Advances and new technologies applied in controlled drug delivery system

Advances and new technologies applied in controlleddrug delivery system

Fatma Bassyouni • Noha ElHalwany •

Mohamed Abdel Rehim • Munir Neyfeh

Received: 15 February 2013 / Accepted: 29 June 2013

� Springer Science+Business Media Dordrecht 2013

Abstract A drug delivery system is defined as a formulation or a device that

enables the introduction of a therapeutic substance into the body and improves its

efficacy and safety by controlling the rate, time, and place of release of drugs in

the body. This process includes the administration of the therapeutic product, the

release of the active ingredients by the product, and the subsequent transport of the

active ingredients across the biological membranes to the site of action. Drug

delivery systems aim to improve patient compliance and convenience, such as, for

example, fast-dissolving tablets. One of the most important goals of pharmaceutical

science is localizing the pharmacological activity of the drug at the site of action.

Drug delivery systems are molecular tools which, without undesired interactions at

other sites, target a specific drug receptor. Keeping in view the advantages of the

delivery system, rapidly disintegrating dosage forms have been successfully com-

mercialized, and, because of increased patient demand, these dosage forms are

expected to become more popular. Modern drug delivery technology has been made

possible by advances in polymer science. These advances have resulted in polymers

with unique properties. Drug delivery systems are made from a variety of organic

F. Bassyouni (&)

Department of Chemistry of Natural and Microbial Products and Department

of Pharmaceutical Research, Center of Excellence for Advanced Sciences,

National Research Center, Cairo 12622, Egypt

e-mail: [email protected]

N. ElHalwany

Department of Polymers and Pigments, National Research Centre, Cairo 12622, Egypt

M. Abdel Rehim

Department of Analytical Chemistry, Stockholm University, 10691 Stockholm, Sweden

M. Neyfeh

Department of Physics, University of Illinois at Urbana-Champaign, 1110 W. Green Street, Urbana,

IL 61801, USA

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Res Chem Intermed

DOI 10.1007/s11164-013-1338-2

and inorganic compounds such as polymers, lipids (liposomes, nanoemulsions, and

solid–lipid nanoparticles), self-assembling amphiphilic molecules, dendrimers, and

inorganic nanocrystals. In addition, hydrogels are novel delivery systems that have

attracted much attention in current pharmaceutical research.

Keywords Transdermal drug delivery � Colon delivery system �Liposomes � Nano-capsules � Carbon nanotubes � Hydrogels

Introduction

Therapeutic efficacy and safety of drugs, administered by conventional methods,

can be improved by more precise spatial and temporal placement within the body,

thereby reducing both the size and number of doses by using a controlled drug

delivery system. An ideal controlled drug delivery system is one which delivers the

drug at a predetermined rate, locally or systemically, for a specified period of time.

An ideal targeted drug delivery system delivers the drug only to its site of action. An

ideal drug delivery system should also deliver the drug at a rate dictated by the

needs of the body over the period of treatment to the site of action. To make this

work in practice, various controlled and targeted drug delivery systems have been

introduced. Controlled delivery of drugs, proteins, and other bioactive agents can be

achieved by incorporating them, in either dissolved or dispersed form, in polymers

[1–5].

The field of drug delivery systems (DDS) utilizing synthetic polymers either by

covalent conjugation or by composites of micellar drugs has become a new domain

for drug development for numerous diseases. The most fascinating features of

polymers arise from their versatility and tunable sensitivity. Each monomer can be

tailored to a homopolymer responding to just one signal as well as to copolymers

answering multiple stimuli. The versatility of polymer sources and their combina-

tion methods make it possible to tune the polymer sensitivity responding to a given

stimulus within a narrow range. These polymer-based new drug entities are called

‘‘polymer therapeutics’’ [6, 7] or macromolecular drugs, and they overlap with

nanomedicine that has become popular in recent years [8]. It may be possible to

tailor ‘‘optimal’’ polymers for given therapeutic applications [9].

Different types of polymeric systems have beentailored in order to achieve

controlled drug delivery. However, most of these polymeric systems, via

recognition by the phagocytic cells (mainly the cells, located in the reticuloendo-

thelial system (RES)) in the liver, spleen, and bone marrow [10], are detected as

foreign products and quickly removed from blood circulation. Various attempts

have been directed towards altering the carriers’ surface properties to reduce their

RES clearance and to achieve long blood circulation times. This alteration has been

performed by adsorbing or chemically attaching appropriate hydrophilic and neutral

polymers to the carrier’s surface [11–17], which will reduce or minimize the

interaction with opsonins.

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To obtain a coating that might prevent opsonization and subsequent recognition

by the macrophages, various types of systems (liposomes, emulsions, micelles,

nanoparticles [18–21], and carbon nanotubes [22]) have been developed over the

last decade in order to achieve controlled drug delivery or targeting to specific

tissues. The aforementioned systems have been found to successfully reduce side

effects while increasing dosage, increasing residence time in the body, offering a

sustained and tunable release, and having the ability to deliver multiple drugs in one

carrier. Moreover, traditional nanomaterial formulations have not so far produced

highly therapeutic formulations due to their passive delivery methods and the lack

of rapid drug release at their intended site. Hydrogels are polymeric biomaterials

with a 3D structure that can absorb a certain amount of water. They were taken up

by the pharmaceutical industry a couple of decades ago as a new pharmaceutical

system with special characteristics [23, 24].

Controlled drug delivery systems

Controlled delivery attempts

Controlled delivery systems is the drug action at a predetermined rate by

maintaining a relatively constant, effective drug level in the body, with concomitant

minimization of undesirable side effects associated with a saw-tooth kinetic pattern.

In the ‘‘ATTEMPTS’’ system, the cell-permeable protein drugs are synthesized by

conjugating proteins to cell-penetrating peptides (CPPs). Thus, the ATTEMPTS

approach provides a multi-functionalized system incorporating the features of

targeting, pro-drug-like, triggerable release, and cell penetration ability for the

delivery of macromolecular anticancer agents. ‘‘ATTEMPTS’’ is represented as:

(1) Localize drug action by spatial placement of a controlled release system (rate-

controlled) adjacent to or in the diseased tissue or organ.

(2) Target drug action by using carriers to deliver drugs to particular target cell

types (Fig. 1).

Fig. 1 Schematic representation of reservoir diffusion-controlled drug delivery device

Advances and new technologies

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Objectives of controlled drug delivery systems

The chief objective of most products should be controlled delivery to reduce dosing fre-

quency to such an extent that once-daily doses are sufficient for therapeutic management

though a uniform plasma concentration at a steady state. The major objectives include

(1) Predict drug release rated form and drug diffusion behavior through polymers,

thus avoiding excessive experimentation.

(2) Elucidate the physical mechanism of drug transport by simply comparing the

release data mathematical models.

(3) Design new drug delivery systems based on general release expressions.

(4) Optimize the release kinetics.

Factors influencing the design and performance of controlled drug delivery

systems

The oral drug delivery method is the most widely utilized route for administration

among all the alternatives that have been explored for systemic delivery of drugs via

various pharmaceutical products of different dosage forms. The popularity of the

route may be because of the ease of administration as well as the traditional belief

that oral administration of the drug is assisted by being well absorbed into the food

stuff ingested daily. These factors are classified below.

