Drug Targeting to Particular Organs Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D Department of Pharmaceutics KLE University College of Pharmacy, BELGAUM-590010, Karnataka, India. Cell No.: 0091-9742431000 E-mail: [email protected]28 February 2013 1 DDSEC, Prince of Songkla University, Hat Yai, Thailand.
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Drug Targeting to Particular Organs Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D Department of Pharmaceutics KLE University College of Pharmacy, BELGAUM-590010,
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Drug Targeting to Particular Organs
Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D
Department of PharmaceuticsKLE University College of Pharmacy,BELGAUM-590010, Karnataka, India.
28 February 2013 1DDSEC, 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 2013 2DDSEC, 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 2013 3DDSEC, 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 2013 4DDSEC, 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 2013 6DDSEC, 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 2013 7DDSEC, 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 2013 11DDSEC, 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 2013 13DDSEC, 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 2013 15DDSEC, Prince of Songkla University, Hat Yai, Thailand.
Targeted delivery to the Respiratory
System
28 February 2013 16DDSEC, 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 2013 18DDSEC, 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 product28 February 2013 19DDSEC, Prince of Songkla University, Hat Yai, Thailand.
Drug Targeting
28 February 2013 20DDSEC, Prince of Songkla University, Hat Yai, Thailand.
Avoiding injections
Bioavailability withoutPromoter
Bioavailability withPromoter
Nasal 2 5–40
Rectal 3 40
Buccal 0.7 25
Conjunctival 0.3–6.6 40
Pulmonary 8–30 100
28 February 2013 21DDSEC, Prince of Songkla University, Hat Yai, Thailand.
Different Types of Targeting
28 February 2013 22DDSEC, Prince of Songkla University, Hat Yai, Thailand.
Drug Delivery to Brain
28 February 2013 23DDSEC, 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 2013 24DDSEC, Prince of Songkla University, Hat Yai, Thailand.
Blood Brain Barrier
28 February 2013 25DDSEC, 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.
28 February 2013 26DDSEC, Prince of Songkla University, Hat Yai, Thailand.
Drug Targeting in the Brain Areas
28 February 2013 27DDSEC, 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 2013 28DDSEC, Prince of Songkla University, Hat Yai, Thailand.
Transport of molecules across the BBB
28 February 2013 29DDSEC, 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 2013 31DDSEC, 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 2013 32DDSEC, Prince of Songkla University, Hat Yai, Thailand.
Motivation
28 February 2013 33DDSEC, Prince of Songkla University, Hat Yai, Thailand.
Blood Brain Barrier Transport Mechanism
28 February 2013 34DDSEC, Prince of Songkla University, Hat Yai, Thailand.
Drug Delivery to Eye
28 February 2013 35DDSEC, Prince of Songkla University, Hat Yai, Thailand.
Anatomy of the Eye
28 February 2013 36DDSEC, 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 vision28 February 2013 37DDSEC, 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 2013 38DDSEC, 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 2013 39DDSEC, Prince of Songkla University, Hat Yai, Thailand.