Advances In Drug Delivery

CONTROLLED DRUG DELIVERY SYSTEM

It is the one which delivers the drugat a predetermined rate,locally or systematically, for a specific period of time. Advantages Improved patient convenience and compliance due to less frequent administration. Reduction in flucutuation in steady state levels and therefore better control of disease and reduced intensity of local or systemic side effects. Increased safety margin of high potency drugs due to better control of plasma levels. Maximum utilization of drug enabling reduction in total amount of dose administered. Reduction in healthcare costs through improved therapy,shorter treatment period,less frequency of dosing

Disadvantages Decreased systemic availability in comparison to immediate release conventional dosage forms,this may be due to incomplete release, increased first pass metabolism,increased instability etc Poor in vitro correlation Higher cost of formulation

ORAL DRUG DELIVERY SYSTEMS

Advantages Disadvantage Dose dumping. Reduced potential for accurate dose adjustment. Need of additional patient education. Stability problem Total dose is low. Reduced GI side effects. Reduced dosing frequency. Better patient acceptance and compliance. Less fluctuation at plasma drug levels. More uniform drug effect Improved efficacy/safety ratio.

Mechanism aspects of Oral drug delivery formulation 1.Dissolution : 1.Matrix 2.Encapsulation 2.Diffusion : 1.Matrix 2.Reservoir 3.Combination of both dissolution & diffusion. 4.Osmotic pressure controlled system

Dissolution Solid substances solubilizes in a given solvent. Mass transfer from solid to liquid. Rate determining step: Diffusion from solid to liquid. Several theories to explain dissolution Matrix Type Diffusion layer theory (imp) Surface renewal theory Limited solvation theory

Also called as Monolith dissolution controlled system. Controlled dissolution by: 1.Altering porosity of tablet. 2.Decreasing its wettebility. 3.Dissolving at slower rate.

First order drug release. Drug release determined by dissolution rate of polymer. Examples: Dimetane extencaps, Dimetapp extentabs.

ENCAPSULATION Called as Coating dissolution controlled system. Dissolution rate of coat depends upon stability & thickness of coating. Masks colour,odour,taste,minimising GI irritation. One of the microencapsulation method is used.

Examples: Ornade spansules, Chlortrimeton Repetabs

Matrix Diffusion Types Rigid Matrix Diffusion Materials used are insoluble plastics such as PVP & fatty acids. Swellable Matrix Diffusion 1. Also called as Glassy hydrogels.Popular for sustaining the release of highly water soluble drugs. 2. Materials used are hydrophilic gums. Examples : Natural- Guar gum,Tragacanth. Semisynthetic -HPMC,CMC,Xanthum gum. Synthetic -Polyacrilamides.

Examples: Glucotrol XL, Procardia XL

Reservoir System Also called as Laminated matrix device. Hollow system containing an inner core surrounded in water insoluble membrane. Polymer can be applied by coating or micro encapsulation. Rate controlling mechanism - partitioning into membrane with subsequent release into surrounding fluid by diffusion. Commonly used polymers - HPC, ethyl cellulose & polyvinyl acetate. Examples: Nico-400, Nitro-Bid

Dissolution & Diffusion Controlled Release system

Drug encased in a partially soluble membrane. Pores are created due to dissolution of parts of membrane. It permits entry of aqueous medium into core & drug dissolution. Diffusion of dissolved drug out of system. Ex- Ethyl cellulose & PVP mixture dissolves in water & create pores of insoluble ethyl cellulose membrane OSMOTIC PRESSURE CONTROLLED SYSTEMS

PARENTERAL CONTROLLED RELEASE SYSTEMS

NANOPARTICLES It is a colloidal drug delivery system. in this system,the particle size of the drug is about 200-500 nm so they are called nanoparticles. The system consists of a drug and a carrier to deposit the drug at the target site. Carriers used are naturally occurring macromolecules like Human serum albumin, BSA and other substances like gelatin, Caesin An aqueous solution of natural macromolecules is prepared drug is mixed in it.If the drug is hydrophobic it is dissolved in small quantity of organic solvent and mixed with carrier taking precaution that the drug is not precipitated. A solvent competitor solute like Na2SO4 or alcohol is then added. This results in the formation of colloidal particles of the drug in nanometer range. These nanoparticles may be hardened, isolated and dried for storage. Nano particles can be dispersed in aqueous systems.