Biopharmaceutical characteristics system for drugs

The basis for the biopharmaceutical characteristics system (BCS) if to categorize

drugs into four types according to their solubility and their permeability. The

objective has been to predict the in vivo pharmacokinetic performances of drugs

from measurements of solubility and permeability. During the drug development

process, the BCS provides an opportunity to optimize the structures or physico-

chemical properties of lead candidates, thereby achieving better deliverability by

displaying the features of BCS class I (high solubility, high permeability) without

compromising their pharmacodynamics, such as:

(1) Molecular weight of the drug.

(2) Aqueous solubility of the drug.

(3) Apparent partition coefficient.

(4) Drug PKa and ionization physiological pH.

(5) Drug stability.

(6) Mechanism and site of absorption.

(7) Route of administration.

Pharmacokinetic characteristics of drugs

The pharmacokinetic characteristics of a drug are currently defined as the study of

the time course of drug absorption, distribution, metabolism, and excretion. Clinical

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pharmacokinetics is the application of pharmacokinetic principles to the safe and

effective therapeutic management of drugs in an individual patient. The primary

goals of clinical pharmacokinetics include enhancing the efficacy and decreasing the

toxicity of a patient’s drug therapy. The development of strong correlations between

drug concentrations and their pharmacologic responses has enabled clinicians to

apply pharmacokinetic principles to actual patient situations, such as:

(1) Absorption rate.

(2) Elimination half-life.

(3) Rate of metabolism.

(4) Dosage form index.

Pharmacodynamic characteristics of drugs

The pharmacodynamic characteristics of a drug refers to the relationship between

the drug concentration at the site of action and the resulting effect, including the

time course and intensity of both therapeutic and adverse effects. The effect of a

drug present at the site of action is determined by that drug’s binding with a

receptor. Receptors may be present on neurons in the central nervous system (i.e.,

opiate receptors) to depress pain sensation, on cardiac muscle to affect the intensity

of contraction, or even within bacteria to disrupt the maintenance of the bacterial

cell wall. They depend on:

(1) Therapeutic range.

(2) Therapeutic index.

(3) Plasma–concentration–response relationship.

Classification of controlled drug delivery systems

In general, for most of the pharmaceutical industry’s existence, drug delivery has

induced simple, fast-acting responses (conventional forms) via oral or injection

delivery routes. Problems associated with this approach have included reduced

potencies because of partial degradation (first pass metabolism), toxic levels of

administration (in cases of excess dose), increased costs associated with excess

dosing, and compliance issues due to administration pain.

The oral controlled drug delivery system provides the continuous oral delivery of

drugs at predictable and reproducible kinetics for a determined delivery throughout

the course of gastrointestinal (GI) transit.

A sustained release drug delivery system is classified as a continuous release

system releasing the drug for a prolonged period of time along the entire length of

the GI tract with normal transit of the dosage form. The various systems under this

category are as follows:

• Dissolution-controlled release system.

• Diffusion-controlled release system.

• Diffusion- and dissolution-controlled release system.

• Ion exchange resin drug complexes.


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• Slow dissolving salt and complexes.

• pH-independent formulations.

• Osmotic pressure-controlled systems.

• Hydrodynamic pressure-controlled systems.

Delayed transit and continuous release systems are designed to prolong their

residence in the GI tract along with their release. Often, the dosage form is

fabricated to be detained in the stomach and hence the drug should be stable to

gastric pH. Systems included in this category are mucoadhesive systems and size-

based systems as follows:

• Altered density systems.

• Mucoadhesive systems.

• Size-based systems.

The delayed release systems are designed to involve the release of a drug only at

specific sites in the GI tract. The drugs contained in such a system are those that are:

• Meant to extend the local effect at a specific GI site.

• Destroyed in the stomach or by intestinal enzymes.

• Absorbed from a specific intestinal site.

The two types of delayed release systems are:

• Intestinal release systems.

• Colonic release systems.

Dissolution-controlled release systems

Dissolution-controlled release can be obtained by slowing the dissolution rate of a

drug in the GI medium, incorporating the drug in an insoluble polymer, and coating

drug particles or granules with polymeric materials of varying thicknesses. The rate-

limiting step for the dissolution of a drug is the diffusion across the aqueous

boundary layer. The solubility of the drug provides the source of energy for the drug

release, which is countered by the stagnant-fluid diffusion boundary layer.

The drug present in such system may be one:

• Having high aqueous solubility and dissolution rate.

• With an inherently slow dissolution rate, e.g., Griseofulvin and Digoxin.

• That produces slow-dissolving forms, when it comes in contact with GI fluids.

Drug formulation/physicochemical properties

The drug delivery system will clearly affect the whole absorption process: particle

deposition, aerosol physics, and the impact of the quantity and quality of excipients

on the metabolic stability and solubility kinetics should be quantified.

The drug’s physicochemical properties to be considered include molecular size,

lipophilicity (log P), solubility, pKa, protein binding, polar surface area, and charge

or rotatable bonds. These properties will in the end influence the permeability of a

compound across the lung epithelial barrier.

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Quality control products

When establishing an in vitro cellular model for drug permeability studies, it is desirable

that it mimics as well as possible the in vivo situation. This includes the establishment of

a cellular barrier able to discriminate compounds according to their permeability (low/

high) and the expression of the efflux transporters that are known to be present in vivo.

The compounds in this group can be used as markers for these properties and as quality

control products that help determine the appropriateness of an epithelial in vitro model.

Parenteral controlled release systems

The parenteral administration route is the most effective and common form of

delivery for active drug substances with poor bio-availability and for drugs with a

narrow therapeutic index. The development of novel technologies in the area of

drug discovery such as genetic engineering, combinatorial chemistry, and high-

throughput screening leads to good numbers of drug candidates with high

therapeutic potentials (Fig. 2). However, the majority of them have poor oral

absorption or a short biological half-life. The emergence of these complex active

Fig. 2 Simplified amalgamation of multifunctional envelope-type nano devices (MENDs), that havebeen employed for non-viral gene therapy development. pDNA cargoes encoding proteins (such asluciferase and GFP) have been delivered, as well as siRNA targeting luciferase and ACTB . MENDpolycations are generally PLL or protamine. Lipid envelopes usually comprise DOTAP, DOPE andcholesterol, but can also include CHEMS. Tetra-lamellar MEND envelopes comprise DOPE/cholesterolinner and DOPE/phosphatidic acid outer layers. Fictionalization of MENDS with GALA/short GALA,STR-R8, PEG and MMP-cleavable PEG and sugar-lipid conjugates have all been reported


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ingredients has drawn considerable attention to the development of novel techniques

to deliver them in an effective and efficient way, such as:

(1) Injectable.

(2) Implants.

(3) Transdermal drug delivery systems.

(4) Ophthalmic drug delivery systems.

(5) Intra-vaginal and intra-uterine drug delivery systems.

(6) Increase of bioavailability.

(7) Localized delivery of drugs.

Advantages of controlled drug delivery systems

Advanced drug delivery systems (DDS) present indubitable benefits for drug

administration. Over the past three decades, new approaches have been suggested

for the development of novel carriers for drug delivery. The main purpose of using a

DDS is, as implied, not only to deliver a biologically active compound in a

controlled manner (time period and releasing rate) but also to maintain drug level in

the body within the therapeutic window. In addition, one can direct the drug towards

a specific organ or tissue (targeted drug delivery).

