Novel Drug Delivery Technologies

Benefits of Novel Drug Delivery

• Improved patient compliance

• Improved outcomes

• Reduction of adverse effects

• Patients acceptance to treatment

• Lower cost of treatment

• Allowing patients to receive medication as outpatient

• Reduction of overall medicinal resources

Iontophoresis

• Used constant low voltage electric current to push a charged drug through the skin

• Historically, clinicians used iontophoresis for topical delivery for decades, but is being rediscovered for systemic circulation

Mechanism of Iontophoresis (Electrorepulsion) 

• A drug reservoir is placed on the skin under the active electrode with the same charge as the drug 

• A counter electrode is positioned elsewhere on the body 

• The active electrode effectively repels the active substance and forces it into the skin 

Mechanism of Iontophoresis (Electroosmosis) 

• Electroosmosis results when an electric field is applied to a charged membrane such as the skin and causes a solvent to slow across this membrane from anode to cathode

• Skin has a pH between 3-4 which causes it negatively charged at physiological pH

• This makes it selectively permeable to cations as these cations move into the skin, it carries mass flow of solvents/water molecules, this phenomena is called electroosmosis 

• This stream of solvent can carry molecules dissolved in the solvent

• Due to electroosmotic flow, the flux of anodal iontophoresis is typically higher

• It enhances the penetration of uncharged (neutral) polar, and larger molecules 

Iontophoresis can be seen as

Patches

Iontophoresis Advantages

• Promising technique for delivery of hydrophilic drugs e.g. peptides

• Scope of programmed delivery

  • Delivery is proportional to applied current

• Improved patient compliance

  • Dosage form included electronics, means to remind patient the dose can be built into the system

Electroporation

• In contrast to iontophoresis where a low voltage is applied electroporation requires a large voltage (100-15000 V) for a short period of 10 us to 100 ms

• Electroporation produces transient hydrophilic pores (aqueous pathway) across the skin barrier

Skin Microporation

• Very promising technology under development for transdermal delivery of proteins and vaccines

• Involves minimal invasive technique in which micron sized pathways are created in skin

• These micron sized holes are huge in comparison to drug dimensions, but still smaller than holes produced by hypodermic needles

Microneedles

• Micron size needles that can pierce int the skin to create pore big enough for drugs to enter but small enough to avoid pain

• Dimensions 100-150 um long and 1 um tip

• Microneedles can be

  • Solid

  • Hollow

  • Drug Coated

Thermal Microporation

• Applies short duration electrical current (ms) through the array of tiny resistive elements to the skin surface

• Cells of the stratum corneum that are in contact with the elements are flash vaporized leaving a microscopic hole (micropore) in the stratum corneum

• In contrast to the creation of pores with other enhancement techniques, such as electroporation, thermal microporation involves a physical removal of cells

• Openings are formed temporarily

Phonophoresis

• Transport of drug molecules through the skin under the influence of ultrasound pulses

Ultrasound Mechanism

• Cavitations

• Acoustic streaming

• Thermal stress

Ultrasound 

• To transfer ultrasound energy to body, a contact or coupling medium is required 

• Coupling medium transfers energy from device to skin

• A gel, emulsion, or ointment can be used for such purpose

• Coupling medium can also be used as drug carrier 

SonoPrep

• Developed by Echo Therapeutics INC

• Low frequency (55kHz)

• Size of sonication site is 0.8 cm²

• Aqueous coupling medium is used

Dispersed Systems

• Dispersed system consists of particulate matter, known as dispersed phase, distributed throughout a continuous phase or dispersion medium

• Size of dispersed materials may range from particles of atomic or or molecular dimension to millimeter size

• Based on the particle size, dispersed systems are classified as:

  • Molecular dispersion particle size (<1)

  • Colloidal dispersion - particle size 1nm - 0.5 nm

  • Coarse dispersion - particle size > 0.5 nm

Classification of Colloids

• Colloids can be classified in different ways, but there are three general classifications based primarily on how and to what degree they interact with their medium

  • Lyophilic

  • Lyophobic

  • Association colloids

Association Colloids

• Formed by the association of dissolved molecules of a substance to create particles of colloidal dimension

• Individual molecules are generally too small to be colloidal particles

  • e.g. surfactant micelle, liposome , and microemulsion

• They interact in such a way so as to minimize contact between the lipophilic portion of the amphiphile and water

  • Casein micelles in milk are colloidal-size complexes of casein proteins with calcium phosphate

Micelles

• Surfactants are interfacially active compounds consisting of a polar head group and non-polar hydrocarbon chain

• Absorb preferably at interfaces and decrease the interfacial tension

• Decrease in surface tension caused by surfactants becomes stronger the more surfactants are adsorbed at the interface

• Once the interface is saturated, addition of more surfactants will not decrease the interfacial tension any further instead of a self organization of the surfactant molecules takes place inside a volume phase

