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loteprednol etabonate

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Loteprednol etabonate.svg
Loteprednol etabonate.png

loteprednol etabonate

  • Molecular FormulaC24H31ClO7
  • Average mass466.952 Da

cas 82034-46-6

chloromethyl (8S,9S,10R,11S,13S,14S,17R)-17-ethoxycarbonyloxy-11-hydroxy-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-17-carboxylate(11b,17a)-17-[(Ethoxycarbonyl)oxy]-11-hydroxy-3-oxo-androsta-1,4-diene-17-carboxylic acid chloromethyl ester
(11b,17a)-17-[(Ethoxycarbonyl)oxy]-11-hydroxy-3-oxoandrosta-1,4-diene-17-carboxylic Acid Chloromethyl Ester
(8S,9S,10R,11S,13S,14S,17R)-17-[(éthoxycarbonyl)oxy]-11-hydroxy-10,13-diméthyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodécahydro-3H-cyclopenta[a]phénanthrène-17-carboxylate de chlorométhyle
129260-79-3[RN]
17a-Ethoxycarbonyloxy-D’-cortienic Acid Chloromethyl Ester
82034-46-6[RN]
Androsta-1,4-diene-17-carboxylic acid, 17-((ethoxycarbonyl)oxy)-11-hydroxy-3-oxo-, chloromethyl ester, (11β,17α)-
Androsta-1,4-diene-17-carboxylic acid, 17-[(ethoxycarbonyl)oxy]-11-hydroxy-3-oxo-, chloromethyl ester, (11β,17α)-
 Loteprednol Etabonate 
CAS Registry Number: 82034-46-6 
CAS Name: (11b,17a)-17-[(Ethoxycarbonyl)oxy]-11-hydroxy-3-oxoandrosta-1,4-diene-17-carboxylic acid chloromethyl ester 
Additional Names: chloromethyl 17a-ethoxycarbonyloxy-11b-hydroxyandrosta-1,4-diene-3-one-17b-carboxylate; 17a-ethoxycarbonyloxy-D¢-cortienic acid chloromethyl ester 
Manufacturers’ Codes: CDDD-5604; HGP-1; P-5604 
Trademarks: Alrex (Bausch & Lomb); Lotemax (Bausch & Lomb) 
Molecular Formula: C24H31ClO7, Molecular Weight: 466.95 
Percent Composition: C 61.73%, H 6.69%, Cl 7.59%, O 23.98% 
Literature References: Ophthalmic corticosteroid. Prepn: N. S. Bodor, BE889563 (1981 to Otsuka); idem,US4996335 (1991). Physicochemical properties: M. Alberth et al.,J. Biopharm. Sci.2, 115 (1991). HPLC determn in plasma and urine: G. Hochhaus et al.,J. Pharm. Sci.81, 1210 (1992). NMR structural studies: S. Rachwal et al.,Steroids61, 524 (1996); idem et al., ibid. 63, 193 (1998). Metabolism and transdermal permeability: N. Bodor et al.,Pharm. Res.9, 1275 (1992). Evaluation of effect on intraocular pressure: J. D. Bartlett et al.,J. Ocul. Pharmacol.9, 157 (1993). Clinical trial in keratoconjunctivitis sicca: S. C. Pflugfelder et al.,Am. J. Ophthalmol.138, 444 (2004). Review of ophthalmic clinical studies: J. F. Howes, Pharmazie55, 178-183 (2000). 
Properties: Crystals from THF + hexane, mp 220.5-223.5°. Soly at 25° (mg/ml): 0.0005 in water; 0.037 in 50% propylene glycol + water. Lipophilicity (log K): 3.04. 
Melting point: mp 220.5-223.5° 
Therap-Cat: Anti-inflammatory (topical). 
Keywords: Glucocorticoid. 
Research Code:HGP-1; CDDD-5604; P-5604Trade Name:Lotemax® / Alrex®MOA:CorticosteroidIndication:Acne rosacea; Superficial punctate keratitis; Postoperative inflammation and pain following ocular surgery; Iritis; Herpes zoster keratitis; Allergic conjunctivitis; CyclitisCompany:Bausch & Lomb (Originator)Sales:ATC Code:S01BA14

Loteprednol etabonate was approved by the U.S. Food and Drug Administration (FDA) on Mar 9, 1998. It was developed and marketed as Lotemax® by Bausch & Lomb.

Loteprednol etabonate is a corticosteroid used in ophthalmology. It is indicated for the treatment of steroid responsive inflammatory conditions of the palpebral and bulbar conjunctiva, cornea and anterior segment of the globe such as allergic conjunctivitis, acne rosacea, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, selected infective conjunctivitides.

Lotemax® is available as drops for ophthalmic use, containing 0.5% of Loteprednol etabonate. The recommended dose is one to two drops into the conjunctival sac of the affected eyes four times daily.

Loteprednol (as the ester loteprednol etabonate) is a corticosteroid used to treat inflammations of the eye. It is marketed by Bausch and Lomb as Lotemax[1] and Loterex.