These advantages can be classified into:

(1) Improved patient convenience and compliance.

(2) Reduction in fluctuation in steady state levels.

(3) Increased safety margin of high potency drugs.

(4) Reduction in dose and employment of minimum doses.

(5) Reduction in health care costs.

(6) Improved efficacy in treatment.

(7) Improved bioavailability of the drugs.

(8) Minimized or eliminated local and systemic side effects.

Disadvantages of controlled drug delivery systems

(1) Decreased systemic availability.

(2) Poor in vitro–in vivo correlations.

(3) Chance of dose dumping.

(4) Dose withdrawal is not possible.

(5) Higher cost of formulation.

(6) Effective drug release period is influenced and limited by GI residence time.

Types of controlled delivery system

A controlled delivery system is one which delivers the drug at a predetermined rate,

locally or systemically, for a specified period of time. A targeted drug delivery

system is one which delivers the drug only to its site of action and not to non-target

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organs or tissues. These agents are formulated to produce maximum stability,

activity, and bioavailability. In-eye drugs are released and dissolved in lachrymal

secretions. The rate of drug release is controlled by its permeation through a

membrane wall. The active agents are homogeneously dispersed through a rate-

controlling polymer matrix, and the rate of drug release is controlled by diffusion

through the polymer matrix.

Theoretically, Fick’s law of diffusion governs the controlled release of drugs. It

depends on the molecular weight of drugs, their aqueous solubility, partitions

coefficient, stability, PKa, and ionization. Controlled delivery systems have

important advantages for drugs without serious side effect [25–29].

Transdermal drug delivery

The transdermal drug delivery system has been accepted as a potential non-invasive

route of drug administration, with the advantages of prolonged therapeutic effects,

reduced side effects, improved bioavailability, better patient compliance, and easy

termination of the drug therapy. However, the delivery of drugs via the transdermal

route is still very challenging. The greatest hindrance in the percutaneous delivery is

the obstruction property of the stratum corneum, the outermost layer of the skin that

has to be overcome for successfully delivering drug molecules to the systemic

circulation by this route. The transdermal route of drug administration has been

recognized as one of the potential routes for both the local and systemic delivery of

drugs. The skin is an exceptionally effective barrier to most chemicals, and very few

drugs can permeate into it in amounts sufficient to deliver a therapeutic dose (Fig. 3).

Therefore, systems that make the skin locally more permeable and thereby enable the

Fig. 3 Transdermal delivery technology refers to delivery of active ingredients across the skin forsystemic distribution


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transdermal delivery of drugs are of great interest. Among different carriers, liposomes

and niosomes are well documented for transdermal drug delivery. Vesicles, consisting

of one or more surfactant bilayers enclosing aqueous spaces, have been of particular

interest because they offer several advantages over liposomes, with respect to

chemical stability, lower cost, and availability of materials. Applied on the skin,

niosomes may act as a solubilizing matrix for poorly soluble drugs and penetration

enhancers, as well as a local depot for sustained drug release [30–33].

Colon delivery system

Colon delivery for achieving either maximum drug absorption or local action has been

extensively investigated over the past two decades. The main advantages associated

with colon delivery is that the colon offers a near neutral pH, reduced digestive enzyme

activity, a long transit time, and increased responsiveness to absorption enhancers.

However, due to its location at the distal part of the alimentary tract, the colon is

particularly difficult to access. In addition, a wide range of pH values and different

enzymes present throughout the GI tract, through which the dosage form has to travel

before reaching the target site, further complicate the reliability and delivery efficiency.

Various approaches employed for delivering drugs to the colon include the use of enteric

polymers, swellable polymers, and polysaccharides. The pH of the colon is lower than

that of the intestine due to secretion of fatty acids. Hence, under physiological

conditions, the colon release dosage form has to resist drug release at a higher pH and

subsequently release it at a lower pH. Although time-controlled systems have been

suggested to satisfy the requirement, the time that the dosage form takes to reach the

colon is often intractable due to wide variations in gastric emptying time. Therefore,

dosage forms making use of enzymatically degradable polymers that would release the

drug after reaching the colon seem to offer great promise in this quest [34–39].

Osmotically controlled drug delivery system

An osmotic system utilizes the principles of pressure for the controlled delivery of

one or more active agents. The release rate of the active agent(s) from the osmotic

core is independent of physiological factors of the GI tract. The release from the

osmotic core depends upon the existence of an osmotic pressure gradient between

the contents of the core and the fluid in the tract. Osmotic delivery has been proved

to be advantageous for delivering many drugs in a controlled manner. Attempts

have also been made to modify the osmotic pumps to achieve efficient drug release

as per the need. Gan et al. have prepared osmotic pump tablets of GLZ using an

inclusion complex with b-CD to improve the solubility of GLZ. The formulation

delivered GLZ with zero order pattern up to 14 h. Ali et al. have developed solid

dispersion of GLZ with PVP. The elementary os solubility and dissolution rate

significantly affected motic pumps prepared with the GLZ–PVP complex, which

was shown by the concentration of PVP [40–42].

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Ocular drug delivery system

The existing ocular drug delivery systems are fairly primitive and inefficient.

However, the design of ocular systems is undergoing a gradual transition from an

empirical to a rational basis. Interest in the broad areas of ocular drug delivery has

increased in recent years due to an increased understanding of a number of ocular

physiological processes and pathological conditions. The approaches made towards

the optimization of ocular delivery systems have included:

(1) Improving ocular contact time.

(2) Enhancing corneal permeability.

(3) Enhancing site specificity.

Ocular penetration enhancers

Penetration enhancers, like actin filament inhibitors, surfactants, bile salts,

chelators, and organic compounds, have been used to increase the bioavailability

of topically applied peptides and proteins, which are otherwise poorly absorbed due

to their unfavorable molecular size, charge, and hydrophilicity, as well as their

susceptibility to degradation by peptidases in the eye. Rathode et al. have developed

pilocarpine-loaded egg albumin microspheres for ophthalmic delivery by a thermal

denaturation process in the size range of 1–12 lm. The factors which may affect the

size and entrapment efficiency of drugs in the microspheres have been studied and

optimized. The microspheres so obtained were evaluated for their size, entrapment

efficiency, release rate, and rheological response by measuring the decreased

intraocular pressure in rabbits and comparing them with marketed products.

Kapadia et al. prepared a niosomal in situ hydrogel system of acyclovir by a

reverse phase evaporation technique with the objective of using niosomes for an

ocular drug delivery system by entrapping them in in situ hydrogel, which will

provide a controlled release and avoid the pre-corneal and naso-lachrymal drainage.

The study concluded that the combined system can be used as an efficient vehicle to

enhance ocular bio-availability and patient compliance [43–50].

Ocular iontophoresis

Iontophoresis is the process in which the direct current drives ions into cells or

tissues as antibiotic, antifungal, anesthetic,and adrenergic agents.

Advantages of the ocular routes of administration are:

• Rapid absorption.

• Ease of administration.

• Good local tolerance.


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Ocular indication of controlled release systems are:

• Short, topical ocular half-life, e.g., heparin for ligneous disease.