  • e.g. micelles form which consist of several clustered surfactant molecules that shield their non-polar chains from the surrounding aqueous phase with their polar head groups

  • The critical micelle concentration CMC is the surfactant concentration at, and above which micelles are formed

Conventional Amphotericin B

• Available for use since the early 1960s to treat invasive systemic fungal infections

• Broad-spectrum activity considered the “gold-standard” of therapy

• Limitations:

  • High rates of nephrotoxicity

  • High rates of infusion-related reactions (fevers, rigors, chills)

• Has earned its nickname of “amphoterrible”

• Clinicians have been forced to alter the dose, frequency, and duration in patients who develop acute kidney injury (AKI) while being treated

• Such changed while avoiding irreversible damage to the kidney, may make therapy subtherapeutic

Amphotericin B Deoxycholate Fungizone 

• Lyophilized powder of amphotericin B with added sodium deoxycholate. Forms upon reconstitution colloidal (micellar) dispersion

• Sodium deoxycholate is a bile acid which acts as a detergent to solubilize fats for intestinal absorption 

  • MOA: drug stabilization: rendering drug biocompatible and enhancing ease of administration after IV injection

Liposomes

• Liposomes are vesicles like structure composed of one or more lipid bilayers encapsulating an aqueous core

• Phospholipid are usually used as lipids

• Being amphiphilic molecules hydrophilic heads face outward in the aqueous environment and hydrophobic chains orientate inward

• Most commonly used preparations on market display a size between 50 and 200 nm

• MOA: altering pharmacokinetics of the free drug

Encapsulation of Drug into Liposomes

• Both water and lipid soluble drugs can be encapsulated

• Hydrophilic drugs are encapsulated in the aqueous core and the aqueous compartments between the bilayers

• Hydrophobic drug can be entrapped in the bilayer structure

Liposome Injections

• Amphotericin B - antifungal

  • Abelcet injection

  • AmBisome for injection

Liposomal Amphotericin B

• During the 1980s and early 1990s, a new AMB formulations based on advances in liposome- and lipid based drug delivery technology were developed

• The main goal was to

  • Allow higher doses over a prolonged period of time

  • Decreases nephrotoxicity

• Between 1995 and 1997 the FDA approved over 3 lipid based AMB nanoformulations Abelcet, AmBisome (smallest size 60-70 nm) and Amphotec

• Advantages of new nano formulations

  • Higher levels of nano formulated AMB to penetrate infected areas

  • Decreasing the exposure to the kidney

DaunoXome Commercial Liposomes 

• DuanoXome 

  • Active ingredient is daunorubicin, an anthracycline antibiotic with antineoplastic activity

  • Indicated for the treatment of advanced HIV-related Kaposi’s Sarcoma

  • Daunorubicin encapsulated in conventional liposomes with mean diameter of about 45 nm

• PK of DaunoXome points to a major retardation of clearance compared to free daunorubicin

Long Circulating (Stealth) Liposomes 

Limitations of conventional liposomes

• Readily taken up by the phagocytic cells of reticuloendothelial system (RES)

• Localized predominately in the liver and spleen

• Conventional liposomes are made of natural lipids hat cells can identify and engulf

• The major strategy towards increasing the longevity of liposomes in the circulatory system is based on modifying the liposomal surface with PEG, a technology which made the development of Doxil possible 

Stealth Liposome Injections

• Example: Doxil

  • Doxorubicin Hydrochloride Liposome Injection

  • Introduced in 1999

  • Doxorubicin - anthracycline drug isolated from Streptomyces peucetius

  • Doxil approved for AIDS related Kaposi sarcoma ovarian cancer, multiple myeloma

Long Circulating (Stealth) Liposomes: Doxil

• Doxil is specially coated form of doxorubicin that starts with the active agent, doxorubicin, and covers it with 2 layers of protective coating

• This coating allows DOXIL to evade detection and destruction by the immune system, which increases the time the drug is in the body

• As a result DOXIL has more time to reach the tumor tissue, where the medication is slowly released

DOXIL: Commercial PEG-Liposome

• Encapsulate cytostatic doxorubicin

• Reduces distribution in the heart where it produces considerable toxic effects

• Half-life is about 55 hours (10 times more than that of DaunoXome)

• Concentrates in tumor tissue via enhanced retention and permeability effect (EPR)

• Compared with plain liposomes, a 4-16 enhancement in drug accumulation

The EPR Effect

• Compared with the blood vessels in the normal tissues, those of growing tumors are frequently more “leaky” to circulating macromolecules and large particles allowing them easy access to the tumors interior 

• Normally these macromolecules would quickly drain away back to the circulatory system, tumor tissues effectively trap them and prevent their escape

• Clearance from tumor tissue is delayed due to the poor lymphatic drainage 

• This property of tumor is called enhanced permeability and retention (EPR) effect

• EPR effect has been exploited for passive targeting