DRUG DELIVERY SYSTEMS

Zeynep SÖNMEZALP

Conventional forms of drug administration generally rely on pills, eye drops, ointments and intravenous solutions. But in the last few years we have witnessed an explosion in research aimed at creating new drug delivery systems.

There are some reasons for this explosion in creating new drug delivery systems;

ü Advances in materials science and biotechnology are permitting the development of new physical and chemical methods for drug delivery.

ü The overall expense to create a pharmaceutical that is a new molecular entity is at least $150 million; the lower cost to improve the delivery of an existing drug is sometimes seen as a better investment.

ü Newer and complex drugs such as proteins becoming available through genetic engineering; the delivery of these drugs is often more complicated than that of more conventional drugs; necessitating novel delivery systems.

ü Many drugs both old pharmaceutical products and new molecular entities, can be administered in ways that not only improve safety and efficacy, but in some cases permit new therapies.

A drug may be chemically modified to selectively alter such properties as biodistribution, pharmacokinetics, solubility or antigenicity. Several experimental approaches have been developed in drugs that are designed to cross a normally impermeable barrier. Drugs are complexed to agents that enable them to cross these barriers.

(i)Drugs have been attached to soluble macromolecules such as protein, polysaccharides or synthetic polymers via degradable linkages. This process alters the drug's size and other properties, resulting in different pharmacokinetics and biodistribution.

When anti-tumor agent neocarzinostatin and styrene-maleic acid copolymer complex was injected intra-arterially into patients with hepatocellular carcinoma, decreases in a-fetoprotein level and tumor size were observed.

(ii) “Targeting” drugs to specific cells involves linkage of a bioactive agent to a monoclonal antibody. This bioactive agent can be drug, radioisotope or toxin.

Antibody conjugates are now being studied in the treatment of cancer, septic shock and acquired immunodeficiency syndrome (AIDS).

(iii)Polymers such as polyethylene glycol (PEG) can be attached to drugs to either lengthen their lifetime or alter their immunogenicity.

PEG uricase reduced serum urate levels in patients with hyperuricemia and gout. PEG asparaginase has been used for patients with leukemia.

Biological approaches (protein engineering and altering glycosylation patterns) affect drug longevity and immunogenicity.

Various types of colloidal drug delivery system

Vesicles are microparticulates or colloidal carriers composed of substances such as proteins, lipids (liposomes), carbohydrates or synthetic polymers.

Liposomes have been used as systemic drug delivery systems for many years because their biomimetic properties allow them to deliver both water-soluble and hydrophobic drugs safely over a relatively long period of time. Liposomes can be formulated with a variety of lipid compositions and structures. They are potentially nontoxic, degradable and nonimmunogenic. However many liposomes exhibit poor stability during storage and use. Liposome stability may be improved by increasing the liposomal cholesterol content or synthesizing polymerizable liposomes, but biodegradability may then be diminished.

Liposomes are becoming increasingly attractive as drug delivery vehicles for improving current methods of cancer chemotheraphy. Compared to unassisted methods of drug delivery, drugs encapsulated within liposomes show reduced toxicity, increased circulation time, and the potential for specific receptor mediated targeting of tumor.

Nanoparticles (dispersed particulate systems with mean diameters below 1mm) have promise as target oriented drug delivery systems and can be prepared from a variety of natural and synthetic macromolecules. Nanoparticles of polymers can be used as drug delivery systems by dissolving, entrapping, adsorbing, attaching or encapsulating the drug.

CONTROLLED RELEASE SYSTEMS

Controlled release systems deliver a drug at a predetermined rate for a definite time period. In general, release rates are determined by the design of the system and are nearly independent of environmental conditions, such as pH. These systems can also deliver drugs for long time periods (days to years). Although vesicles or drug macromolecule conjugates may prolong release, optimal control is afforded if the drug is placed in a polymeric material or pump.

Controlled release systems differ from older “sustained release” or “slow release” preparations that include complexes, suspensions, emulsions, slowly dissolving coatings that do not dissolve in the intestine and compressed tablets. Generally, sustained release systems emit drugs in less than a day and environmental conditions influence release rates, which leads to patient to patient variations.