• Small, topical ocular, therapeutic index, e.g., Pilocarpine for chronic open-angle

glaucoma, possibly nucleoside, antiviral.

• Systemic side effects, e.g., Timolol for glaucoma and cyclosporin A for graft

rejection.

Advances in polymers for drug delivery systems

The search for new drug delivery approaches and new modes of action represents

one of the frontier areas which involves a multidisciplinary scientific approach to

provide major advances in improving the therapeutic index and bioavailability for

site-specific delivery.

A number of drug delivery systems are currently under investigation to

circumvent the limitations commonly found in conventional dosage forms and to

improve the potential of the respective drug. New drug delivery systems include

nanoparticles, carbon nanotubes, liposomes, micelles, and polyelectrolytes as drug

delivery systems. Many of these technologies have reached the market, thus proving

the benefits of these new carriers (Fig. 4).

Colloidal-sized nanoparticles as drug carriers

The nano-size range of these colloidal delivery systems allows them to be injected

directly into the systemic circulation without the risk of blocking blood vessels [51].

Fig. 4 Generalized schematic setup of a nanodimensional particle of a calcium orthophosphate suitablefor both imaging and drug delivery purposes. The charge of the particles influences their ability to passthrough the cellular membrane and a positive charge is beneficial, positively charged nano-sized particlesof calcium orthophosphate/polymer biocomposites were successfully applied for photodynamic therapy

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It has been shown that the size of the nanoparticle is a major aspect determining the

in vivo fate of the particles. Researchers have established that opsonization and

subsequent recognition and phagocytosis by macrophages is robustly correlated

with the size of the particle [52, 53]. It has been found that particles under 200 nm

in diameter display a decreased rate of clearance and thus an extended circulation

time as compared to those with a larger diameter [54].

The circulation time of nanoparticles is further increased by the inclusion of

surface-bound hydrophilic molecules such as polyethylene glycol (PEG) [55, 56].

PEG chains create a highly water-bound barrier on the particle surface which blocks

the adhesion of opsonins. The extended circulation time combined with the small

diameter of the particles has been shown to lead to increased accumulation of the

entrapped drugs in tissues, with increased vascular permeability and impaired

lymphatic drainage, such as in tumors and inflamed tissues [57, 58]. This

phenomenon, referred to as the enhanced permeability and retention (EPR) effect,

can be exploited as a way of passively targeting the encapsulated drug to its site of

action, thus reducing the accumulation in healthy tissues and subsequent adverse

effects. Commonly, nanoparticles composed of biodegradable polymers exhibit

controlled release of their drug payload by diffusion, polymer degradation, or

micelle dissociation mechanisms [59–61]. These systems may provide prolonged

exposure of the drug at their site of action once they have accumulated at their

target. Nanoparticles composed of biocompatible materials have also been used to

increase the aqueous solubility of several hydrophobic drugs via solubilization

within the hydrophobic core of the nanoparticles [62]. Solid lipid nanoparticles

(SLN) are another type of nanoparticles. They are submicron colloidal carriers

which are composed of physiological lipids dispersed in water or in aqueous

Fig. 5 Basic structure of polymeric nanoparticles, nanoemulsions, solid lipid nanoparticles (SLN) andnanostructured lipid carriers (NLC) (=all matrix particles) versus drug nanocrystals. The SLN are madefrom a solid lipid only, the NLC from a blend of a solid and a liquid lipid (oil), but both being solid atbody temperature. The matrix particles have drug distributed throughout the matrix and/or adsorbed ontotheir surface (drug loading �100 %); the nanocrystals consist of 100 % drug


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surfactant solutions. SLN have a wide range of advantages over other types of

nanoparticles. Thus, SLN can be used extensively as an alternative to the existing

drug carrier systems, providing more flexibility with respect to the area of

applications and also for aspects for commercialization [63] (Fig. 5).

Liposomes

Liposomes are the most extensively investigated among various colloidal carriers.

They are microscopic vesicles consisting of one or more concentric spheres of lipid

bilayers separated by aqueous or buffer compartments. These spherical structures

can have diameters ranging from 80 nm to 100 lm [64]. Liposomes are composed

of smectic mesophases of phospholipids organized into bilayers [65–67].

Fig. 6 Simple liposomes are vesicles that have a shell consisting of a lipid bilayer. a Liposome can traphydrophobic guest molecules a few nanometres in diameter (red spheres) within the hydrophobic bilayer,and hydrophilic guests up to several hundred nanometres (green star) in its larger interior. b In ‘stealth’liposomes developed for drug-delivery applications, the lipid bilayer contains a small percentage ofpolymer lipids. Peptides (blue rectangle) that target specific biological targets may also be attached to thepolymers. c Most cationic liposome–DNA complexes have an onion-like structure, with DNA (purplerods) sandwiched between cationic membranes. d Liposomes in which the bilayer assembles fromcavitands—vase-shaped molecules—to which the authors attached hydrophobic and hydrophilic chains.The cavitands can trap angstrom-sized guest compounds (yellow diamonds) in their hydrophobic cavities.These vesicles can therefore encapsulate guest molecules of different sizes in the cavitands, the bilayerand the liposome’s interior

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Amphiphilic nature of phospholipids allows these molecules to form lipid bilayers.

This unique feature is utilized for the preparation of liposomes [68].

The most generally used phospholipids are egg phosphatidylcholine, synthetic

dipalmitoyl-DL-a-phosphatidyl choline, brain and synthetic phosphatidylserine,

sphingomyelin, phosphatidylinositol, and ovolecithin. Structurally, there are three

principal types of liposomes: multilamellar, single compartment, and macrovesicles.

Multilamellar or multiple compartment liposomes are non-uniform aggregates each

containing several layers of phospholipids separated from each other by water

molecules. The net charge of liposomes can conveniently be altered. Addition of a

long chain amine (usually stearylamine) results in positively charged liposomes.

Negatively charged liposomes are prepared by the addition of phosphatidylserine or

dicetyl phosphate. Liposomes containing only cholesterol and phospholipid are

neutral. Both hydrophobic and polar drugs can be entrapped in liposomes. The

ability of liposomes to entrap hydrophilic and hydrophobic drugs with concomitant

reduction in their toxicity potential, their versatility, and their amenability for

surface modification are the major factors responsible for their popularity in drug

delivery research (Fig. 6).

Positively charged liposomes display better corneal permeation than the neutral and

negatively charged liposomes. Neutral liposomes upon systemic administration evade

the elimination by the reticuloendothelial system (RES). However, these vesicles

possess a higher self-aggregation tendency. In contrast, negatively and positively

charged liposomes exhibit a lower aggregation tendency but undergo rapid clearance

by RES cells due to their higher interaction with serum proteins [69].

Micelles

Due to the unique structure of amphiphilic molecules they have a tendency to

accumulate at the boundary of two phases and thus are termed surfactants. In

aqueous solutions, amphiphilic molecules orientate themselves so that the

hydrophobic blocks are removed from the aqueous environment in order to achieve

a state of minimum free energy. At a specific and narrow concentration range of

amphiphiles in solution, termed the critical micelle concentration (CMC), several

amphiphiles will self-assemble into colloidal-sized particles termed micelles.

