Chem. Rev., vol. 99, pp. 2205-2218, 1999.
7 Y. Cao, et al., A Simple and Efficient Method for Radiolabeling . . . , J. Phar,. Pharmaceut. Sci., pp. 31-37, 1998.

 

 

 

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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