Novel Drug Delivery Systems (NDDS) and Drug Targeting

existing

__________ drug delivery system: the purpose is to confine a drug in a dosage form and there is no control on the drug once it is inside the body. Not all of the drug reaches its target, so side effects may occur when the dose is increased

patient

NDDS is beneficial for the ____________ because they improve performance in terms of compliance, safety, and efficacy.

pharma industry

NDDS is beneficial for the ___________________ because it offers a competitive advantage, extends patent life, and increases market share

10-12

a new chemical entity typically costs $500 million and takes ____________ years to bring to market

3-4

novel drug delivery costs $20-50 million and takes ______________ years to bring to market

NDDS

allow for drug release control, control of absorption/release site location, alternative route to bypass liver, drug targeting, and stimuli-responsiveness (ex: pH, temperature, pathological conditions)

hold, release, target, bio-compatible

An ideal delivery system will:

____________ the drug until it reaches its target, ____________ the drug once it reaches its target, will _____________ the drug, and is _______________ (won't hurt the body)

disease

NDDS targets the specific location of the _______________, whereas conventional drug therapy targets the systemic circulation which may result in side effects and toxicity since a larger dose is required

drug targeting

drug accumulation in the target zone irrespective of the delivery system and route of administration

targeted drug delivery

goal is to increase drug concentration in selective parts of the body

-prolongs and localizes therapeutic effect on diseased tissue

-minimizes adverse effects

-reduces the frequency and dose of medication

-reduces concentration fluctuation in target organs

localization

mechanisms of ____________________: passive targeting, active targeting, and phagocytosis

active targeting

mechanism of localization that uses ligands and antibody that utilize a specific cellular transport mechanism; target of drug molecule to the particular area by attaching an area-specific vector or ligand

phagocytosis

mechanism of localization that uses the characteristics of the drug to cause uptake by phagocytic cells (drug gets phagocytized)

direct application

method of drug administration that directly puts the drug at the site of interest

-intra-articular administration of hormonal drugs in therapy of arthritis

-intracoronary infusion of thrombolytic enzymes in the therapy of thrombus-induced myocardial infarction

passive targeting

uses the body's conditions to control movement of the drug. Ex: enhanced permeation and retention (EPR) effect

EPR effect

passive targeting mechanism that takes advantage of the size of the spaces between endothelial cells for drug delivery; the drug delivery system is small enough that it will pass through cancerous vasculature but not healthy tissues

greater

the space between cancerous endothelial cells is ________________ than the space between the healthy endothelial cells (leaky vasculature)

physical targeting

use of abnormal pH or temperature in the pathological zone; stimuli-responsive drug carriers that can disintegrate at lower pH values or higher temperature than in normal tissues releasing the entrapped drug

magnetic targeting

method of drug targeting in which the drug is entrapped on paramagnetic materials and applied with the help of external magnetic field

Ex: removal of cancer from peritoneum in ovarian cancer

prodrug

a therapeutic administered in inactive form that requires bioactivation by metabolic process once transported to its target organ/cell. Has improved bioavailability and selectivity

tumor:normal

an issue in drug targeting is that many times the normal tissue from which tumors are derrived cannot be safely destroyed; the ratio of ________________ tissue is often not high enough for the target to be unique (expressed in normal tissues)

mutation

an issue in drug targeting si the loss of target antigen expression due to rapid ________________ (antigen-loss variants)

classified

NDDS are ____________________ by design, route of administration, and type of drug molecule (small molecule, macromolecule, protein, or DNA/RNA)

BCS (biopharmaceutical classification system)

a guide for predicting the intestinal drug absorption provided by the U.S. Food and Drug Administration; restricts the prediction using the parameters solubility and intestinal permeability

type I

BSC class in which the drug is highly soluble and permeabile - drug can reach its target tissue and enter the cell. Gets into the blood fast

type II

BSC class in which the drug is permeable through the target cell but is not soluble - requires a system to dissolve it

type III

BSC class in which the drug is soluble but is not permeable though the intestines; requires a system to get it into the cell

type IV

BSC class in which the drug is not soluble and is not permeable to get into the target cell. Not ideal

solubility, permeability

the biopharmaceutical classification system (BCS) restricts the prediction of intestinal drug absorption using the parameters _____________ and intestinal _________________

EOP (elementary osmotic pump)

the ___________________ is an oral controlled release tablet in which drug molecules get released when the plastic osmotic membrane gets pushed back

oral fast-dispersing dosage forms

AKA fast dissolving, rapid-dissolve, rapid-melt, mouth-dissolving, and quick-disintegrating tablets