Micelles are classified as association or amphiphilic colloids, but should not be

considered solid particles [70]. Micelles typically have diameters ranging from 10 to

100 nm and are characterized by a core–shell architecture in which the inner core is

composed of the hydrophobic regions of the amphiphiles creating a cargo space for

the solubilization of lipophilic drugs [71–75] (Fig. 7). The core region is surrounded

by a palisade or corona composed of the hydrophilic blocks of the amphiphiles. The

hydrophilic blocks forming the corona region become highly water-bound and adopt

a ‘‘splayed’’ appearance, giving rise to different conformations such as a polymer

‘‘brush’’ [76]. These conformations sterically suppress opsonization by blood

components, thus resisting phagocytosis by macrophages and decreasing clearance

by the reticuloendothelial system (RES), resulting in prolonged circulation times

[76–80].


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Polymeric micelles

Polymeric micelles (PMs) are another class of nanovectors and have gained much

attention for encapsulating and delivering hydrophobic drugs. The driving forces of

polymeric chains to form micelles are the hydrophobic, electrostatic, p–p, and

hydrogen bonding interactions. PMs composed of poly(ethylene oxide-aspartate)

block copolymers conjugated to an anti-cancer drug, doxorubicin, exhibited a

sustained systemic circulation [79], reduced uptake by the RES, and a higher

accumulation in a tumor-bearing mouse model of Colon-26 [81]. Polymeric

micelles have also been employed in active targeting applications [82]. A plethora

of formulation techniques have been reported in the literature for targeting drugs to

specific sites. Polymeric micelles (PMs) can be targeted to tumor sites by passive as

well as active mechanisms [83].

PMs consist of a core and shell structure: the inner core is the hydrophobic part of

the block copolymer, which encapsulates the poorly water-soluble drug, whereas the

outer shell or corona of the hydrophilic block of the copolymer protects the drug

from the aqueous environment and stabilizes the PMs against recognition in vivo by

the reticuloendothelial system (RES). The core can sometimes be made up of a

water-soluble polymer that is rendered hydrophobic by the chemical conjugation of

a water-insoluble drug [84, 85] and by complexation of the two oppositely charged

polyions, called polyion complex (PIC) micelles [86]. PIC micelles are formed by

block copolymer, in which part is a charged segment and other part is a neutral

polymer chain; the whole molecule is totally water-soluble and narrowly distributed

[87]. The polymer always contains a nonionic water-soluble segment [e.g.,

polyethylene glycol (PEG)] and an ionic segment that can be neutralized by an

oppositely charged surfactant to form a hydrophobic core. The electrostatic

interaction between the ionic segment of the block polymer and the surfactant group

changes these segments from water-soluble to water-insoluble, leading to a

Fig. 7 Micelles are structures that form when lipids are placed in water

F. Bassyouni et al.

123

hydrophobic core in the micelles. The nonionic water-soluble shell stabilizes the

hydrophobic core of micelle [88].

PMs can be engineered by means of ligand coupling or the addition of pH-

sensitive moieties according to the biological characteristics of the diseased site for

active targeting. Various ligands such as different sugars, transferrin, folate

residues, and peptides have been attached to PMs for active targeting. Thus, PMs act

as ideal drug carriers for targeting cancerous cells. On reaching the target site, PMs

are internalized into the cells via fluid-state endocytosis, even without any surface

ligand for targeting [89].

Polymeric micelles, as drug delivery vehicles, must achieve specific targeting

and high stability in the body for efficient drug delivery [90] (Fig. 8). Recently, the

preparation of polyanion-coated biodegradable polymeric micelles by coating

positively charged polymeric micelles consisting of poly(L-lysine)–block-poly(L-

lactide) (PLys–b-PLLA) AB diblock copolymers with anionic hyaluronic acid (HA)

by polyion complex (PIC) formation were reported [91]. The obtained HA-coated

micelles showed significantly higher stability in aqueous solution.

Types of polymers used

Amphiphilic diblock copolymers are mainly used for the preparation of PMs.

However, triblock copolymers and graft copolymers are also used. Each of these

Fig. 8 Polymeric micelles with integrated smart functions, such as targetability on the surface as well asstimuli sensitivity in the intermediate layer and the core, e.g., cyclic RGD peptide ligand, detachablePEGylation, and cross linking stabilization through a disulfide bond, which is cleaved in intracellularreductive conditions


123

copolymers has unique advantages for drug delivery, so an appropriate polymer can

be chosen to achieve critical purposes so as to modify the drug release profile, to

prolong circulation time, or to introduce targeting moieties. The hydrophilic outer

part can be made up of polyethers like PEG and poly(ethylene oxide) (PEO). Other

hydrophilic shells are made up of polymers such as poly(acryloylmorpholine),

poly(trimethylene carbonate) [92], and poly(vinylpyrrolidone) [93]. Sometimes, the

hydrophilic part is made up of a mixture of polymers like PEO and polyelectrolyte

[94]. These hydrophilic polymers give stealth properties to PMs, allowing them to

avoid uptake by the RES, which is crucial for achieving long circulation times in

blood. PEG chains mostly have chain lengths of 1–15 kDa [95], but longer PEG

chains will give a denser hydrophilic corona, thus increasing stealth properties and

circulation time in vivo. Block copolymers like PEO–poly(L-amino acids) are used

which provide functional groups that can be derivatized into enhanced properties of

core-forming blocks as per the need of drug delivery.

The hydrophobic core is made up of the poly(L-amino acid), polyesters and

Pluronics (BASF). Commonly used poly(L-amino acids) are poly(L-aspartate) and

poly(L-glutamate), which can be derivatized at their functional groups. For drug

delivery purposes, some of the most commonly used polyesters are poly(glycolic

acid), poly(D-lactic acid), poly(D,L-lactic acid), copolymers of lactide/glycolide, and

poly(e-caprolactone). Pluronics are the triblock copolymers, also known as

poloxamers; these are a poly(ethylene oxide)–b-poly(propylene oxide)–b-poly(eth-

ylene oxide) type of block copolymers generally expressed as PEOm/2–b-PPOn–b-

PEOm/2, where m and n designate the total average number of the PEO and PPO

repeat units and b stands for ‘‘block’’. The size of the PPO block influences CMC

and the partitioning of hydrophobic moieties in the micelles [96].

Nanospheres

A polymeric nanosphere may be defined as a matrix-type, solid colloidal particle in

which drugs are dissolved, entrapped, encapsulated, chemically bound, or adsorbed

to the constituent polymer matrix [97, 98]. These particles are typically larger than

micelles having diameters between 100 and 200 nm and may also display

considerably more polydispersity.

Even though elimination may be slowed by the submicron particle size of

nanospheres, clearance is still inevitable due to capture by the RES, sequestering

particles within organs such as the liver and spleen [99]. It has been shown that the

hydrophobic surfaces of these particles are highly susceptible to opsonization and

clearance by the RES. Hence, it became clear that, in order to prolong the

circulation of nanoparticles, the surfaces must be modified to ‘‘look like water’’ so

that they appear to be invisible to the RES. Attempts have been made to alter the

surface of nanoparticles by adsorbing various surfactants to the particle surface

including poloxamine, poloxamer, and Brij [100, 101].

Although surfactant coating reduced the total uptake by the RES organs over

short periods of time, no difference between uncoated and coated particles was

found over longer periods, likely due to desorption of the surfactant [102].

