Drug Delivery System A Challenge for New Therapeutic

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Drug Delivery System "A Challenge" for New Therapeutic Era 5 th International Conference and

Drug Delivery System "A Challenge" for New Therapeutic Era 5 th International Conference and Exhibition on Pharmaceutics & Novel Drug Delivery Systems March 16 -18, 2015 Crowne Plaza, Dubai, UAE Dr. B. B. Barik, Professor, Dept. of Pharmaceutics College of Pharmacy, Jazan University, Kingdom of Saudi Arabia. E-mail: bbbarik 2003@gmail. com

NOVEL Drug Delivery Challenges: Delivering the drug at the right place, at the right

NOVEL Drug Delivery Challenges: Delivering the drug at the right place, at the right concentration for the right period of time. Goal: to deploy medications intact to specifically target parts of the body. Obstacles: large molecules, low solubility, instability in the formulation, degradation in the biological system, rapid clearance , toxicity, inability to cross biological barriers, bioavailability & biodistribution etc. Sophistication: The association of the drug with a carrier. Advances: Micro- and nanotechnology

Why is Novel DDS needed Ø Controlled drug delivery Ø Targeted drug delivery Ø

Why is Novel DDS needed Ø Controlled drug delivery Ø Targeted drug delivery Ø Maximum efficacy with minimum side effects Ø Optimize drug’s therapeutic effect, convenience & dose Ø To enhance a product life- cycle Ø Improve patient compliance Ø Control over all healthcare cost

Need for new drug delivery systems Controlled release/ Targeted delivery Individual ized therapy Drug

Need for new drug delivery systems Controlled release/ Targeted delivery Individual ized therapy Drug absorption, distribution and metabolism vary among individuals

Various types of Drug delivery Conventio nal/Oral Injection based Transd ermal Carrier based Controlled/

Various types of Drug delivery Conventio nal/Oral Injection based Transd ermal Carrier based Controlled/ Targeted DDS

Oral Drug delivery systems

Oral Drug delivery systems

Injection based Drug delivery system • Provide fast systemic effects bypassing firstpass metabolism •

Injection based Drug delivery system • Provide fast systemic effects bypassing firstpass metabolism • Drugs can be administered in unconscious or comatose patients • Drugs having short halflife can be infused continuously

Transdermal Drug delivery system • Adhesive patches containing the drug are applied on the

Transdermal Drug delivery system • Adhesive patches containing the drug are applied on the skin • The drug crosses the skin surface by diffusion by percutaneous absorption and goes into systemic circulation • Bypasses first-pass hepatic inactivation

Transderm-SCOP (Scoplamine) Used for motion sickness Hydrogel transdermal patch: Used in treatment of burns

Transderm-SCOP (Scoplamine) Used for motion sickness Hydrogel transdermal patch: Used in treatment of burns

Thin film drug delivery • GI specific drugs Oral drug strips to administer drugs

Thin film drug delivery • GI specific drugs Oral drug strips to administer drugs via absorption through buccal or sublingual route Hydrogels: (a)hydrogel preparation (b) After imbibition

Osmotic pressure controlled system

Osmotic pressure controlled system

Inhalation/Pulmonary Drug delivery system • Inspiration through the nose or mouth • Alveolar epithelium

Inhalation/Pulmonary Drug delivery system • Inspiration through the nose or mouth • Alveolar epithelium offers good surface area especially for lipid -soluble drugs • The drugs are also excreted by this route

Inhalational drug delivery system �Fastest growing drug delivery system Delicate molecules allowing systemic administration

Inhalational drug delivery system �Fastest growing drug delivery system Delicate molecules allowing systemic administration without degradation Offer flexibility for multiple formulations from nasal drop to suspension spray Good ranging for sight specific delivery of bio tech products such as insulin and other hormones

Approaches for Controlled Drug Delivery: - Reservoir Systems with a Rate Controlling Membrane -

Approaches for Controlled Drug Delivery: - Reservoir Systems with a Rate Controlling Membrane - Monolithic Systems - Laminated Systems - Chemical Systems Approaches for Targeted Delivery: - Local Targeted Delivery - Differential Metabolism Approach - Biological Recognition - Bio-physical Approach - Prodrugs

Types of polymers used for controlled release

Types of polymers used for controlled release

Swelling controlled drug delivery system Hydrogels are three dimensional networks of hydrophilic polymers that

Swelling controlled drug delivery system Hydrogels are three dimensional networks of hydrophilic polymers that are insoluble in water at a physiological temperature and p. H but swells.

