RIBOFLAVIN

Documentazione distribuita da A.I.CHE. - Associazione Italiana CHEratoconici ONLUS (www.assocheratocono.org)RIBOFLAVINOPHTHALMIC MEDICAL DEVICEEdoardo Stagni, MDSIENA X-LINKING: I° CORSO NAZIONALE ABILITANTE, SIENA 2 FEBBRAIO 2007

Documentazione distribuita da A.I.CHE. - Associazione Italiana CHEratoconici ONLUS (www.assocheratocono.org)RICROLIN(RIBOFLAVIN0,1%)RICROLIN is anophthalmic drug (drops)used for a newtherapeutical procedure:the corneal collagencross-linkingfor thetreatment of keratoconusand secondary cornealectasias

Documentazione distribuita da A.I.CHE. - Associazione Italiana CHEratoconici ONLUS (www.assocheratocono.org)RIBOFLAVIN(VIT. B2)• Was discovered in 1927 byPaul Gyorgy and it wassynthesized by RichardKuhn in 1935.• Initially it was calledLactoflavin, because of itshigh concentration in milk.• Successively a ribitolmolecule was found andthe name of Vit. B2 waschanged in Riboflavin.

Documentazione distribuita da A.I.CHE. - Associazione Italiana CHEratoconici ONLUS (www.assocheratocono.org)RIBOFLAVIN(VIT. B2)• Riboflavin is anheterocyclic mixturederived from anisoallosazine moleculelinked with a ribitolchain.• It’s s a yellow substancebarely soluble in water,it is heating resistantand highly fluorescentwhen excited by UVlight.

Documentazione distribuita da A.I.CHE. - Associazione Italiana CHEratoconici ONLUS (www.assocheratocono.org)RIBOFLAVIN(VIT. B2)• Riboflavin is widely representedin nature, and is found in mammaliantissues as a coenzymatic form.• Riboflavin is involved in manymethabolic reactions.• It looses its vitaminic properties (ribitolradical detachment) during a lightexposure when a photolitic reactionoccurs.

Documentazione distribuita da A.I.CHE. - Associazione Italiana CHEratoconici ONLUS (www.assocheratocono.org)• Composition:100 ml of solution contains:Riboflavin phosphate 0,125 gDextran T50020 gExcipient : dihydrateRICROLIN(RIBOFLAVIN0,1%)dihydrate monobasic phosphate sodium, dihydratedibasic phosphate sodium, sodium chloride, water for injectablesolution q.b. a 100 g• Tonicity:slightly hypotonic ophthalmic solution (290mOsm/l)• pH: 7,25.• RICROLIN is preservative free

Documentazione distribuita da A.I.CHE. - Associazione Italiana CHEratoconici ONLUS (www.assocheratocono.org)RICROLINRIBOFLAVIN 0,1%StabilityAccelerated stability tests at 5months (20months of ordinarystability) show a Riboflavin titreabove 97%, in accordance withthe Good Laboratory Practice.

Documentazione distribuita da A.I.CHE. - Associazione Italiana CHEratoconici ONLUS (www.assocheratocono.org)RICROLINRIBOFLAVIN 0,1%• RICROLIN ophthalmic solution is sterile,according to current GLP rules.• RICROLIN is a Medical Device (CE0373)

Documentazione distribuita da A.I.CHE. - Associazione Italiana CHEratoconici ONLUS (www.assocheratocono.org)RICROLIN(RIBOFLAVIN0,1%)PropertiesRiboflavin, combined with UV-A A light,generate a photo-polymerizyingpolymerizying effect oncorneal collagen. The increase in rigidityof the corneal structure is due to theformation of new links between collagenfibers. This is the base of cross-linkingtreatment.

Documentazione distribuita da A.I.CHE. - Associazione Italiana CHEratoconici ONLUS (www.assocheratocono.org)The Cross-Linkingof collagen• In 90’ started research of the“biologicalglue” activable by thermicor light sources and able to increasethe resistance of stromal collagen.These studies showed that the linkingaction was due to an oxidativemechanism induced by the release ofoxyhydrilic free radicals.

Documentazione distribuita da A.I.CHE. - Associazione Italiana CHEratoconici ONLUS (www.assocheratocono.org)• The clinical evidence that diabeticpatients are rarely affected bykeratoconus supported these studies.In affected patients the natural cross-linking effect of glucose produces anincrease of corneal resistance(Maillard’s reaction).• An increase in corneal resistance, dueto natural collagen glycosilation,occurs also with ageing.

