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ChemSpider 2D Image | Mirabegron | C21H24N4O2SMIRABEGRON
  • Betanis
  • Myrbetriq
  • UNII-MVR3JL3B2V
  • YM 178
  • YM178
Мирабегрон ميرابيغرون 米拉贝隆
2-(2-Amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide
MF: C21H24N4O2S =396.5
Mirabegron (YM-178, Astellas Pharma), is an orally active, first-in-class selective β₃-adrenoceptor agonist for the symptomatic treatment of overactive bladder (OAB), and has been approved for urinary frequency and urinary incontinence associated with OAB

Mirabegron (YM-178) is the first β3-adrenoceptor agonist that is clinically effective for overactive bladder. Mirabegron (0.3 and 1 mg/kg) inhibits mechanosensitive single-unit afferent activities (SAAs) of Aδ fibers in response to bladder filling. Mirabegron activates the β3 adrenergic receptor in the detrusor muscle in the bladder, which leads to muscle relaxation and an increase in bladder capacity. Mirabegron (YM-178) acts partly as an irreversible or quasi-irreversible metabolism-dependent inhibitor of CYP2D6. Mirabegron at a dose of 3 mg/kg i.v. decreased the frequency of rhythmic bladder contraction induced by intravesical filling with saline without suppressing its amplitude in anesthetized rats. Mirabegron decreases primary bladder afferent activity and bladder microcontractions in rats. Mirabegron (YM-178) also reduced non-micturition bladder contractions in an awake rat model of bladder outlet obstruction.

Mirabegron is a white crystalline powder, not hygroscopic and freely soluble in dimethyl sulfoxide, soluble in methanol and soluble in water between neutral to acidic pH. The chemical name is 2-(2- Amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2- phenylethyl]amino}ethyl)phenyl]acetamide., Mirabegron exhibits stereoisomerism due to the presence of one chiral centre. The R enantiomer has been used in the manufacture of the finished product. The enantiomeric purity is controlled routinely by chiral HPLC-UV. Polymorphism has been observed for the active substance. The polymorphic form α is routinely and consistently produced by the synthetic process and it is used in the manufacture of the finished product…….http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002388/WC500137308.pdf

Mirabegron (formerly YM-178, trade name MyrbetriqBetmiga in Spain) is a drug for the treatment of overactive bladder.[2] It was developed by Astellas Pharma and was approved in the United States in July 2012.[3]
Mirabegron activates the β3 adrenergic receptor in the detrusor muscle in the bladder, which leads to muscle relaxation and an increase in bladder capacity.[4]\
NMR PREDICT
NMR CHEMDOODLE
PAPER
Journal of Chemical and Pharmaceutical Research, 2015, 7(4):1473-1478
In the first approach, the introduction of the chiral hydroxyl group was planned at the later stage (Scheme 1). Accordingly, 2-(4-nitrophenyl)ethyl amine 4 was protected as the Boc-derivative 5, followed by the reduction of the nitro group using stannous chloride to furnish corresponding aniline 6. Alternate reducing conditions such as hydrogenation in the presence of 10% Pd-C were also provided the desired 6 in good yield. Amide coupling of the aniline 6 with 2-(2-aminothiazol-4-yl) acetic acid 7 in the presence of EDC, HOBt/DIPEA furnished the desired amide 8. Interestingly, lower reactivity of 2-aminothiazole precluded any self-coupling of 7.
MIRA SYN 1
Removal of Boc-group in 8, set the stage for the critical step of introducing the chiral hydroxyl by means of stereocontrolled ring opening of the chiral (R)-styrene epoxide 10. Epoxide opening reaction of 10 was initially attempted with amine 9 in the presence of Et3N in MeOH as the solvent. Alternatively, epoxy opening was also performed under simple isopropanol reflux condition to get the desired 1. The desired product 1 was isolated in 27% yield after purification by column chromatography. This is due to the formation of N-alkylated derivatives of 1 by undesired reaction of 10 with amino functionalities of 1. However, the inefficiency of the epoxide opening reaction precluded a high purity of final product, Mirabegron 1. Since it is not practical to embark on repeated purifications at the last stage (which leads to poor yields), this route was not pursued for further optimization.
13C NMR PREDICT
C-NMR MOLBASE
1H NMR PREDICT
H-NMR MOLBASE
………………
1H NMR PREDICT
H EXPLODED H-NMR NMRDB GRAPHH-NMR NMRDB VAL
13C NMR PREDICT
C-NMR NMRDB GRAPH C-NMR NMRDB VAL
COSY PREDICT
COSY NMR prediction (24)CN 103896872
http://www.google.com/patents/CN103896872A?cl=en