Preparation of Hydrogels

Preparation of Hydrogels

Drug absorption barriers in the intestine Mucosal absorption of protein-based pharmaceuticals is highly inefficient

Drug absorption barriers in the intestine Mucosal absorption of protein-based pharmaceuticals is highly inefficient as these large molecular weight compounds do not efficiently cross the epithelial surfaces

Parameter for drug selection Parameter : Preferred value Molecular weight/ size: < 1000 Solubility:

Parameter for drug selection Parameter : Preferred value Molecular weight/ size: < 1000 Solubility: > 0. 1 µg/ml for p. H 1 to p. H 7. 8 Pka Non ionized moiety: > 0. 1% at p. H 1 to p. H 7. 8 Apparent partition coefficient: High Absorption mechanism: Diffusion General absorbability: From all GI segments Release: Should not be influenced by p. H and enzymes

PHARMACOKINETIC PARAMETER FOR DRUG SELECTION Parameter Elimination half life: Total clearance: dependent Elimination rate

PHARMACOKINETIC PARAMETER FOR DRUG SELECTION Parameter Elimination half life: Total clearance: dependent Elimination rate constant: Apparent vol of distribution (Vd): larger Absolute bioavailability: Intrinsic absorption rate: rate Therapeutic concentration Css av: Toxic concentration: Comment Preferably between 0. 5 and 8 h Should not be dose Required for design The larger Vd and MEC, the will be the required dose size. Should be 75% or more Must be greater than release The lower Css av and smaller Vd, the loss among of drug required Apart the values of MTC and MEC, safer the dosage form.

Carrier based drug delivery system

Carrier based drug delivery system

Targeted Drug Delivery

Targeted Drug Delivery

Monoclonal antibodies m. Abs act directly when binding to a cancer specific antigen and

Monoclonal antibodies m. Abs act directly when binding to a cancer specific antigen and induce immunological response to cancer cells m. Abs was modified for delivery of a toxin, cytokine or other active conjugates monospecific antibodies that are the same because they are made by identical immune cells that are all clones of a unique parent cell, Monoclonal antibodies have monovalent affinity, in that they bind to the same epitope.

Monoclonal antibodies & their targets

Monoclonal antibodies & their targets

Nasal vaccines �First site of contact with the inhaled allergen �Influenza A & B

Nasal vaccines �First site of contact with the inhaled allergen �Influenza A & B �Proteosoma-influenza �Adenovirus �Parainfluenza �HIV �Hep B

Liposomal Drug delivery Pre-clinical and clinical liposomal packed drugs exhibit reduced toxicities with enhanced

Liposomal Drug delivery Pre-clinical and clinical liposomal packed drugs exhibit reduced toxicities with enhanced efficiency Due to altered pharmacokinetics-drug accumulation at disease sites and reduced distribution to sensitive tissue-target delivery of drugs Liposomes are self-assembling closed colloidal structures composed of lipid bilayers and have a spherical shape in which an outer lipid bilayer surrounds a central aqueous space. Syn from cholesterol

Application of liposomal drug delivery Liposomal doxorubicin- ALL, HIV associated Kaposi s sarcoma Liposomal

Application of liposomal drug delivery Liposomal doxorubicin- ALL, HIV associated Kaposi s sarcoma Liposomal amphotericin B – visceral leishmaniasis Liposomal PEG doxorubicin- met breast CA, ovarian ca, MM, AIDS related Kaposi s sarcoma L Vincritine—prolonged expression of neoplastic cells , increased drug retention L IL 2 - RCC L IL 7 – improves antibody titer, enhanced immunogenicity due to prolonged release over 6 days Liposomal gene transfer –CFTR gene to nasal epithelium of cystic fibrosis patients – under phase 1 trial To overcome the BBB- using thiamine transporter

Triggerable Liposomes

Triggerable Liposomes

Nanoparticle based drug delivery q. Using nanotechnology the drug can be targeted to a

Nanoparticle based drug delivery q. Using nanotechnology the drug can be targeted to a precise location which would make the drug much more effective & reduce the chances of possible side-effects • More specific drug targeting & delivery • Reduction in toxicity while maintaining therapeutic efficiency • Nanocarriers, Nanoparticles, Nanotubule, Nanoshell

Advantages of Nanoparticles: Particle size and surface characteristics of Nanoparticles can be easily manipulated

Advantages of Nanoparticles: Particle size and surface characteristics of Nanoparticles can be easily manipulated to achieve both passive and active drug targeting after parenteral administration. They control and sustain release of the drug during the transportation and at the site of localization Subsequent clearance of the drug so as to achieve increase in drug therapeutic efficacy and reduction in side effects. Drug Loading is relatively high and drugs can be incorporated into the systems without chemical reaction. Site-specific targeting can be achieved by attaching targeting ligands to surface of particles. The system can be used for various routes of administration including oral, nasal, parenteral, intra-ocular etc. ,

Nanoparticles for Drug Delivery • Metal-based nanoparticles-Au, Ag, Cd-Se, Zn-S etc • Lipid-based nanoparticles-Liposome

Nanoparticles for Drug Delivery • Metal-based nanoparticles-Au, Ag, Cd-Se, Zn-S etc • Lipid-based nanoparticles-Liposome & Neosome • Polymer-based nanoparticles-Dendrimer, Micelle • Biological nanoparticles-Bovine-albumin serum • Designing nanoparticles to be taken orally. • The development of particles that are nano scaled has created great opportunities in the of improved drug delivery systems.