Appln ---Cancer Therapy

Erthrocytes Erythrocytes can be used to obtain controlled release of drugs. Lifespan of RBC is 120 days. RBC can allow a drugto circulate in the body for long time which helps in slow release of drug in the blood. Resealed erythrocytes are prepared by putting them into a hypotonic medium, they swell and pores of RBC open. Aqueous soln of drug is added to the medium so that the drug gets into the erythrocytes through the open pores. When isotonicity is adjusted,the erythrocytes shrink,thus the drug is encapusulated inside them. These erythrocytes may be suspended in normal saline solns for preparing injections. Applns Resealed erythrocytes of urease is used in cases of kidney failure to degrade serum urea.

LIPOSOMAL DRUG-DELIVERY SYSTEMS

Liposomes are microscopic spheres with an aqueous core surrounded by one or more outer shell(s) consisting of lipids arranged in a bilayer configuration. The potential use of liposomes as drug carriers was recognized more than 25 years ago and, since that time, liposomes have been used in a broad range of pharmaceutical applications Liposome technology Preparation of liposomes Liposomes can be prepared by a variety of methods In general, on the basis of size and lamellarity (number of bilayers present within a liposome), liposomes are classified into three categories: multilamellar vesicles (MLVs), large unilamellar vesicles (LUVs), small unilamellar vesicles (SUVs).

Drug loading

Drug loading can be achieved either passively (i.e. the drug is encapsulated during liposome formation) or actively (i.e. after liposome formation). Hydrophobic drugs, such as amphotericin B. taxol or annamycin, can be directly incorporated into liposomes during vesicle formation, and the extent of uptake and retention is governed by drug-lipid interactions. Passive encapsulation of water-soluble drugs relies on the ability of liposomes to trap aqueous buffer containing a dissolved drug during vesicle formation. liposomes with prolonged circulation lifetimes A significant advance in the development of liposomal drugs has come with the use of

specialized lipids, such as monosialoganglioside GM, or polyethylene glycol modified phosphatidyl ethanolamine (PEG-PE), that engender long circulation lifetimes when incorporated into liposomes . Alternatively, the presence of entrapped cytotoxic drug can
also lead to extended circulation times . Liposomes can extravasate in these regions, thus leading to preferential accumulation within tumors.

Targeted delivery It is envisioned that the next generation of liposomal pharmaceuticals will consist of drug-loaded liposomes with surface-associated targeting information Site-directing targeting ligands, such as monoclonal antibodies, can be attached to liposomes by either covalent or non-covalent methods . The advent of novel PEG-PE lipids that allow targeting ligands to be conjugated at the distal ends of the PEG spacer has afforded both effective target binding in vitro and prolonged circulation times. Intracellular delivery Liposomes can facilitate the intracellular delivery of drugs by fusing with the target cell. Alterations in the lipid composition can render liposomes pH sensitive, leading to enhanced fusogenic tendencies in low pH compartments such as endosomes . The inclusion of lipids that are able to form non-bilayer phases, such as dioleoylphosphatidyl ethanolamine (DOPE), can promote destabilization of the bilayer, in-

ducing fusion events. DOPE has been particularl yuseful for cationic liposomes complexed with plasmid DNA for gene delivery Eg- Amphotericin B Liposomal amphotericin B drugs are presently approved for sale in certain European countries and are nearing regulatory approval in North America. Acute toxicities associated with amphotericin B are markedly reduced with liposomal formulations, without losing broad-spectrum antifungal activity. Early studies on a variety of formulations of liposomal amphotericin B demonstrated the successful treatment of fungal infections in mice

