Drug Targeting to Particular Organs Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D Department of Pharmaceutics KLE University College of Pharmacy, BELGAUM , Karnataka, India. Cell No.: February 20131DDSEC, Prince of Songkla University, Hat Yai, Thailand.

CONTENT Drug Delivery to respiratory system. Problems of drug delivery to the brain and targeting to brain. Drug delivery to Eye. Drug targeting in Neoplastic diseases. 28 February 20132DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Targeting all respiratory system Dosing to the complete respiratory system has previously only been possible by special nebulizer. Dosing to the complete respiratory system has only been regarded as an option for a very narrow range of therapeutics. 28 February 20133DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Pulmonary dose + Nasal dose Delivery to both nasal and pulmonary airways, it will be possible to target the complete airway system. Two separate formulation technologies for reaching nasal airways and for the pulmonary airways. Nasal delivery and pulmonary delivery places each their requirements on the powder formulation characteristics. 28 February 20134DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Targeting Lung Regions Extrathoracic and alveolar regions can effectively be targeted with mono- and polydisperse aerosols respired steadily. Effective targeting of the bronchial region can only be achieved with bolus inhalations. When particles are suspended in a gas heavier than air, targeting the alveolar region can be enhanced. 28 February 2013 DDSEC, Prince of Songkla University, Hat Yai, Thailand. 5

Targeting Lung Regions Optimization Particle and Breathing Parameters Bolus Inhalation Gas Composition 28 February 20136DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Optimization Particle and Breathing Parameters Targeting extrathoracic, upper bronchial, lower bronchial, and alveolar region for steady state breathing of aerosols. The targeting efficiency can be increased for mono-as well as polydisperse aerosols to more than 90% by combining extrathoracic and upper bronchial regions and lower bronchial and alveolar regions. 28 February 20137DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Monodisperse particles 28 February 2013 DDSEC, Prince of Songkla University, Hat Yai, Thailand. 8

Mono and Polydisperse particles 28 February 2013 DDSEC, Prince of Songkla University, Hat Yai, Thailand. 9

Targeting Combined regions 28 February 2013 DDSEC, Prince of Songkla University, Hat Yai, Thailand. 10

Bolus Inhalation Boluses are very suitable for targeting as long as the particle sizes and breathing patterns are used. Particles 1 μm in size are ideal for this purpose because of their very low deposition on their way to the targeted region and their large deposition in the small peripheral lung structures during breath-holding. 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Hydrophobic 1µm particles 28 February 2013 DDSEC, Prince of Songkla University, Hat Yai, Thailand. 12

Gas Composition The particle-loaded inhaled gas is heavier (lighter) than air, particles penetrate deeper (less deep) into the lungs. Deposition occurs deeper in the lungs when particle-loaded sulphox rather than particle loaded heliox is inhaled. 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Gas composition 28 February 2013 DDSEC, Prince of Songkla University, Hat Yai, Thailand. 14

Emerging Carriers for Respiratory Drug Delivery Nanoparticle Formulations for Inhalation Vaccine delivery Gene therapy 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Targeted delivery to the Respiratory System 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Liposomes as drug delivery systems to alveolar macrophage 28 February 2013 DDSEC, Prince of Songkla University, Hat Yai, Thailand. 17

Protein and Peptide Drugs to the Respiratory System Improving the transport of the drug to its site of action Improving the stability of the drug in vivo Prolonging the residence time of the drug at its site of action by reducing clearance Decreasing the nonspecific delivery of the drug to non-target tissues 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Protein and Peptide Drugs to the Respiratory System Decreasing irritation caused by the drug Decreasing toxicity due to high initial doses of the drug Altering the immunogenicity of the protein Improving taste of the product Improving shelf life of the product 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Drug Targeting 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Avoiding injections Bioavailability without Promoter Bioavailability with Promoter Nasal25–40 Rectal340 Buccal0.725 Conjunctival0.3–6.640 Pulmonary8– February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Different Types of Targeting 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Drug Delivery to Brain 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Problems of Drug Delivery to the Brain The relative impermeability of the BBB results from tight junctions between capillary endothelial cells which are formed by cell adhesion molecules. Approximately 98% of the small molecules and nearly all large molecules (mwN1 kD, kilodaltons), such as recombinant proteins or gene-based medicines do not cross the BBB. 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Blood Brain Barrier 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Drug Targeting to Brain To bypass the BBB and to deliver therapeutics into the brain, three different approaches are currently used. 1.Invasive approach 2.Pharmacological approach 3.Physiological approach 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Drug Targeting in the Brain Areas 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Pharmacological approach Pharmacological approach consists of modifying, through medicinal chemistry, a molecule that is known to be active against a CNS target to enable it to penetrate the BBB. Modification of drugs through a reduction in the relative number of polar groups increases the transfer of a drug across the BBB. Lipid carriers have been used for transport. 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Transport of molecules across the BBB 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Pharmacological approach Formulation of drugs facilitates brain delivery by increasing the drug solubility and stability in plasma Limitations: The modifications necessary to cross the BBB often result in loss of the desired CNS activity. Increasing the lipophilicity of a molecule to improve transport can also result in making it a substrate for the efflux pump P-glycoprotein (P- gp). 28 February 2013 DDSEC, Prince of Songkla University, Hat Yai, Thailand. 30