Ex: effervescent dosage forms: ibuprofen, paracetamol, cimetidine, naproxen, paracetamol and codeine combination product

colon

______________ delivery is ideal for local and systemic effect because it is a neutral pH area with few enzymes; therapy of IBD and colorectal adenocarcinoma; problem is having to go through stomach and intestines - use time based coating

enteric

pH sensitive ___________ polymers dissolve in pH 6-7 (intestines)

3

small intestinal transit time (SITT); relatively consistent = ______ +/- 1 hours

4

time-based coating for colon delivery breaks after __________ hours

BBB (blood brain barrier)

consists of tight junctions between endothelial cells and astrocytes that make sure there are no spaces between cells so that nothing gets to the brain - makes the brain difficult to target

invasive

___________________ brain targeting:

-intra-cerebral injection/implant

-disruption of blood brain barrier (BBB)

non-invasive

___________________ brain targeting: takes advantage of transporters through the BBB

-prodrug

-drug conjugates

-particulate/vesicular delivery

-nanotechnology

-ligans for active targeting: nutrients, antibody, transporters

-lontophoretic

-intranasal

lipophilic

_____________ drug molecules pass through the BBB via the transcellular lipophilic pathway

hydrophilic

_____________ drug molecules pass through the BBB through transport proteins (glucose, amino acids), receptor-mediated transcytosis (insulin), and adsorptive transcytosis (albumin)

transdermal drug delivery (TDD)

diffusion of the medication (drug) through skin into systemic circulation for distribution and therapeutic effect; absorption primarily occurs by passive diffusion through the stratum corneum

hydrogel

hydrophilic, polymeric networks capable of imbibing large amounts of water or biological fluids; homopolymers or copolymers are insoluble due to the presence of physical and chemical crosslinking - just swell (still absorb water - just don't dissolve)

micelle

surfactant molecules that arrange themselves in a spherical form in aqueous solutions; the formulation is a response to the amphipathic nature

Ex: polysorbates, polyoxyethylated caster oil, polyoxyethylated glycerides, lauroyl macroglycerides, and mono- and di-fatty acid esters of low molecular weight polyethylene glycols

Critical Micelle Concentration (CMC)

when the concentration of surfactants exceeds their _________________, micelle formation occurs, entrapping the drugs within the micelles

vessicular

micelles and liposomes are examples of _____________ systems;

advantages: better efficacy and less toxicity

disadvantages: rapid clearance by RES primarily liver, spleen, and kidney

surfactants

have one head and one chain --> form micelles

lipids

have one head and two chains --> form lipid bilayer

liposomes

vesicular structures based on lipid bilayers surrounding aqueous compartments

proliposomes

liposome that avoids difficulties encountered with the manufacturing of liposomes by forming liposomes at the point of drug delivery

stealth liposomes

liposomes in which attaching polyethylene glycol on the liposome form long-circulating liposomes - body sees the PEGs and does not attack (disguised)

amphotericin B

drug that has less side effects when delivered in a liposome

cyclodextrin

carbohydrate ring with a hydrophilic exterior and lipophilic core; each can only carry one drug inside; used for water insoluble drugs

complexation

the association between two or more molecules to form a non bonded entity with a well defined stoichiometry

0.1 and 100

microparticles are between ______ and _____ mcm in size

microparticles

advantages: protection of the encapsulated active agent, precisely and pre-programmed drug release over hours to months, and easy administration

disadvantages: difficulty of large-scale manufacturing, inactivation of drug during fabrication, and poor control of drug release rates

Ex: Lupron Depot and Nutropin Depot

protein/peptide

problems with _____________________ delivery:

-poor oral bioavailability

-protein denaturation in the digestive system

-acid hydrolysis in the stomach

-enzymatic degredation

-poor adsorption due to size

-poor adsorption due to polar/charge distribution

Ex: insulin for diabetes, interferon or mabs for cancer, TNF-a for inflammation, etc.

gene delivery

traps DNA/RNA in lipid nanoparticle to be taken up via endocytosis by target cell; used for mRNA vaccines

virus

a replication-defective _____________ vector is used for DNA vaccines

Pulsatile

_____________ drug delivery system: drug release is programmed by external stimuli like magnetism, ultrasound, electrical effect and irradiation - use osmosis, solubilization, and rupture of membrane

RIDDS (remote intelligent drug delivery system)

device implanted under the skin with inbuild sensors to monitor biomarkers of patient's symptoms, pulse rate, or blood oxygen levels

use wireless control

nanotechnology

broadly defined as science at nanometer range; the art of managing structures, devices and systems by controlling shape and size at the nanometer scale

next-generation delivery systems

Ex: including pulsatile drug delivery system, responsive drug delivery system, intelligent drug delivery system, remote intelligent drug delivery system (RIDDS), and nanotechnology