Documentazione distribuita da A.I.CHE. - Associazione Italiana CHEratoconici ONLUS (www.assocheratocono.org)Cross-Linkingtypes• Enzymatic Cross-linkinglinking:-thephysiological cross-linkingis performed byLysyl-oxidaseenzyme-theAGEs (AdvancedGlycation Endproducts) areliable for cross-linkingin diabetes• Chemical Cross-linkinglinking:-glutaraldehyde, formaldehyde• Photochemical Cross-linkinglinking:-UVrays, ionizing radiation• Photo-oxidativeoxidative Cross-linkinglinking:-RIBOFLAVIN- UVA

Documentazione distribuita da A.I.CHE. - Associazione Italiana CHEratoconici ONLUS (www.assocheratocono.org)RICROLINROLE OF RIBOFLAVIN in Cross-Linkingtreatment1. Absorption of UV radiation2. Photo-sensitizingagent: production ofreactive oxygen species3. Corneal endothelium and other eyestructures protection

Documentazione distribuita da A.I.CHE. - Associazione Italiana CHEratoconici ONLUS (www.assocheratocono.org)RICROLINROLE OF RIBOFLAVIN in Cross-LinkingtreatmentThe parameters currently used does not leadto any risk to the corneal endothelium [0,1%Riboflavin reduces UV intensity up to 95% % (0,15(mw/cmcm2)]Without Riboflavin the UV absorption of almost30% by the endothelium and 50% by the lenswas measured.

Documentazione distribuita da A.I.CHE. - Associazione Italiana CHEratoconici ONLUS (www.assocheratocono.org)RICROLINROLE OF RIBOFLAVIN in Cross-LinkingtreatmentCross-linkingeffects are directed to theanterior cornea because of Riboflavin highUV-A absorption capacity.Thus corneal endothelium, lensand retina will be protected

Documentazione distribuita da A.I.CHE. - Associazione Italiana CHEratoconici ONLUS (www.assocheratocono.org)RICROLINROLE OF T 500 DEXTRANRICROLIN contains Dextran T 500 20%(500.000000 D) that:1. Maintains the osmolarity:– Corneal stroma: 380-420mosmol/l– Riboflavin solution 0,1% - Dextran T 500 20%:400 mosmol/l2. Avoids corneal soaking and swelling duringthe treatment

Documentazione distribuita da A.I.CHE. - Associazione Italiana CHEratoconici ONLUS (www.assocheratocono.org)RICROLINIndicationRICROLIN associated to an UV-A rays source issuitable for the parasurgical treatment of:•Progressivekeratoconus•Cornealectasias

Documentazione distribuita da A.I.CHE. - Associazione Italiana CHEratoconici ONLUS (www.assocheratocono.org)RICROLINIndicationThe administration of both Ricrolin and UV-Arays induces a decrease in keratoconusprogression, thus preventing a cornealtransplantation(howevernot excluded in future)

Documentazione distribuita da A.I.CHE. - Associazione Italiana CHEratoconici ONLUS (www.assocheratocono.org)RICROLINMethods of use• 5-10minutes before irradiation, instill severaltimes RICROLIN ophthalmic solution with theproper syringe-dispenser• During the treatment with UV-A, administerRICROLIN every 5 minutes, for an overalltime of 30 minutes.

Documentazione distribuita da A.I.CHE. - Associazione Italiana CHEratoconici ONLUS (www.assocheratocono.org)RICROLINSide effects and contraindications• RICROLIN is contraindicated in case ofhypersensitivity to any drug component orany chemically correlated substances.• No side effects (neitherocular nor systemic)have been reported• No systemic toxic side effects have beenreported in case of exceeding or prolongedintake. The absorption of riboflavin is indeeda saturable biological system (upto 25 mg)and, moreover, it exists a maximum tresholdfor its body storage.

Documentazione distribuita da A.I.CHE. - Associazione Italiana CHEratoconici ONLUS (www.assocheratocono.org)RICROLINPrecautions• RICROLIN should be stored with atemperature range between +4 and+8 °C.• RICROLIN is sterile and disposable.• RICROLIN is a product for externalocular usage

Documentazione distribuita da A.I.CHE. - Associazione Italiana CHEratoconici ONLUS (www.assocheratocono.org)RICROLINPrecautions• Don’t touch ocular surface with theneedle to avoid any risk ofcontamination• Don’t use the product 1 hour afterthe opening.• Keep away from light.• Don’t use the drug after its expirationdate or if the container is damaged.

Documentazione distribuita da A.I.CHE. - Associazione Italiana CHEratoconici ONLUS (www.assocheratocono.org)