Figure CN103896872AD00082
Figure CN103896872AD00091

Third, Mira Veron synthesis:
reaction:

Figure CN103896872AD00092

in 500mL three-necked flask, 2- (2-aminothiazol-4-yl) acetic acid 17.42g (0.086mol), N, N- dimethylformamide 180mL, then added H0BT15.12g (0.104 mol), was added (R) _2 _ ((4- aminophenyl) amino) phenyl-ethan-l-ol -1_ 20g (0.078mol), was added triethylamine 13.04g (0.13mol), was added portionwise EDCI21. 46g (0.104mol), under magnetic stirring, room temperature for 5h, TLC until the reaction was complete tracking.
After treatment: After the completion of the reaction, the reaction solution was poured into 900mL saturated saline water, and then extracted with 400mL of dichloromethane each time, and extracted three times, each time the organic phase is then washed with 200mL of saturated aqueous sodium carbonate solution, washed three times, each time with distilled water and then 200mL of water, washed three times, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a white solid in methylene chloride was distilled off Mira Veron crude, the crude product was recrystallized from methanol solution, wherein the methanol solution of methanol and water, the volume ratio of 10: 4, and recrystallized to give 25.08g, yield 81.0%.
The present embodiment Mira Veron synthesized for testing and structural identification:
mp138 ~ 140 ° C (137 ~ 139 ° C)
[α] 20-18. ~ -22. (CH3OH)
chemical purity HPLC: 99.96%
Optical purity: 97.55ee%
HRMS (ES1-MS, m / z) calcd: for C21H25N4O2S [M + H] + 397.16.Found:. 397.16
1H Mffi (400MHz, DMS0) Sl0.00 (s, lH), 7.50 ( d, J = 8.5Hz, 2H), 7.30 (dd, J = 9.5,5.1Hz, 4H), 7.23 (dd, J = 6.0, 2.7Hz, 1H), 7.12 (d, J = 8.5Hz, 2H), 6.90 (s, 2H), 6.30 (s, 1H), 5.24 (s, 1H), 4.60 (s, 1H), 3.45 (s, 2H), 2.74 (dd, J = 9.8, 3.5Hz, 2H), 2.64 (m, 4H).
13C NMR (101MHz, DMSO) δ 168.69 (s), 168.26 (s), 146.35 (s), 145.03 (s), 137.66 (s), 135.51 (s), 129.24 (s ), 128.38 (s), 127.22 (s), 126.33 (s), 119.46 (s), 103.03 (s), 71.88 (s), 57.94 (s), 51.20 (s), 40.40 (s), 40.20 (s ), 39.99 (s), 39.78 (s), 39.57 (s), 35.77 (s)

1H NMR FIG2…SEE…….http://orgspectroscopyint.blogspot.in/2015/08/mirabegron.html

1H NMR

13C NMR FIG3

 13C NMR

………….

CN 103193730
http://www.google.com/patents/CN103193730A?cl=en
Figure CN103193730AD00081