Advantages of controlled release systems over conventional drug therapies

ü A controlled release preparation maintains the drug in the desired therapeutic range by a single administration.

ü Localized delivery of the drug to a particular body compartment, thereby lowering the systemic drug level.

ü Preservation of medications that are rapidly destroyed by the body (this is particularly important for biologically sensitive molecules such as proteins)

ü Reduced need for follow-up care

ü Increased comfort

ü Improved compliance

After ingestion or injection of standard dosage forms, the blood level of the drug rises, peaks and then declines. Since each drug has a therapeutic range above which it is toxic and below which it is ineffective, oscillating drug levels may cause alternating periods of ineffectiveness and toxicity. Although sustained release preparations attenuate the peaks and valleys, they do not eliminate them. In contrast, a controlled release preparation maintains the drug in the desired therapeutic range by a single administration.

New Methods of Drug Delivery-Robert Langer

Polymer release mechanisms

The most common release mechanism is diffusion, where by the drug migrates from its initial position in the polymeric system to the polymer’s outer surface and then to the body.

ü Diffusion may occur through a reservoir, it’s able to produce constant release rates.(A)

ü Drug core is surrounded by a polymer film or matrix; it can be uniformly distributed through the polymeric system. It’s inexpensive to manufacture.(B)

ü Drugs can also be released by chemical mechanisms such as degradation of the polymer.(C)

ü Cleavage of the drug from a polymer backbone can be occur.(D)

ü Exposure to a solvent can also activate drug release. The drug may be locked into place by polymer chains and upon exposure to environmental fluid, the outer polymer region begin to swell, allowing the drug to move outward.(E)

ü Water may permeate a drug polymer system as a result of osmotic pressure, causing pores to form and bringing about drug release.(F)

ü Some polymer systems can be externally activated to release more drugs when needed, using forces such as magnetism.(G)

ü An external magnetic field causes polymer-embedded magnetic beads to squeeze drug containing pores, forcing more drug out of a matrix.(H)

One of the first clinically used controlled release polymer systems was Ocusert, a reservoir system designed to improve therapy for glaucoma, one of the world’s leading causes of blindness. The conventional treatment involved the use of pilocarpine eye drops (which reduce intraocular pressure) four times a day. The eye drops often caused side effects, and patient compliance was sometimes poor. Despite its advantages, the Ocusert never achieved widespread use, initially because of its expense and poor acceptance by older patients who were reluctant to adjust to this system and later because of the introduction of timolol, a drug that requires only two applications per day.

Controlled Release Systems for Peptides and Proteins

For many years, controlled release systems were capable of slowly releasing drugs of only low molecular weight. Large molecules such as proteins were not considered too large to slowly diffuse through most polymeric materials.

Large molecules could diffuse through highly porous membranes such as millipore filters or certain gels such as polyacrylamide. However in these cases diffusion was generally too rapid to be of value and tissue damage was usually observed.

The first report of sustained release of macromolecules was from Davis in 1972. In his studies, polyacrylamide and polyvinylpyrolidone were used as vesicles. However these polymers were inflammatory and permitted only brief periods of sustained release.

The discovery that matrices of solid hydrophobic polymers containing powdered macromolecules enabled molecules of nearly any size to be released for over 100 days permitted controlled delivery of a variety of proteins, polysaccharides. Nondegradable ethylene-vinyl acetate and degradable lactic acid-glycolic acid copolymers are the examples of polymers perform in this way.

Factors influencing release rates include;

ü Protein particle size and loading

ü Protein solubility and molecular weight

ü Polymer composition and molecular weight

ü The dimensions and shape of the matrix

Degradable polymers

New Methods of Drug Delivery-Robert Langer

For polymers, to maximize control over release, it is often desirable for a system to degrade only from its surface.

For surface eroding systems, the drug release rate is proportional to the polymer erosion rate.

Achieving surface erosion requires that

ü The degradation rate on the polymer matrix surface be much faster than the rate of water penetration into the matrix bulk.

ü The polymer should be hydrophobic but should have water-labile linkages connecting monomers.

In surface eroding polyester systems, additives are placed inside the polymer matrix and cause the surface to degrade at a different rate than the rest of the matrix. Such a degradation pattern can occur because these polymers erode at very different rates, depending on pH and additives.