It was patented in 1980 and approved for medical use in 1998.[2]

Loteprednol Etabonate is the etabonate salt form of loteprednol, an ophthalmic analog of the corticosteroid prednisolone with anti-inflammatory activity. Loteprednol etabonate exerts its effect by interacting with specific intracellular receptors and subsequently binds to DNA to modify gene expression. This results in an induction of the synthesis of certain anti-inflammatory proteins while inhibiting the synthesis of certain inflammatory mediators. Loteprednol etabonate specifically induces phospholipase A2 inhibitory proteins (collectively called lipocortins), which inhibit the release of arachidonic acid, thereby inhibiting the biosynthesis of potent mediators of inflammation, such as prostaglandins and leukotrienes.

Loteprednol etabonate is an etabonate ester, an 11beta-hydroxy steroid, a steroid ester, an organochlorine compound, a steroid acid ester and a 3-oxo-Delta(1),Delta(4)-steroid. It has a role as an anti-inflammatory drug. It derives from a loteprednol.

Loteprednol Etabonate (LE) is a topical corticoid anti-inflammatory. It is used in ophthalmic solution for the treatment of steroid responsive inflammatory conditions of the eye such as allergic conjunctivitis, uveitis, acne rosacea, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, and selected infective conjunctivitides. As a nasal spray, it can be used for the treatment and management of seasonal allergic rhinitis. Most prescription LE products, however, tend to be indicated for the treatment of post-operative inflammation and pain following ocular surgery. A number of such new formulations that have been approved include Kala Pharmaceutical’s Inveltys – the first twice-daily (BID) ocular corticosteroid approved for this indication, designed specifically to enhance patient compliance and simplified dosing compared to all other similar ocular steroids that are dosed four times daily. Moreover, LE was purposefully engineered to be a ‘soft drug’, one that is designed to be active locally at the site of administration and then rapidly metabolized to inactive components after eliciting its actions at the desired location, thereby subsequently minimizing the chance for adverse effects.

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2012-09-28New dosage formLotemaxPostoperative inflammation and pain following ocular surgeryGel0.5%Bausch & Lomb 
2011-04-15New dosage formLotemaxPostoperative inflammation and pain following ocular surgeryOintment0.5%Bausch & Lomb 
1998-03-09First approvalLotemaxAllergic conjunctivitis,Acne rosacea,Superficial punctate keratitis,Herpes zoster keratitis,Iritis,CyclitisSuspension/ Drops0.5%Bausch & Lomb 

More

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2014-11-26Marketing approval露达舒/LotemaxAllergic conjunctivitis,Acne rosacea,Superficial punctate keratitis,Herpes zoster keratitis,Iritis,Cyclitis,Postoperative inflammation and pain following ocular surgerySuspension滴眼剂,0.5%(2.5ml:12.5mg,5ml:25mg)Bausch & Lomb 
2011-11-05Marketing approval露达舒/LotemaxAllergic conjunctivitis,Acne rosacea,Superficial punctate keratitis,Herpes zoster keratitis,Iritis,Cyclitis,Postoperative inflammation and pain following ocular surgerySuspension滴眼剂,0.5%(2.5ml:12.5mg,5ml:25mg); 滴眼剂,0.5%(10ml:50mg,15ml:75mg)Bausch & Lomb

Route 1

Reference:1. US4710495A / US4996335A.Route 2

Reference:1. CN103183714A.

SYN

doi:10.1016/0960-0760(91)90120-T doi: 10.1016/j.steroids.2011.01.006

File:Loteprednol synthesis.png
Clinical data
Trade namesLotemax
Other names11β,17α,Dihydroxy-21-oxa-21-chloromethylpregna-1,4-diene-3,20-dione 17α-ethylcarbonate
AHFS/Drugs.comMicromedex Detailed Consumer Information
Routes of
administration
Eye drops
Drug classCorticosteroidglucocorticoid
ATC codeS01BA14 (WHO)
Legal status
Legal statusUS: ℞-only
Pharmacokinetic data
BioavailabilityNone
Protein binding95%
MetabolismEster hydrolysis
MetabolitesΔ1-cortienic acid and its etabonate
Onset of action≤2 hrs (allergic conjunctivitis)
Elimination half-life2.8 hrs
Identifiers
showIUPAC name
CAS Number82034-46-6 
PubChem CID444025
IUPHAR/BPS7085
DrugBankDB14596 
ChemSpider392049 
UNIIYEH1EZ96K6
KEGGD01689 
ChEBICHEBI:31784 
ChEMBLChEMBL1200865 
CompTox Dashboard (EPA)DTXSID2046468 
ECHA InfoCard100.167.120 
Chemical and physical data
FormulaC24H31ClO7
Molar mass466.96 g·mol−1
3D model (JSmol)Interactive image
Melting point220.5 to 223.5 °C (428.9 to 434.3 °F)
Solubility in water0.0005 mg/mL (20 °C)
showSMILES
showInChI
  (what is this?)  (verify)
wdt-16

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////////////////////////////////////////