F. Bassyouni et al.

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Nanospheres prepared using amphiphilic copolymers such as MePEG–b-PLA with

high molecular weight hydrophobic blocks provided conjugated PEG coatings with

greater stability [103] (Fig. 9). Diblock copolymer nanospheres show a phase-

separated structure with a solid core [55].

Surface-modified poly(D,L-lactide-co-glycolide) (PLGA) nanospheres (NS) for

use as cellular drug and gene delivery systems have been prepared using an

emulsion solvent diffusion method. PLGA NS were hybrid-modified using both a

cationic polymer, poly L-lysine (PLL), and a nonionic surfactant, polysorbate 80, to

improve cellular uptake in serum-containing medium (SCM) [104].

Nanocapsules and polymersomes

Polymeric nanocapsules and polymersomes are colloidal-sized, vesicular systems in

which the drug is confined to a reservoir or within a cavity surrounded by a polymer

membrane or coating. There are two possible variations, depending on the core and

the structure of the surrounding polymer. Frequently, the core is an oily liquid, the

surrounding polymer is a single layer of polymer, and the vesicle is referred to as a

nanocapsule. These systems have found utility in the encapsulation and delivery of

hydrophobic drugs including Ru 58668, methotrexate, xanthone, and

Fig. 9 Schematic representation of a mixed micelle composed of the diblock copolymers mPEG–b-P(HPMA-Lac-co-His), mPEG–b-PLA, and Cy5.5–PEG–PLA and loaded with doxorubicin. The dual-responsive drug carrier is designed with stealth behavior in blood circulation. a Micelle permeatedthrough the tumor interstitial space and maintained accumulation in the tumor matrix. Finally, dualresponsive micelle disintegrated and releases the anticancer drug rapidly in the tumor matrix.b Evaluation of the change in micelle size and polydispersity index of Dox-micelle in PBS solution(pH 7.4) at 37 �C, as determined by dynamic light scattering. Mean ± SD (n = 3). c Transmissionelectron micrographs of Dox-micelle at 1 h and in PBS (pH 7.4)


123

3-methylxanthone [105, 106]. Polymers used for the formation of nanocapsules

have typically included polyester homopolymers such as PLA, PLGA, and PCL. In

recent years, copolymers of PEG and PLA have been used to avoid opsonization of

the particles, similar to nanospheres. Nanocapsules composed of a copolymer of

PEG and chitosan have recently been used for the oral delivery of salmon calcitonin.

The PEG was found to increase the stability of the nanocapsules in gastrointestinal

fluid while reducing their cytotoxicity [107]. Alternatively, if the core of the vesicle

is an aqueous phase and the surrounding coating is a polymer bilayer, the particle is

referred to as a polymersome [108].

These vesicles are analogous to liposomes and find utility in the encapsulation

and delivery of water-soluble drugs which can be entrapped in their aqueous

reservoir, but they differ from liposomes in that the external bilayer is composed of

amphiphilic copolymers. The diblock copolymers PEG–b-PBD (polybutadiene) and

PEG–b-PEE (polyethylethylene) are strong vesicle or polymersome formers [109,

110]. These materials are bioinert but not biodegradable, and therefore investiga-

tions have focused on the development of polymersomes composed of pegylated

polyesters such as PEG–b-PDLLA and PEG–b-PCL, either as the sole constituent of

the vesicle or blended with PEG–b-PBD [111, 112]. Polymersomes generally

possess a greater PEG surface density and longer circulation times compared to

PEGylated liposomes [113].

Recently, nanohybrids and carbon nanotubes (CNTs) have been proposed as drug

delivery carriers. Nanohybrids combine biological or bio-functionalized molecules

giving rise to a system capable of drug delivery.

CNTs, on the other hand, are synthetic nano-materials, made from carbon atoms,

which can be functionalized to act as a drug delivery system [114] (Fig. 10).

Fig. 10 Nanoparticulate drug delivery systems formed by amphiphilic block copolymers and theirgeneral characteristics

F. Bassyouni et al.

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Polymeric nanohybrid materials as drug delivery systems

Polymeric nanohybrid materials comprise a core material, a therapeutic ‘‘payload’’,

and a biological surface modification that aids in the biodistribution and selective

cell-targeting moieties (Fig. 11). The nanohybrid materials/nanovectors in con-

junction with drugs are mostly delivered intravenously, as they bear the key

characteristic of their ability to be tailored to bypass the biological/physiological

and immunological barriers of the body. The use of nanovector drug delivery

vehicles has gained importance in biomedical applications, as they enable the

encapsulation and the successful delivery of drugs with poor aqueous solubility

profiles such as paclitaxel, an antitumor agent [105–107]. Paclitaxel bound to

albumin nanoparticles is an FDA-approved nanoparticle formulation, under the

market name Abraxane, for delivery to metastatic breast cancer patients [108, 109].

Another advantage of utilizing polymeric nanovectors is the potential for non-

invasive targeting to the tumor. Nanohybrid materials exhibit multifunctional

features that facilitate imaging, targeting, and drug delivery. Other polymeric

nanovector composites that have received much attention in cancer drug delivery

are polylactide–polyglycolide copolymers entrapping leutinizing hormone-releasing

hormone (LHRH), marketed as goserelin (Zoladex) and leuprolide (Lupron Depot)

[110, 111], and liposomes encapsulating daunorubicin and doxorubicin, marketed as

DaunoXome and Doxil/Caelyx, respectively [112, 113]. Other polymers include N-

(2-hydroxyl propyl)methacrylamide (HPMA) copolymers, polyglycolic acid (PGA)

with paclitaxel, marketed as XyotaxTM [113, 114], and polycaprolactones and

natural polymers like albumin, gelatin, alginate, collagen, and chitosan.

Fig. 11 Multifunctional polymeric nanohybrid devices for targeted drug delivery system


123

Carbon nanotubes as new drug delivery carriers

Carbon nanotubes (CNTs) are synthetic nanomaterials made from carbon and

belonging to the family of fullerene (Fig. 12). Structurally, carbon nanotubes can be

pictured as rolled sheets of graphene rings built from sp2 hybridized carbon atoms

into hollow tubes. There are two categories of carbon nanotubes: single-walled

carbon nanotubes (SWNTs) and multi-walled carbon nanotubes (MWNTs). SWNTs

contain one layer of graphene sheet with a diameter of 1–2 nm with a length ranging

from 50 to several hundred nanometers, whereas MWNTs are co-axially arranged

multiple layers of SWNTs, positioned within one another with a diameter ranging

from 5 to 100 nm [115]. There are various techniques to produce CNTs. The three

main techniques are (1) electric arc discharge [116], (2) laser ablation [117], and (3)

chemical vapor deposition [118].

Functionalization of carbon nanotubes for drug delivery

The functionalization of carbon nanotubes for biomedical applications involves

covalent or non-covalent modifications. Covalent modifications are carried out by

reacting carbon atoms on the sidewall of carbon nanotubes to a therapeutic molecule.

In biological applications, oxidation and grafting polymers on the sidewalls of carbon

nanotubes are widely adopted. In the process of oxidation, the raw (pristine) carbon

nanotubes are refluxed in nitric acid, which results in open tubes and tips that bear

oxygenated functions, mainly carboxyl acids [119, 120]. Another important covalent

modification of carbon nanotubes involves 1,3-dipolar cycloaddition reactions [121].