By and O ° C under nitrogen protection temperature conditions, 7.3g (R) -2- amino _1_ benzeneethanol added 250mL three-necked flask, the stirring was dissolved in 50mL of dichloromethane Mira Veron Intermediate C was added dropwise to the reaction solution to form three-necked flask. Stirred for I hour under nitrogen, with stirring 4.12g of sodium borohydride was added to the reaction mixture. The reaction mixture was stirred (under TC 3 hours to TLC the reaction was complete. The reaction is complete the reaction mixture was added dropwise a saturated aqueous ammonium chloride solution IOmL quenched reaction was washed twice with 40mL of water, the organic phase was separated. The The organic phase at the conditions at 0 ° C was added concentrated sulfuric acid was stirred IOmL until TLC after 0.5 hours the reaction was complete, then was added 20mL of 20% aqueous sodium hydroxide solution to complete the reaction of the organic phase was adjusted to pH 10 and stirred for 15 minutes minutes solution. The organic phase first with 50mL saturated brine I times with IOg anhydrous sodium sulfate and concentrated to give crude product was recrystallized from methanol and water to give 18.7g of the final product Mira Veron purity of 99.33%, chiral purity of 99.01%, a yield of 88.12%.
Mira Veron use randomly selected samples prepared by the synthesis method of the present invention is detected by liquid chromatography.
Test conditions: Instrument: Agilent 1100 HPLC;
Column: Luna C18, 4.6mmX 250mm, 5 μ m;
Column temperature: 25 ° C;
flow rate: 1.0mL / min;
The detection wavelength: 2IOnm;
Injection volume: 5ul;
Mobile phase A: acetonitrile;
Mobile phase B: 0.1% phosphoric acid aqueous solution;
Running time: 40min.
FIG liquid chromatography after detection of the sample shown in Figure 1; results are shown in Table I.
Table 1: The Mira Veron chromatographic analysis sample preparation method of the present invention

Figure CN103193730AD00121

……….

http://www.google.co.in/patents/EP1440969A1?cl=en

Figure 00090001

      Example 4 (Production of the α-form crystal from wet cake of the β-form crystal) :
  • The same procedures as in Example 2 were followed to obtain 23.42 kg of a wet cake of the β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide from 6.66 kg of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol monohydrochloride. This cake was added with and dissolved in 92 L of water and 76 L of ethanol by heating at about 80°C, and the solution was cooled at a rate of about 10°C per hour, to which was then added 8.4 g of the α-form crystal at 55°C. Thereafter, the mixture was cooled to 20°C. A crystal was filtered and dried to obtain 6.56 kg of the α-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide.
  • Powder X-ray diffraction diagram and thermal analysis diagram of the α-form crystal are shown in Fig. 4 and Fig. 5, respectively.
    1H-NMR (DMSO-d 6, 500 MHz) δ (ppm) = 1.60 (1H, s), 2.59 to 2.66 (4H, m), 2.68 to 2.80 (2H, m), 3.45 (2H, s), 4.59 (1H, br), 5.21 (1H, br), 6.30 (1H, s), 6.89 (2H, s), 7.11 (2H, d, J = 8.5 Hz), 7.19 to 7.23 (1H, m), 7.27 to 7.33 (4H, m), 7.49 (2H, d, J = 8.5 Hz), 9.99 (1H,s). FAB-MS m/z: 397 (M+H)+.

References

  1.  “mirabegron (Rx) – Myrbetriq”Medscape Reference. WebMD. Retrieved 17 November 2013.
  2.  Gras, J (2012). “Mirabegron for the treatment of overactive bladder”. Drugs of today (Barcelona, Spain : 1998) 48 (1): 25–32. doi:10.1358/dot.2012.48.1.1738056PMID 22384458.
  3.  Sacco, E; Bientinesi, R et al. (Apr 2014). “Discovery history and clinical development of mirabegron for the treatment of overactive bladder and urinary incontinence”. Expert Opin Drug Discov9 (4): 433–48. doi:10.1517/17460441.2014.892923PMID 2455903.
  4.  “New Drug Approvals 2012 – Pt. XIV – Mirabegron (MyrbetriqTM)”ChEMBL. 5 July 2012. Retrieved 28 September 2012.
  5.  “MYRBETRIQ (mirabegron) tablet, film coated, extended release [Astellas Pharma US, Inc.]“DailyMed. Astellas Pharma US, Inc. September 2012. Retrieved 17 November 2013.
  6.  “Betmiga 25mg & 50mg prolonged-release tablets”electronic Medicines Compendium. Astellas Pharma Ltd. 22 February 2013. Retrieved 17 November 2013.
  7.  Cypess, Aaron; Weiner, Lauren; Roberts-Toler, Carla; Elía, Elisa; Kessler, Skyler; Kahn, Peter; English, Jeffrey; Chatman, Kelly; Trauger, Sunia; Doria, Alessandro; Kolodny, Gerald (6 January 2015). “Activation of Human Brown Adipose Tissue by a β3-Adrenergic Receptor Agonist”Cell Metabolism 21 (1): 33–38. doi:10.1016/j.cmet.2014.12.009PMID 25565203. Retrieved 26 January 2015.