Pulsatile polymeric controlled release systems

It would be desirable if polymeric systems could be designed to release increased levels of drug when needed; this would mimic the body’s physiological processes.

Magnetic field and ultrasound can be used to enhance drug release rates from polymers.

Both open-loop and closed-loop approaches are being studied. In one closed-loop polymeric system, glucose oxidase was immobilized to agarose beads contained within a polymer matrix. The acid formed when external glucose reacts with the immobilized enzyme lowers the pH, which changes the solubility of insulin and the diffusional driving force. Increased release rates to glucose challenges were observed in vitro and in vivo. Stability of insulin, enzymes and the rapidity of movement of insulin from the polymer matrix to the circulation is critical.

Pulsatile systems involving pH sensitive and temperature sensitive are also studied.

TARGETED DRUG DELIVERY

For the majority of pharmaceuticals currently in use, the activity against certain diseases or disease sites is not based on their ability to accumulate selectively in the pathological organ, tissue or cell.

Usually the pharmaceutical agent is rather evenly distributed within the body. Moreover, to reach the site of action the drug has to cross many biological barriers, such as other organs, cells and intracellular compartments, where it can be inactivated or express undesirable influence on organs and tissues that are not involved in the pathological process.

As a result, to achieve a required therapeutic concentration of a drug in a certain body compartment, one has to administer the drug in large quantities (the great part of which is just wasted in normal tissues). In addition, under these circumstances cytotoxic and antigenic drugs can become the cause of many negative side effects.

In a very general sense, one understands drug targeting as the ability of the drug to accumulate in the target organ or tissue selectively and quantitatively, independent of the site and methods of its administration.

Ideally the local concentration of the drug at the disease site(s) should be high, while its concentration in other non-target organs and tissues should be below certain minimal level to prevent any negative side-reactions.

Advantages of drug targeting;

ü Drug administration protocols may be simplified

ü Drug quantity required to achieve a therapeutic effect may be greatly reduced as well as the cost of therapy

ü Drug concentration in the required sites can be sharply increased without negative effects on non-target compartments

The concept of drug targeting, suggested by Paul Ehrlich almost a century ago, considered a hypothetical `magic bullet' as an entity consisting of two components the first one should recognize and bind the target, while the second one should provide a therapeutic action in this target. Currently, the concept of magic bullet includes a coordinated behavior of three components: (a) drug;

(b) targeting moiety;

(c) pharmaceutical carrier used to multiply the number of drug molecules per single targeting moiety. Pharmaceutical carriers include soluble polymers, microcapsules, microparticles, cells, cell ghosts, lipoproteins, liposomes, and micelles. All of them can be made targeted in one way or another.

The recognition of the target can occur:

ü On the level of a whole organ

ü On the level of certain cells specific for a given organ

ü On the level of individual components characteristic of these cells, such as cell surface antigens.

The most universal form of target recognition is the recognition on the molecular level based on the fact that every organ or tissue certain compounds can be found that are specific only for the organ of interest. For successful targeting another compound can be used as a transporting unit, which is capable of the specific interaction with the specific target component

In the liposomal delivery of chemotherapeutic drug doxorubicin, the drug was targeted specifically to C6 gioma in vitro by coupling transferrin to the distal ends of liposomal polyethylene glycol (PEG) chains. The transferrin receptor is overexpressed on glioma, with the extent of overexpression correlated to the severity of the tumor. Significantly increased gliomal doxorubicin uptake was achieved by drug encapsulation within transferrin-coupled liposomes compared to other liposome populations.

Principal schemes of targeted drug delivery

ü (a) direct application of the drug into the affected zone (organ, tissue);

ü (b) passive accumulation of the drug through leaky vasculature (tumors, infarcts, inflammation);

ü (c) `physical' targeting based on abnormal pH and/or temperature in the target zone, such as tumor or inflammation (pH- and temperature-sensitive drug carriers);

ü (d) magnetic targeting of drugs attached to paramagnetic carriers under the action of external magnetic field;

ü (e) use of vector molecules possessing high specific affinity toward the affected zone. In a certain sense, cases (c) and (d) can be considered together as a `physical targeting'.