Using this method, azomethine ylides are added to the graphitic surface of CNTs,

forming pyrrolidine-fused rings (Fig. 13). These covalent modifications lead to the

generation of various functional moieties on the ends and sidewall of CNTs and enable

the conjugation of various fluorescent dyes, drugs, peptides, etc. [122, 123].

A detailed review on attaching various compounds and drugs covalently to

CNTs, following the two above-mentioned methods, has been published [124].

Fig. 12 Carbon nanotubes, pristine (left) and multi-walled (right), in drug delivery

F. Bassyouni et al.

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Polymer electrolytes PE as efficient drug carriers

Polyelectrolyte (PE) represents a simple but very interesting route with significant

importance in delivery of ionic drugs. The therapeutic moiety is ionically bound to the

oppositely charged drug leading to formation of a polyelectrolyte complex (PEC). A

significant advantage of such a system over a matrix system is that the drug forms a

major part of the total delivery system, permitting very high loadings. Therefore, the

knowledge about the factors that determine the interaction between ionic or ionizable

drugs and PE is relevant in the design of pharmaceutical dosage forms.

Drug complexes with linear polyelectrolytes have been studied [126–132]. In this

approach, the drug is released by an ionic exchange process with the electrolytes of

the dissolution medium. Upon drug release, the ionized polymer dissolves without

forming a gel, eroding the delivery system. Most materials studied consisted of

copolymers of an ionogenic monomer with a non-ionizable, hydrophobic one (e.g.,

methyl methacrylate) [126, 127, 129, 131, 132]. While the charged monomer

imparts the ionic binding capability, the hydrophobic monomer imposes the slow

chain hydration and dissolution required for extended release. First of all,

composition characterization of the copolymers is required for each study. Due to

differences in the reactivity ratios of the monomers, differences between the

composition feed and the composition of the copolymers are commonly found,

making it difficult to obtain the desired composition [129]. A further disadvantage is

the inclusion of non-ionizable monomers in the polymer chain, possibly decreasing

the loading capacity of the polyelectrolyte. Recently, the synthesis of a series of

poly (carboxyalkyl methacrylates) [133]) have been developed. These weak

polyelectrolytes are shown in (Fig. 14). In these materials, hydrophobicity increases

as the number of methylene groups (n) in the side chain increases, maintaining the

ionizable group in each monomeric unit.

These materials allow us to control hydrophobicity without decreasing the

proportion of ionizable groups, which can interact with cationic drugs.

Recently, controllable exploding polyelectrolyte microcapsules have been

developed by layer-by-layer assembly of poly (allylamine hydrochloride) (PAH)

and poly (sodium 4-styrenesulfonate) (PSS) on a dextran microgel core containing a

cleavable disulfide bond fabricated via click chemistry [134].

Fig. 13 Functionalization of carbon nanotubes via 1,3-dipolar cycloadditions. The 1,3-dipolarcycloaddition of azomethine ylides on CNT is generated by in situ thermal condensation of aldehydesand a-amino acids. Azomethine ylides are very reactive intermediates and efficiently attack the p-systemof the CNT causing large numbers of pyrrolidine rings fused to the CNT side wall, which helps insolubilization of CNTs [125]


123

Polyelectrolyte complex (PEC)

Mixing oppositely charged polyelectrolytes in solution will result in their self-

assembly or spontaneous association due to the formation of strong, but reversible,

electrostatic links. These direct interactions between the polymeric chains lead to the

formation of polyelectrolyte complex networks with non-permanent structures while

avoiding the use of covalent cross-linkers. Since chitosan is positively charged at low

pH values (below its pKa value), it spontaneously associates with negatively charged

polyions in solution to form polyelectrolyte complexes [135] (Fig. 15).

These complexes are therefore good candidate excipient materials for the design

of different types of dosage forms. Many different polyelectrolyte complexes

between chitosan and anionic natural polymers have been prepared and investi-

gated. However, some of these polyelectrolyte complexes have been formed and

characterized but not yet investigated for drug delivery purposes, such as those

formed between chitosan and polygalacturonic acid [136], sodium dextran sulfate

[137], carboxymethyl cashew gum [138], fibroin [139], sodium carboxymethyl

cellulose [140], and ‘‘angico’’ gum [141].

Hydrogels as controlled delivery systems and clinical application

Hydrogels are polymeric biomaterials with a 3D structure that can absorb a certain

amount of water. They were taken up by the pharmaceutical industry a couple of

Fig. 14 Structure of series ofcarboxyalkyl methacrylatesstudied (n = 4, 5, 7, and 10)

Fig. 15 Formation of polyelectrolyte complexes

F. Bassyouni et al.

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decades ago as a new pharmaceutical system with special characteristics. These

biomaterials showed that their possibilities as a modified release form are countless

because a careful design of its chemical structure could result in a selective release

of the drug under specific conditions.

Hydrogels are natural or synthetic cross-linked polymeric materials designed to

contain a large amount of water, and characterized by their biocompatibility,

biodegradability, and low toxicity. Although there is not an accepted criterion

regarding the classification of the hydrogels, it is quite common to classify them into

physical hydrogels—formed by direct interactions between polymeric chains—and

covalently cross-linked hydrogels, which need to include a chemical cross-linking in

their structure.

Hydrogels have great potential as drug carriers since their physical properties

(high water content, consistency, and low surface tension) are similar to those of

living tissues. The properties of hydrogels are dependent on their structure,

composition, and degree of cross-linking, and therefore, besides the selected starting

materials, the production method is crucial for their ability to contain water and

other characteristics, such as consistency, stability, oxygen permeability, elasticity,

viscosity, or surface tension. Hydrogels can even exhibit bio-adhesive properties,

which cause an increase in the residence time at the absorption site, enhancing the

effectiveness of the drug (Fig. 16).

Hydrogels are a versatile alternative for the design of these controlled release

forms, by selecting a suitable combination of polymer, solvent, and drug. Other

desirable properties already mentioned are their biocompatibility, low toxicity, and

susceptibility to enzymatic degradation. Three possible release mechanisms have

been described: diffusion, swelling-controlled, or chemical-controlled, with the

Fig. 16 Classification of hydrogel biomaterials


123

potential to be combined and further sophisticated by tailoring the release to a

particular stimulus. For these reasons, hydrogels already have clinical applications

in many areas such as tissue engineering and regenerative medicine, diagnostics,

cellular immobilization, separation of bio-molecules or cells, and barrier materials

to regulate biological adhesions [24, 146]. However, nowadays, there are limitations

for the use of some hydrogels, such as the low mechanical strength, the limited

duration and homogeneity of drug loading, and problems related to the application

due to an insufficient deformability. Some strategies could solve these highlighted

issues and are explained in detail elsewhere.

The definition of smart or intelligent hydrogels

Among the hydrogels, the so-called smart or intelligent hydrogels stand out for their

potential as therapeutic carriers due to the control they can exert on drug release.

Intelligent hydrogels are able to change their structure or form in response to an

external stimulus, such as temperature, pH, electric field, magnetic field, or medium

ionic strength, allowing the switching on and off of drug release [142].

