Drug Targeting to Particular Organs Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D Department of...

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.

Cell No.: 0091-9742431000E-mail: [email protected]

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.


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.


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.


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


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.


Monodisperse particles


Mono and Polydisperse particles


Targeting Combined regions


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.


Hydrophobic 1µm particles


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.


Gas composition


Emerging Carriers for Respiratory Drug

Delivery

• Nanoparticle Formulations for Inhalation

• Vaccine delivery

• Gene therapy


Targeted delivery to the Respiratory

System


Liposomes as drug delivery systems to alveolar

macrophage


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


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


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


Different Types of Targeting


Drug Delivery to Brain


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.


Blood Brain Barrier


Drug Targeting to Brain

• To bypass the BBB and to deliver therapeutics into the brain, three different approaches are currently used.

1.Invasive approach2.Pharmacological approach3.Physiological approach


Drug Targeting in the Brain Areas


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.


Transport of molecules across the BBB


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).


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


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


Motivation


Blood Brain Barrier Transport Mechanism


Drug Delivery to Eye


Anatomy of the Eye


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.



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



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


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


Classification

Mucoadhesive dosage forms

Ocular inserts

Collagen shield

Drug presoaked hydrogel type contact lens

Ocular iontophoresis

Polymeric solutions


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


Drug targeting to Neoplastic Diseases


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.


Cancer Treatments • Tumor penetration is a key issue for successful

chemotherapy


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.


Nanoparticle Targeting and Accumulation

• To maximize their effectiveness, the microenvironment of the tumor must be quantified and vectors developed to specifically target the tumor.

NecroticQuiescentProliferating

Therapeutic


Thank YouThank YouE-mail: [email protected]

Cell No: 00919742431000


Drug Targeting to Particular Organs Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D Department of...

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