Direct application of drugs

In certain cases, drug targeting may be achieved by a very simple way. A drug is administered directly into the affected organ or tissue. The successful examples of this approach include the intra-articular administration of hormonal drugs in the therapy of arthritis.

Passive drug targeting(Spontaneous drug accumulation in `leaky' areas)

European Journal of Pharmaceutical Sciences,Drug Targeting,Oct.200

In such areas like tumors and hypoxic areas of infarcted myocardium, with the increased vascular permeability even relatively large particles, such as micelles and liposomes ranging from 10 to 500 nm in size, can extravasate and accumulate inside the interstitial space.

If these particles are loaded with a certain drug, they can bring this drug into the `leaky' zone where the drug can be released as a result of normal carrier degradation.

Physical targeting of drugs

European Journal of Pharmaceutical Sciences,Drug Targeting,Oct.200

Physical factors able to mediate targeted drug delivery may be of both, endogenous and exogenous origin.

ü In the first case, the targeting effect is based on the fact that pathological area differs from normal tissues in certain properties, such as temperature and pH.

Anti-cancer drug methotrexate incorporated into temperature-sensitive liposomes and injected intravenously into mice with inoculated tumors was accumulated in tumors several times faster, especially under conditions when the localized external heat was applied onto tumor area.

ü An interesting example of targeted drug delivery by external physical force is the magnetic drug transport. For this purpose, the drug is immobilized on a microparticulate carrier possessing ferromagnetic properties.

Targeting moieties

European Journal of Pharmaceutical Sciences,Drug Targeting,Oct.200

The most natural and universal way to impart the affinity toward the target to a non-specific drug is the binding of this drug with another molecule (usually referred to as a targeting moiety of vector molecule) capable of specific recognition and binding to a target site.

The following substances can be used as targeting moieties: antibodies and their fragments, lectins, other proteins, lipoproteins, hormones, charged molecules, mono-, oligo- and polysaccharides, some low-molecular-weight ligands, such as folate.

Cross-linked hyaluronic acid hydrogel films: new biomaterials for drug delivery

Hyaluronic acid is a naturally-occurring linear polysaccharide comprised of β-1,4-linked D-glucuronic acid (b-1,3) N-acetyl-D-glucosamine disaccharide units. It is the only non-sulfated glycosaminoglycan in the extracellular matrix of all higher animals.

Hyaluronic acid has been implicated in water homeostasis of tissues, in the regulation of the permeability of other substances by steric exclusion phenomena, and in the lubrication of joints. Hyaluronic acid binds specifically to proteins in the extracellular matrix, on the cell surface, and within the cell cytosol, thereby having a role in cartilage matrix stabilization

Unmodified HA has many important applications in drug delivery and surgery. For example, HA is used as an adjuvant for opthalmic drug delivery, and was found to enhance the absorption of drugs and proteins via mucosal tissues.

Preparation

Hyaluronic acid was first converted to the adipic dihydrazide (HA-ADH) derivative. Then crosslinked with the macromolecular homobifunctional reagent poly(ethylene glycol) propiondialdehyde to give a polymer network .

ü HA-ADH was dissolved in H2O at a concentration of 5 mg/ml (solution A). PEG-diald was dissolved in H2O at a concentration of 50 mg/ml (solutionB).

ü Solution A and B were added to a small petri dish and mixed with gentle swirling.

ü A hydrogel began to form within 60 seconds.

ü The mixture was agitated on an orbital platform for an additional 24 h to obtain a solid, uniform hydrogel.

ü Hydrogels were stored in an open dish overnight at 37°C to allow solvent evaporation and thus provide a flexible, hydratable HA hydrogel film

The chemistry of the crosslinking reaction involves hydrazone formation, which is rapid and occurs at neutral to acidic pH. The hydrogel thus formed can be used directly in virtually any biological system, as both the hydrogel and its two macromonomer components are biocompatible and biodegradable, has significant advantages for purification and drug loading, since alkaline conditions, high temperatures, and small toxic crosslinkers can be avoided.

Drug loading and drug release

Drug molecules were loaded into the hydrogel films via the in situ polymerization method.