Factors: ØSize of Nanoparticles required. Ø Inherent properties of the drug, e. g. :

Factors: ØSize of Nanoparticles required. Ø Inherent properties of the drug, e. g. : aqueous solubility and stability. Ø Surface characteristics such as charge and permeability. Ø Degree of biodegradability, biocompatibility and toxicity. Ø Drug release profile desired. Ø Antigenicity of the final product.

Carbon Nanotubules Gold Nanoparticles Used in treatment of Bronchial asthma ADR: Foreign body granuloma

Carbon Nanotubules Gold Nanoparticles Used in treatment of Bronchial asthma ADR: Foreign body granuloma and intestitial fibrosis Cancer chemotherapy -free radical generation

Difference between Liposomes and Nanoparticles: Liposomes Nanoparticles Ø Protecting drugs from degradation. Ø Increase

Difference between Liposomes and Nanoparticles: Liposomes Nanoparticles Ø Protecting drugs from degradation. Ø Increase the stability of drugs. Ø Less targeting to site of action. Ø More targeting to site of action. Ø Reduction toxicity or side effects. Ø Low encapsulation efficacy. Ø Rapid leakage of water soluble drug in the presence of blood components and poor storage stability. Ø Increase the encapsulation efficacy. ØMinimize the leakage of water soluble drug in the presence of blood components.

Nanoerythrosomes are resealed erythrocytes that can carry proteins, enzymes & macromolecules. They are used

Nanoerythrosomes are resealed erythrocytes that can carry proteins, enzymes & macromolecules. They are used in the treatment of liver tumor, parasitic disease & enzyme disease

 (A) By the enhanced permeability and retention (EPR) effect, nanoparticles (NPs) can be

(A) By the enhanced permeability and retention (EPR) effect, nanoparticles (NPs) can be passively extravasated through leaky vascularization, allowing their accumulation at the tumor region. In this case, drugs may be released in the extracellular matrix and then diffuse through the tissue. (B) Active targeting can enhance therapeutic efficacy of drugs by the increased accumulation and cellular uptake of NPs through receptor-mediated endocytosis.

CHALLENGES OF NANO DRUG DELIVERY ØSmall size & large surface area can lead to

CHALLENGES OF NANO DRUG DELIVERY ØSmall size & large surface area can lead to particle aggregation. ØPhysical handling of nano particles is difficult in liquid and dry forms. ØLimited drug loading. ØToxic metabolites may form.

Although new delivery systems have a number of therapeutic benefits, but they do have

Although new delivery systems have a number of therapeutic benefits, but they do have certain limitations such as : a) If systems fail, overdosing occurs due to doses dumping. b) The large physical size of the dosage unit poses problems in usage. c) Often sub optimum bio-availability is observed. d) Variability in drug levels is also observed.

A Research and Development work will continue to be an integral part of developing

A Research and Development work will continue to be an integral part of developing novel drug delivery systems for ultimate commercial exploitation in the coming years. a) A number of problems for basic research which need to be resolved at the molecular and cellular levels. b) Reticulo-endothetial clearance and drug release into the target cells. c) Developmental work in terms of formulation of different drugs for new therapeutic drugs should be an ongoing effort. d) Polymer formulation to suit individual applications should be the work of a developmental nature.

Gene therapy • • • Somatic Germ line Vectors Viral and non viral Non

Gene therapy • • • Somatic Germ line Vectors Viral and non viral Non viral – Dendrimers – Sonoporation – Magnetofection – Electroporation

GENETIC TRANSFER SYSTEM Under evaluation & III Phase clinical trials for Adenovirus & HIV

GENETIC TRANSFER SYSTEM Under evaluation & III Phase clinical trials for Adenovirus & HIV

Future opportunities Nanoparticles provide massive advantages regarding drug targeting, delivery with additional potential to

Future opportunities Nanoparticles provide massive advantages regarding drug targeting, delivery with additional potential to combine diagnosis and therapy Anti-tumour therapy , gene therapy , AIDS therapy, radiotherapy Involved in delivery of virostatics, vaccines and as vesicles to pass blood brain barrier

Future aspects Dendrimer Modified Buckyball Dendrimer-highly branched They deliver radioactive atoms to cancerous material.

Future aspects Dendrimer Modified Buckyball Dendrimer-highly branched They deliver radioactive atoms to cancerous material. Eg: C-60 against CA globular Biodegradable colon Transfer of radiation is within the synthetic molecule. ball hence minimise strong radiation to healthy tissue

THANK YOU … …

THANK YOU … …