Physiological approach Physiological approach is recognized by the scientific community as the onewith the most likely chance of success. Transporter-mediated delivery Receptor-mediated transcytosis Receptors at the blood–brain barrier 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Physiological approach Transferrin receptor (TR) Insulin receptor Liposomes coated with targeting molecules such as antibodies, Trojan Horses Liposomes (THL) Nanoparticles coated with transferrin or transferrin receptor antibodies 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Motivation 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Blood Brain Barrier Transport Mechanism 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Drug Delivery to Eye 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Anatomy of the Eye 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Drug Delivery to Eye  Ophthalmic preparation  Applied topically to the cornea, or instilled in the space between the eyeball and lower eyelid  Solution Dilutes with tear and wash away through lachrymal apparatus Administer at frequent intervals  Suspension Longer contact time Irritation potential due to the particle size of drug  Ointment Longer contact time and greater storage stability Producing film over the eye and blurring vision 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

 Emulsions Prolonged release of drug from vehicle but blurred vision, patient non compliance and oil entrapment are the drawbacks.  Gels Comfortable, less blurred vision but the drawbacks are matted eyelids and no rate control on diffusion. Drug Delivery to Eye 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

 Controlled delivery system – Release at a constant rate for a long time – Enhanced corneal absorption – Drug with not serious side effect or tolerate by the patient Drug Delivery to Eye 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Advantages  Increase ocular residence, hence, improving bioavailability.  Possibility of providing a prolonged drug release and thus a better efficacy.  Lower incidence of visual and systemic side effects.  Increased shelf life with respect to aqueous solutions.  Exclusion of preservatives, thus reducing the risk of sensitivity reactions 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

 Possibility of targeting internal ocular tissue through non-corneal routes  Reduction of systemic side effects and thus reduced adverse effects.  Reduction of the number of administration and thus better patient compliance.  Administration of an accurate dose in the eye, which is fully retained at the administration site, thus a better therapy. Advantges 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Classification Mucoadhesive dosage forms Ocular inserts Collagen shield Drug presoaked hydrogel type contact lens Ocular iontophoresis Polymeric solutions 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Ocular penetration enhancers Phase transition systems Particulate system like, microspheres and nanoparticles Vesicular systems like liposomes, niosomes, phamacosomes and discosomes Chemical delivery system for ocular drug targeting Classification 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Drug Delivery to Eye 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Drug targeting to Neoplastic Diseases 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Targeted Delivery to Tumors Goal is to inject treatment far from tumor and have large accumulation in tumor and minimal accumulation in normal cells/organs. 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Cancer Treatments Tumor penetration is a key issue for successful chemotherapy 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Nanoparticle use in Cancer Treatments Because of their small size, nanoparticles can pass through interstitial spaces between necrotic and quiescent cells. Tumor cells typically have larger interstitial spaces than healthy cells Particles collect in center bringing therapeutics to kill the tumor from inside out. 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Nanoparticle Targeting and Accumulation To maximize their effectiveness, the microenvironment of the tumor must be quantified and vectors developed to specifically target the tumor. Necrotic Quiescent Proliferating Therapeutic 28 February DDSEC, Prince of Songkla University, Hat Yai, Thailand.

Thank You Cell No: February DDSEC, Prince of Songkla University, Hat Yai, Thailand.