Drug Delivery System "A Challenge"

for New Therapeutic Era

Dr. B. B. Barik, Professor, Dept. of Pharmaceutics

College of Pharmacy, Jazan University, Kingdom of Saudi Arabia.

E-mail: bbbarik2003@gmail.com

5th International Conference and Exhibition on Pharmaceutics & Novel Drug Delivery Systems March 16-18, 2015 Crowne Plaza, Dubai, UAE

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

Controlled drug delivery

Targeted drug delivery

Maximum efficacy with minimum side effects

Optimize drug’s therapeutic effect, convenience &

dose

To enhance a product life- cycle

Improve patient compliance

Control over all healthcare cost

Drug absorption, distribution

and metabolism vary among individuals

Individualized therapy

Controlled

release/

Targeted

delivery

Need for new drug delivery systems

Various types of Drug delivery

Conventional/Oral

Injection based

Transdermal

Carrier based Controlled/

Targeted DDS

Oral Drug delivery systems

Oral Drug delivery systems

Injection based Drug delivery system

• Provide fast systemic effects bypassing first-pass metabolism

• Drugs can be administered in unconscious or comatose patients

• Drugs having short half-life can be infused continuously

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

Thin film drug delivery • GI specific drugs

Hydrogels: (a)hydrogel preparation(b) After imbibition

Oral drug strips to administer drugs via absorption through buccal or sublingual route

Osmotic pressure controlled system

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 without degradation

Offer flexibility for multiple formulations ranging from nasal drop to suspension spray

Good 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

- 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

Swelling controlled drug delivery system Hydrogels are three dimensional networks of

hydrophilic polymers that are insoluble in water at a physiological temperature and pH but swells.

Preparation of Hydrogels

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 : Preferred value

Molecular weight/ size: < 1000

Solubility: > 0.1 µg/ml for pH 1 to pH 7.8

Pka Non ionized moiety: > 0.1% at pH 1 to pH 7.8

Apparent partition coefficient: High

Absorption mechanism: Diffusion

General absorbability: From all GI segments

Release: Should not be influenced by pH and enzymes

Parameter for drug selection

PHARMACOKINETIC PARAMETER FOR DRUG SELECTION

Parameter Comment

Elimination half life: Preferably between 0.5 and 8 hTotal clearance: Should not be dose dependentElimination rate constant: Required for designApparent vol of distribution (Vd): The larger Vd and MEC, the larger will be the required dose size.Absolute bioavailability: Should be 75% or moreIntrinsic absorption rate: Must be greater than release rateTherapeutic concentration Css av: The lower Css av and smaller Vd, the loss among of drug requiredToxic concentration: Apart the values of MTC and MEC, safer the dosage form. Also suitable for drugs with very short half-life.

Carrier based drug delivery system

Targeted Drug Delivery

Monoclonal antibodies mAbs act directly

when binding to a cancer specific antigen and induce immunological response to cancer cells

mAbs 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

Nasal vaccines

First site of contact with the inhaled allergen

Influenza A & BProteosoma-influenzaAdenovirusParainfluenzaHIVHep B

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 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 IL2 - 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

Nanoparticle based drug delivery

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 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 & 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:Size of Nanoparticles required.

Inherent properties of the drug, e.g.: aqueous solubility and stability.

Surface characteristics such as charge and permeability.

Degree of biodegradability, biocompatibility and toxicity.

Drug release profile desired.

Antigenicity of the final product.

Carbon Nanotubules

Used in treatment of Bronchial asthmaADR: Foreign body granuloma and intestitial fibrosis

Gold Nanoparticles

Cancer chemotherapy-free radical generation

Difference between Liposomes and Nanoparticles:

Liposomes Nanoparticles

Protecting drugs from degradation.

Less targeting to site of action.

Reduction toxicity or side effects.

Low encapsulation efficacy.

Rapid leakage of water soluble drug in the presence of blood components and poor storage stability.

Increase the stability of drugs.

More targeting to site of action.

Increase the encapsulation efficacy.

Minimize the leakage of water soluble drug in the presence of blood components.

Nanoerythrosomes

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 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 the therapeutic efficacy of drugs by the increased accumulation and cellular uptake of NPs through receptor-mediated endocytosis.

CHALLENGES OF NANO DRUG DELIVERY

Small size & large surface area can lead to particle aggregation .

Physical handling of nano particles is difficult in liquid and dry forms.

Limited drug loading.

Toxic metabolites may form.

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 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 viral –Dendrimers – Sonoporation–Magnetofection– Electroporation

GENETIC TRANSFER SYSTEM

Under evaluation & III Phase clinical trials for Adenovirus & HIV

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 opportunities

Dendrimer Modified Buckyball

They deliver radioactive atoms to cancerous material.Eg:C-60 against CA colon Transfer of radiation is within the ball hence minimise strong radiation to healthy tissue

Dendrimer-highly branched globular Biodegradable synthetic molecule.

Future aspects

THANK YOU … …