External links

Mirabegron
Mirabegron2DACS2.svg
Systematic (IUPAC) name
2-(2-Amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide
Clinical data
Trade names Myrbetriq (US), Betanis (Japan), Betmiga (EU)
Licence data EMA:LinkUS FDA:link
Pregnancy
category
  • US: C (Risk not ruled out)
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability 29-35%[1]
Protein binding 71%[1]
Metabolism Hepatic via (direct) glucuronidation, amide hydrolysis, and minimal oxidative metabolism in vivo byCYP2D6 and CYP3A4. Some involvement of butylcholinesterase[1]
Biological half-life 50 hours[1]
Excretion Urine (55%), faeces (34%)[1]
Identifiers
CAS Registry Number 223673-61-8
ATC code G04BD12
PubChem CID: 9865528
ChemSpider 8041219
Synonyms YM-178
Chemical data
Formula C21H24N4O2S
Molecular mass 396.506 g/mol
Patent Submitted Granted
Alpha-form or beta-form crystal of acetanilide derivative [US7342117] 2005-01-06 2008-03-11
Pharmaceutical composition for treating stress incontinence and/or mixed incontinence [US2006004105] 2006-01-05
Pharmaceutical composition comprising a beta-3-adrenoceptor agonist and a serotonin and/or norepinephrine reuptake inhibitor Pharmaceutical composition comprising a beta-3-adrenoceptor agonist and a serotonin and/or norepinephrine reuptake inhibitor [US2009012161] 2005-11-24
Pharmaceutical composition consisting of a beta-3-adrenoceptor agonist and alpha-agonist [US2005154041] 2005-07-14
Pharmaceutical composition consisting of a beta-3-adrenoceptor agonist and an active substance which influences prostaglandin metabolism [US2005119239] 2005-06-02
Pharmaceutical Composition For Treating Stress Incontinence And/Or Mixed Incontinence [US2007129435] 2007-06-07
Remedy for overactive bladder comprising acetic acid anilide derivative as the active ingredient [US7750029] 2006-06-01 2010-07-06
[alpha]-form or [beta]-form crystal of acetanilide derivative [US7982049] 2008-09-04 2011-07-19
BETA ADRENERGIC RECEPTOR AGONISTS FOR THE TREATMENT OF B-CELL PROLIFERATIVE DISORDERS [US2010009934] 2010-01-14
PHARMACEUTICAL COMPOSITION FOR IMPROVING LOWER URINARY TRACT SYMPTOMS [US2010261770] 2010-10-14
11 to 16 of 16
Patent Submitted Granted
PHARMACEUTICAL COMPOSITION FOR MODIFIED RELEASE [US2010144807] 2010-06-10
BENZYLAMINE DERIVATIVE OR PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALT THEREOF, AND USE THEREOF FOR MEDICAL PURPOSES [US8148427] 2010-04-22 2012-04-03
Pharmaceutical composition containing a beta-3-adrenoceptor agonist and an alpha antagonist and/or a 5-alpha reductase inhibitor [US2005101607] 2005-05-12
REMEDY FOR OVERACTIVE BLADDER COMPRISING ACETIC ACID ANILIDE DERIVATIVE AS THE ACTIVE INGREDIENT [US2009093529] 2009-04-09
PHARMACEUTICAL COMPOSITION FOR TREATING OVERACTIVE BLADDER [US2010240697] 2010-09-23
Pharmaceutical composition comprising beta-3-adrenoceptor-agonists and antimuscarinic agents [US2005261328] 2005-11-24
US Patent No Patent Expiry patent use
6346532 Oct 15, 2018
6562375 Aug 1, 2020
6699503 Sep 10, 2013
7342117 Nov 4, 2023
7750029 Dec 18, 2023 U-913
7982049 Nov 4, 2023
Exclusivity Code Exclusivity Date
NCE Jun 28, 2017

U-913……….TREATMENT OF OVERACTIVE BLADDER WITH SYMPTOMS OF URGE URINARY INCONTINENCE, URGENCY, AND FREQUENCY

//////Mirabegron, Overactive bladder, FDA 2012, ASTELLAS PHARMA, YM-178, MyrbetriqBetmiga

Updates…….

