Age Related Nuclear Cataract Treatment

Age Related Nuclear Cataract interferenceP750 LOGBOOK 5 STUDENT ID 6469969Age related nuclear cataract is the anterior portion sickness and it is the clouding of ocular lens characterized by reduced antioxidant levels in the lens core. Antioxidant cystine is a amino bitter having molecular(a) lading 240.3 g/mol and solubility of 50 mg/ml in 1 M Hcl is used to prevent cataract mixtureation.To treat cataract, cystine is utilise topically in the invent of eye put downs. The factors that reduce cystine bioavailability ar,Tear film - Topically applied medicines get out head start encounter file film and it is considered as first protective structure.Nasolacrimal drainage system - After the application cystine eye drops tear fluid turnover doubles it is called as washout effect. Due to pH and foreign body sensation reflex tearing volition occur.Cornea - It is the main(prenominal) mechanical barrier. Due to its sandwich like structure drugs with molecular weight less than 5 K Da and partition coefficient of 10 to century can pass through it. Cornea is composed of three points, the outermost layer is epithelium which is lipophilic in nature, middle layer is stroma which is hydrophilic in nature and innermost layer is endothelium which is lipophilic in nature.FORMULATION PARAMETERS The aspect parameters to be considered in framingulating a topical cystine eye drops be,Physico chemical drug properties -Partition coefficient log p of the formulation should string from 10 to 100. molecular weight molecular weight of the formulation should be less than 5 K Da.Charge charge of the drug should be validating.Buffer capacity and pH - eye drops should be formulated with a pH range of 7.0 to 7.7.If the pH is 7, 99% of the drug remains in unionized form and favors the permeation through lipophilic epithelium.If the pH is more than 7, most of the drug ionizes and easily diffuses through the hydrophilic stroma.Viscosity viscosity of the eye drop prep aration must be around 15 m Pa. instilment volume - instillation volume must be less than 30 l because cul de sac can hold up to 30 l.Osmotic pressure - osmotic pressure of the eye drop must range between 310 to 350 m osm/kgAntioxidants - cystine itself acts as a antioxidant, no other preservatives ar required.FORMULATION APPROACH Colloidal ocular speech communication systems like micro emulsions are used to deliver the antioxidant cystine in the form of topical eye drops.Micro emulsions Micro-emulsions acts as vehicles for the delivery of antioxidant cystine in the form of topical eye drops.In micro emulsions kind transition will occur between the bi-continuous micro-emulsion, oil in wet emulsion, water in oil emulsion, and lamellar crystals.Components of micro emulsions are,Water.Oils like mineral oil, vegetable oils, di and triglycerides, fatty acid ester.Surfactant non ionic, amphoteric and less commonly anionic and cationic surfactants are used.Co-surfactant short a nd medium chain alcohols are used as co-surfactants.Advantages of phase transitions of micro-emulsionsW/O micro -emulsion these micro-emulsions are responsible for protection of water soluble drugs and sustained release of water soluble drugs.O/W micro-emulsions - these micro-emulsions are responsible for increasing solubility of lipophilic drugs.Bi-continuous micro-emulsions - these micro-emulsions are having safe(p) wetting and spreading properties on the ocular surface hence these are used in ocular drug delivery systems.Micro-emulsions are having offset viscosity hence it is delicate to instill.These micro-emulsions are thermodynamically stable.These are easy to prepare, no mixing is required.In these micro-emulsions we can detect the phase time interval easily, drug precipitation and microbial contamination.Micro-emulsions are used as vehicles payable to solubilization of hydrophilic and lipophilic drugs.By using the micro-emulsions as vehicles we can annex the bio-avail ability of drugs.Glaucoma is anterior segment disease characterized by raised intra ocular pressure, which results in the loss of regional ganglia cells and degeneration of optic nerve. Glaucoma is the main ocular disease responsible for blindness. Antisense oligonucleotides (As ODN) helps in curing glaucoma disease.Antisense oligonucleotides (As ODN) These are single stranded deoxyribonucleic acid fragments of 10 to 30 nucleotides, complementary to the target template RNA.Mechanism of action Generally, desoxyribonucleic acid transcripts mRNA in the nucleus and this mRNA enters into the cytoplasm and ribosomes translate the mRNA. at long last results in the formation of proteins. Antisense oligonucleotides (As ODN) having complementary base sequence to that of mRNA binds with mRNA and prevents the formation of Cx proteins from it.Delivery despatch I would like to discern intra-vitreous delivery route because, periocular snaps of antisense oligonucleotides is responsible fo r poor stability and it is difficult for antisense oligonucleotides to click through the cells.Intra-vitreous injection It is the injection of antisense oligonucleotides into the vitreous with the help of a needle. In the treatment of many of the ocular diseases intra-vitreous administration of drugs is used.Advantages of intra-vitreous injection This delivery route is responsible for achieving high concentration of drug in the vitreous.There will be no side effects, because it is not a systemic administration. damages of intra-vitreous injection From the vitreous, many drugs are rapidly cleared due to blood retinene barrier, therefore repeated dose administration is required.Frequent injections leads to endopthalmitis, lens damage, breakup of retina.FORMULATION PARAMETERS -Chemical modification chemical modification of antisense oligonucleotides leads to increased or decreased solubility, stability etc..Phospho-diester assembly -By replacing oxygen from the phospho-dieste r group with sulphur, stability and solubility increases and RNase H cleavage will occur.By replacing oxygen with methyl group there is increased stability but decrease in solubility, due to lack of charge cellular uptake will not occur, no RNase H activity. net moiety modification -By adding a alkyl group at the 2nd position of ribose, there is increase in hydrophilicity and binding likeness but mismatches will occur and no RNase H cleavage. otherwise modification -Replacement of phospho-diester group with polyamide results in high similitude to mRNA but aqueous solubility decreases, cellular uptake decreases and no RNase H cleavage.FORMULATION APPROACH -To prevent antisense oligonucleotides (As ODN) from enzymatic humiliation and to improve the cellular uptake a variety of formulation approaches deem been put forward. They are, liposomes, nanoparticles, peptides, dendrimers, and physical methods. Among these i would like to choose multi functional dendrimer carriers.Dendrimer carriers -Dendrimers are branched molecules and spherical in nature. Dendrimers are divided into low molecular weight and high molecular weight species. The properties of dendrimers depends on the functional groups at their molecular level. Dendrimers are cationic in nature and possess positive charge on it.Antisense oligonucleotides shows its therapeutic effect at cytoplasmic level and these antisense oligonucleotides are anionic in nature and possess negative charge. During the formulation, dendrimer undergoes complexation and abridgement with antisense oligonucleotides. The functional groups present at the molecular level are.Cell stabbing peptide -TAT peptide is derived from human immunodeficiency virus and it acts as a cell precipitous peptide. TAT helps in cellular uptake of dendrimer antisense oligonucleotide complex.Fusogenic peptide -Dendrimer- antisense oligonucleotide complex binds to the cell tissue layer than enters in to the cell through endocytosis. These fusogenic peptide helps in endisomal escape. Influenza virus hemagglutinin subunit-2 is a fusogenic peptide.Lipoamino acid -This functional group helps in improving permeability and stability. Example, C14Disadvantage of dendrimer carrier cytotoxicity increases due to the presence of cell penetrating peptides and fusogenic peptidesREFERENCE -Dr Ilva Rupenthal yack away notes given on 4th April 2014.