The pH-responsive hydrogels are the best known and studied of the intelligent

gels. They are formed by polymers with ionizable groups. Changes in the pH of the

medium around the pKa of these groups affect the degree of ionization and, thus, the

hydrogel structure. Since the oral administration route is the most physiological one

and pH varies in the range of 1–8, these gels have a large potential application (Fig.

17) for drug-controlled release in the intestine. One of the first examples was the

hydrogel formed from acrylic acid and polyvinyl alcohol designed by Nho et al.

[143], which allowed the selective release of insulin in the colon. More recently,

Mundargi et al. [144] have obtained a copolymeric hydrogel to release insulin with

nanoparticles sensitive to pH. In this case, the system is based on N-vinylprolactam

and methacrylic acid monomers. Modifying these ionizable groups, it is possible to

obtain molecules that respond to very small changes in pH. Gupta et al. [145]

Fig. 17 Smart self-handling hydrogels

F. Bassyouni et al.

123

designed a pH-sensitive hydrogel to prevent HIV transmission prepared from N-

isopropylacrylamide, butyl methacrylate, and acrylic acid, which contains an

antiviral agent that is released in response to pH change produced by semen

presence. Amphiphilic copolymers with amine groups in their structure are able to

form micelles that retain drugs at a slightly basic pH (such as that observed in the

bloodstream, pH = 7.4) and release the drug when the micelles penetrate cells by

endocytosis because the pH in the endosomes or lysosomes is lower (pH 5–6) [146].

Temperature-responsive hydrogels are those that pass from liquid state to a gel,

depending on the temperature; for example, they behave as liquids in a range of

temperatures and jellify at higher and/or lower temperatures. These gels have been

used as injectable forms for controlled release of peptides and proteins. In their

liquid state, they are suitable for injection but acquire the consistency of a gel within

the body. This approach is useful to avoid invasive surgery when placing an

implant. The polymers poly(N-isopropyl acrylamide), poly(N-vinylpiperidine), and

poly(N-vinylcaprolactam) and others exhibit this behavior and can be used alone or

in combination with other polymers. These temperature-sensitive systems can also

be modulated externally by incorporating metal particles with the other components.

Local irradiation with laser light produces an increase of the temperature of the

selected area and the subsequent localized drug delivery [147].

However, the final goal is to design smart materials that are able to release the

drug in the presence of a chemical stimulus and to switch it off when the stimulus

stops, simulating the regulation mechanisms of biological systems (Fig. 18). For this

purpose, the hydrogels need a sensor mechanism that reacts to a precise level of a

particular bio-molecule in the media. In this line of work, very promising systems

releasing insulin when glucose reaches certain values have been designed. Other

areas of research include antigen-responsive gels, which will activate drug release

only under active disease conditions [148, 149].

Similarly, other stimuli, such as radiative, electric, and magnetic fields, or

oxidizing agents, have been used to develop sensitive hydrogels. The current

challenge is the obtaining of intelligent systems capable of simultaneously

controlling the release of several drugs in response to different stimuli [150]. The

design of these systems involves the computerized analysis of the stimulus, data

processing, and signal activation to timely release the drugs.

Fig. 18 Smart hydrogels and biomaterials


123

Future potential applications for drug delivery systems

The pH-sensitive hydrogels have been extensively used as a controlled release

system in specific sections of the GI tract. For example, polyelectrolyte complexes

composed of chitosan and poly-acrylic acid have been used to provide controlled

release of pentosan polysulfate in the colon due to the reversibly linked gel structure

of the two oppositely charged polymers, which is sensitive to the colon pH. Several

glucose-sensitive systems for oral administration have been developed using

different mechanisms for insulin release [151–153] (Fig. 19). The intelligent

hydrogels are able to respond not only to changes in pH and temperature but also to

glucose levels. These kinds of hydrogels are known as multi-responsive systems that

intend to mimic the physiological control mechanisms [154] (Fig. 20). On the other

hand, the design of smart systems for oral delivery of chemotherapeutics is

particularly attractive due to the patient acceptance of this route of administration,

leading to a better treatment adherence in long-term and chronic patients and to an

increased quality of life. An oral-controlled release system allows the reduction of

the high plasma levels of these toxic drugs and could provide a more selective

exposure to the antitumoral drug [155]. For example, micellar nanogels formed by

copolymers of polyethylenimine and polybutylcyanoacrylate and Pluronic surfac-

tants have demonstrated a slow release of paclitaxel. Chemotherapeutics formulated

as hydrogels can also be administered locally by injecting the system-containing

potent anticancer drugs, such as doxorubicin or paclitaxel [156, 157].

It should be highlighted that the subcutaneous administration of chitosan

hydrogels has been used to deliver different growth factors to cartilage, bone, and

nerves to improve tissue regeneration [158, 159]. Moreover, recent studies on

Fig. 19 Conceptual scheme of controlled release of ODN from a hydrogel composed of a CyD-containing molecular network by mechanical compression

F. Bassyouni et al.

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hydrogels applications suggest that these systems may also be useful in stem-cell

delivery in tissue engineering.

Hydrogels with bioadhesive properties have been extensively explored for

mucosal delivery in oral, nasal, vaginal, and pulmonary dosage forms [160, 161].

The adhesive properties are also interesting for ophthalmic administration because

the extended residence time of the formulation in contact with the conjunctiva

improves drug ocular absorption. A pH-sensitive system of polyacrylic acid and

hydroxyethyl cellulose loaded with timolol maleate has been used to achieve a

relevant and stable reduction of intraocular pressure [162]. Several nanoparticulate

systems for ophthalmic-controlled release of drugs have been designed by Barbu

et al. [163, 164] based on acrylic acid–functionalized chitosan, N-isopropylacryl-

amide, or 2-hydroxyethyl methacrylate. Another promising use of temperature-

sensitive hydrogels is the subconjunctival administration of insulin for the treatment

of diabetic retinopathy, as has been demonstrated in in vivo assays carried out in

rats.

Conclusion

The technologies described here represent small fraction of the development of drug

delivery systems and a few of them are still at the experimental level. The need for

research into drug delivery systems extends beyond ways to administer new

pharmaceutical therapies. The safety and efficacy of current systems can be

improved if their delivery rate, biodegradation, and site-specific targeting can be

predicted, monitored, and controlled. The help of advances in biotechnology,

chemistry, and chemical engineering will enable researchers to obtain drug delivery

Fig. 20 Schematic diagrams of several common samples investigated for the delivery of growth factors(GFs) to the periodontium (components not scale to actual size). a Nano- (green) and micro-particle (red)vehicles. b GFs immobilized into a three-dimensional (3D) scaffold. c GFs incorporated into hydrogels.d GF-loaded particulates incorporated into a polymeric scaffold. e Gene delivery for releasing GFs


123

systems with minimum side effects and maximum effectiveness. Polymeric

micelles, nanocapsules, polymersomes, and carbon nanotubes used as drug delivery

vehicles must achieve specific targeting and high stability in the body for efficient

drug delivery systems. In addition, hydrogels have clinical applications in many

areas such as tissue engineering and regenerative medicine, diagnostics, cellular

immobilization, separation of bio-molecules or cells, and barrier materials to

regulate biological adhesion systems.

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Advances and new technologies applied in controlled drug delivery system