Figure

Overactive bladder (OAB) is characterized by symptoms of urinary urgency, with or without urgency incontinence, usually with increased daytime frequency and nocturia.(1-3) Current guidelines recommend oral antimuscarinics drugs as the first-line pharmacologic therapy in the management of OAB despite the companion adverse effects.(4, 5) Mirabegron is an orally active β3 adrenoceptor agonist approved by the FDA for treatment of OAB in 2012, which is an important step toward the better treatment options for the management of OAB.(6)

(R)-Styrene oxide 1 and 4-nitrophenethylamine 2 were exploited as starting materials in the first synthesis of mirabegron (Scheme 1). Heating 1 and 2 in i-propanol afforded amino alcohol 3, and then the amino group was protected by di-tert-butyl dicarbonate (Boc2O), followed by a condensation with 2-aminothiazol-4-acetic acid. Deprotection of the condensation product 7 finally afforded mirabegron.(7-10) Although reactions in the whole process were all conventional reactions, optically pure 1 was not industrially available, which restricted its application in industry.

(R)-Mandelic 8 and 4-nitrophenethylamine hydrochloride 9 were exploited as starting materials in an alternate route (Scheme 2). Condensation of 8 and 9 in the presence of 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), and triethylamine in N,N-dimethylformamide (DMF) furnished the corresponding amide 10, which was further reduced in the presence of borane-tetrahydrofuran complex in a mixed solution of 1,3-dimethyl-2-imidazolidinone (DMI) and tetrahydrofuran (THF), affording amine 11. The nitro group of 11 was then reduced by hydrogenation affording aniline 12 which was further amidated by an aqueous EDCI coupling affording mirabegron. This route was rather concise with only four steps, in which the sole stereogenic center was introduced via a bulk starting material 8.(11-13) However, usage of the costly EDCI twice, especially in the first step, led to a high cost and more impurities.

Figure

mail: chm_zhenggx@ujn.edu.cn,  chm_zhenggx@ujn.edu.cn

  1. 1   AbramsP.CardozoL.FallM.GriffithsD.RosierP.UlmstenU.Van KerrebroeckP.VictorA.Wein,A. UROLOGY 20036137DOI: 10.1016/S0090-4295(02)02243-4

  2. 2.AbramsP.ChappleC.KhouryS.RoehrbornC.de la RosetteJ. J. Urol. 20091811779DOI: 10.1016/j.juro.2008.11.127

  3. 3.JaiprakashH.BenglorkarG. M. RJPBCS 20145 ( 3213

  4. 4.LucasM. G.RuudJ. L.BoschR. J. L.BurkhardF. C.CruzF.MaddenT. B.NambiarA. K.Neisius,A.de RidderD. J. M. K.TubaroA.TurnerW.PickardR. Eur. Urol. 2012621130DOI: 10.1016/j.eururo.2012.08.047

  5. 5.GormleyE. A.LightnerD. J.BurgioK. L.ChaiT. C.ClemensJ. Q.CulkinD. J.DasA. K.FosterH. E.ScarperoH. M.TessierC. D.VasavadaS. P. J. Urol. 20121882455DOI: 10.1016/j.juro.2012.09.079

  6. 6.SaccoE.BientinesiR. World J. Obstet Gynecol 20132 ( 465DOI: 10.5317/wjog.v2.i4.65

  7. 7.MaruyamaT.SuzukiT.OndaK.HayakawaM.MoritomoH.KimizukaT.MatsuiT. US6346532,2002.

  8. 8.KawazoeS.SakamotoK.AwamuraY.MaruyamaT.SuzukiT.OndaK.TakasuT. EP144096A1,2004.

  9. 9.TakasuT.SatoS.UkaiM.MaruyamaT. EP1559427A1, 2005.

  10. 10ZhangH.LiY.ChenS.ShenM.WangX. CN103896872A, 2014

//////////


1 Comment

  1. prasada reddy says:

    dear sir can u clarify the biperiden hydrochloride final specifications.

    Regards, Prasadareddy.Meka Sr.Research Scientist Maithili Life Sciences Pvt.Ltd. APIIC,Gajulamandyam,Tirupathi Mobile: +91 9849524456

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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 29 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 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 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 29 year tenure till date Aug 2016, Around 30 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, 25 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 13 lakh plus views on New Drug Approvals Blog in 212 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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