Medical uses

Applications for this drug include the reduction of inflammation after eye surgery,[1] seasonal allergic conjunctivitisuveitis,[3] as well as chronic forms of keratitis (e.g. adenoviral and Thygeson’s keratitis), vernal keratoconjunctivitispingueculitis, and episcleritis.[citation needed]

Contraindications

As corticosteroids are immunosuppressive, loteprednol is contraindicated in patients with viralfungal or mycobacterial infections of the eye.[1][3][4]

Adverse effects

The most common adverse effects in patients being treated with the gel formulation are anterior chamber inflammation (in 5% of people), eye pain (2%), and foreign body sensation (2%).[5]

Interactions

Because long term use (more than 10 days) can cause increased intraocular pressure, loteprednol may interfere with the treatment of glaucoma. Following ocular administration, the drug is very slowly absorbed into the blood, therefore the blood level is limited to an extremely small concentration, and interactions with drugs taken by mouth or through any route other than topical ophthalmic are very unlikely.[1]

Pharmacology

Mechanism of action

Main article: Glucocorticoid § Mechanism of action

Pharmacokinetics

Neither loteprednol etabonate nor its inactive metabolites Δ1cortienic acid and Δ1-cortienic acid etabonate are detectable in the bloodstream, even after oral administration. A study with patients receiving loteprednol eye drops over 42 days showed no adrenal suppression, which would be a sign of the drug reaching the bloodstream to a clinically relevant extent.[1]

Steroid receptor affinity was 4.3 times that of dexamethasone in animal studies.[1]

Retrometabolic drug design

Loteprednol etabonate was developed using retrometabolic drug design. It is a so-called soft drug, meaning its structure was designed so that it is predictably metabolised to inactive substances. These metabolites, Δ1-cortienic acid and its etabonate, are derivatives of cortienic acid, itself an inactive metabolite of hydrocortisone.[1][4][6]

  • Cortisol, a naturally occurring corticosteroid, known as hydrocortisone when used as a drug
  • Δ1-Cortienic acid, inactive metabolite of loteprednol
  • Cortienic acid, inactive metabolite of hydrocortisone

Chemistry

Loteprednol etabonate is an ester of loteprednol with etabonate (ethyl carbonate). The pure chemical compound has a melting point between 220.5 °C (428.9 °F) and 223.5 °C (434.3 °F). Its solubility in water is 1:2,000,000,[4] therefore it is formulated for ophthalmic use as either an ointment, a gel, or a suspension.[7]

Loteprednol is a corticosteroid. The ketone side chain of classical corticosteroids such as hydrocortisone is replaced by a cleavable ester, which accounts for the rapid inactivation.[8] (This is not the same as the etabonate ester.)

Hydrocortisone

Loteprednol etabonate

Chemical synthesis

 

 [9]

References

  1. Jump up to:a b c d e f g Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  2. ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 488. ISBN 9783527607495.
  3. Jump up to:a b Loteprednol Professional Drug Facts.
  4. Jump up to:a b c Dinnendahl V, Fricke U (2008). Arzneistoff-Profile (in German). 6 (22 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.
  5. ^ “Highlights of Prescribing Information: Lotemax” (PDF). 2012.
  6. ^ Bodor N, Buchwald P (2002). “Design and development of a soft corticosteroid, loteprednol etabonate”. In Schleimer RP, O’Byrne PM, Szefler SJ, Brattsand R (eds.). Inhaled Steroids in Asthma. Optimizing Effects in the Airways. Lung Biology in Health and Disease. 163. Marcel Dekker, New York. pp. 541–564.
  7. ^ “Loteprednol (Professional Patient Advice)”. Retrieved October 4, 2018.
  8. ^ Pavesio CE, Decory HH (April 2008). “Treatment of ocular inflammatory conditions with loteprednol etabonate”. The British Journal of Ophthalmology92 (4): 455–9. doi:10.1136/bjo.2007.132621PMID 18245274S2CID 25873047.
  9. ^ Druzgala P, Hochhaus G, Bodor N (February 1991). “Soft drugs–10. Blanching activity and receptor binding affinity of a new type of glucocorticoid: loteprednol etabonate”. The Journal of Steroid Biochemistry and Molecular Biology38 (2): 149–54. doi:10.1016/0960-0760(91)90120-TPMID 2004037S2CID 27107845.

Further reading

  • Stewart R, Horwitz B, Howes J, Novack GD, Hart K (November 1998). “Double-masked, placebo-controlled evaluation of loteprednol etabonate 0.5% for postoperative inflammation. Loteprednol Etabonate Post-operative Inflammation Study Group 1”. Journal of Cataract and Refractive Surgery24 (11): 1480–9. doi:10.1016/s0886-3350(98)80170-3PMID 9818338S2CID 24423725.

////////////loteprednol etabonate

CCOC(=O)OC1(CCC2C1(CC(C3C2CCC4=CC(=O)C=CC34C)O)C)C(=O)OCCl

wdt-9

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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 LIFE SCIENCES 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 PLUS year tenure till date June 2021, 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, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, 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 33 lakh plus views on New Drug Approvals Blog in 233 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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