ü Drugs were initially dissolved in H2O (for pilocarpine and diclofenac sodium) or ethanol (for indomethacin, hydrocortisone, prednisolone, corticosterone).

ü Mixed with solution A

ü The crosslinking protocol was followed by adding solution B to produce a drug containing hydrogel

ü During solidification, each drug-loaded hydrogel was agitated for 24 h, and drug-containing hydrogel films were obtained by drying slowly at 37°C.

Dried hydrogel films loaded with drug molecules were cut into 6-mm diameter disks. Each disk was placed in a cuvette suitable for a UV-Vis instrument, and the in vitro drug release in the stirred cuvette was measured in 3 ml PBS buffer at 37°C. the drug concentration released into the PBS buffer was detected by UV as a function of time.

After completion of the drug release time course, the HA hydrogel film was removed from PBS buffer, and its surface was washed with distilled H2O. Each film was then immersed into 3 ml of 1 M NaOH; the film was fully degraded after 24 h at room temperature. After filtration through a 0.2 m membrane, the remaining drug content in the film was determined by optical absorbance.

To evaluate the ability of HA hydrogel for controlled drug delivery, several anti-inflammatory agents in clinical use were selected for drug release studies.

ü Some of the drugs such as pilocarpine, hydrocortisone, prednisolone were rapidly released from the hydrogel film(10 min.)

ü Similar release profiles were obtained with diclofenac sodium, indomethacin and corticosterone

ü In contrast dexamethasone shows sustained release for 1h, and prednisone showed sustained release for almost 24 h.

There is a linear relationship between the hydrophobicity of drug molecule and its release rate from the HA hydrogel film, with the more hydrophobic steroids being released more slowly. These results indicate that this HA hydrogel film has excellent potential for controlled drug release based on drug hydrophobicity, thus allowing this new biomaterial to act as a local delivery device at wound sites.

Journal of Controlled Release,Cross-linked Hyaluronic acid hydrogel films,Oct.200

SEM images were obtained to characterize the surface of the HA hydrogel films. HA hydrogel film samples in dried hydrogel and hydrated states were prepared. The flat and featureless images indicate that the HA films have a condensed structure when dry. The surface and cross-sectional images of freeze-dried HA hydrogel films clearly show the appearance of a highly-porous structure in the swollen hydrogel.

Journal of Controlled Release,Cross-linked Hyaluronic acid hydrogel films,Oct.200

Degradation of the HA hydrogel films by HAse was examined by SEM. The control sample of HA hydrogel film immersed in enzyme-free PBS buffer for 3 days retained an intact, condensed surface structure. In contrast, addition of 100 U/ml of HAse to the buffer produced significant surface erosion of the HA hydrogel film. The surface differences of the HA hydrogel films in buffer with or without enzyme clearly demonstrated that HAse can recognize and process the crosslinked HA, and that the HA hydrogel films would be expected to be bioerodable in vivo.

References

ü Improved Drug Delivery Using Microemulsions: Rationale,Recent Progress and New Horizons-Critical Reviews in Therapeutic Carrier Systems.18(1):77-140(2001)

ü New Methods of Drug Delivery- Robert Langer,24 September 1990

ü Science Direct-Current Opinion in Chemical Biology-Drug Delivery:an odyssey of 100 years

ü Science Direct-Journal of Controlled Release-Croslinked hyaluronic acid hydrogel films: new biomaterials for drug delivery

ü Science Direct-European Journal of Pharmaceutical Sciences-Drug targeting

ü Science Direct-Expert Opinion on Therapeutic Patents: Targeted Drug Delivery

ü Biomedical Polymers Polymeric Materials and Pharmaceuticals for Biomedical Use-Controlled Release of Macromolecules from Polymers-Robert Langer, Judah Folkman

ü Localized drug delivery using crosslinked gelatin gels containing liposomes: Factors influencing liposome stability and drug release-Valerio DiTizio, Caroline Karlgard, Lothar Lilge, Antoine E.Khoury, Marc W. Mittelman, Frank DiCosmo

ü Wiley-Targeted drug delivery to C6 glioma by transferrin-coupled liposomes

ü Biodegradable Polymers for Controlled Drug Delivery-Mark Chasin

ü Nanocapsules for Controlled Drug Delivery-Jo Whelan