LIPOSOME MEDIATED DRUG DELIVERY

TRANSDERMAL DRUG DELIVERY SYSTEMS

Transdermal drug delivery systems (TDDS), also known as patches, are dosage forms designed to deliver a therapeutically effective amount of drug across a patients skin. In order to deliver therapeutic agents through the human skin for systemic effects, the comprehensive morphological, biophysical and physicochemical properties of the skin are to be considered. Transdermal delivery provides a leading edge over injectables and oral routes by increasing patient compliance and avoiding first pass metabolism respectively. Transdermal delivery not only provides controlled, constant administration of the drug, but also allows continuous input of drugs with short biological half-lives and eliminates pulsed entry into systemic circulation, which often causes undesirable side effects Thus various forms of Novel drug delivery system such as Transdermal drug delivery systems, Controlled release systems, Transmucosal delivery systems etc. emerged. Several important advantages of transdermal drug delivery are limitation of hepatic first pass metabolism, enhancement of therapeutic efficiency and maintenance of steady plasma level of the drug. The common ingredients which are used for the preparation of TDDS are as follows.

Drug: Drug is in direct contact with release liner. Ex: Nicotine, Methotrexate and Estrogen.

Liners: Protects the patch during storage. Ex: polyester film. Adhesive: Serves to adhere the patch to the skin for systemic delivery of drug. Ex:
Acrylates, Polyisobutylene, Silicones.

Permeation enhancers: Controls the Release of the drug. Ex: Terpenes, Terpenoids,
Pyrrolidones. Solvents like alcohol, Ethanol, Methanol. Surfactants like Sodium Lauryl sulfate, Pluronic F127, Pluronic F68.

Backing layer: Protect patch from outer environment. Ex: Cellulose derivatives, poly
vinyl alcohol, Polypropylene Silicon rubber.

TYPES OF TRANSDERMAL PATCHES: a) Single layer drug in adhesive: In this type the adhesive layer contains the drug. The adhesive layer not only serves to adhere the various layerstogether and also responsible for the releasing the drug to the skin. The adhesive layer is surrounded by a temporary liner and a backing.

b) Multi -layer drug in adhesive: This type is also similar to the single layer but it contains a immediate drug release layer and other layer will be a controlled release along with the adhesive layer. The adhesive layer is responsible for the releasing of the drug.This patch also has a temporary linerlayer and a permanent backing.

c) Vapour patch: In this type of patch the role of adhesive layer not only serves to adhere the various layers together but also serves as release vapour. The vapour patches are new to the market, commonly used for releasing of essential oils in decongestion. Various other types of vapor patches are also available in the market which are used to improve the quality of sleep and reduces the cigarette smoking conditions. d) Reservoir system: In this system the drug reservoir is embedded between an impervious backing layer and a rate controlling membrane. The drug releases only through the ratecontrolling membrane, which can be micro porous or non porous. In the drug reservoir compartment, the drug can be in the form of a solution, suspension, gel or dispersed in a solid polymer matrix. Hypoallergenic adhesive polymer can be applied as outer surface polymeric membrane which is compatible with drug. e) Matrix system: i. Drug-in-adhesive system: In this type the drug reservoir is formed by dispersing the drug in an adhesive polymer and then spreading the medicated adhesive polymer by solvent casting or melting (in the case of hot-melt adhesives) on an impervious backing layer. On top of the reservoir, unmediated adhesive polymer layers are applied for protection purpose. ii. Matrix-dispersion system: In this type the drug is dispersed homogenously in a hydrophilic or lipophilic polymer matrix. This drug containing polymer disk is fixed on to an occlusive base plate in a compartment fabricated from a drug impermeable backing layer. Instead of applying the adhesive on the face of the drug reservoir, it is spread along with the circumference to form a strip of adhesive rim. f) Microreservoir system: In this type the drug delivery system is a combination of reservoir and matrix-dispersion system. The drug reservoir is formed by first suspending the drug in an aqueous solution

of water soluble polymer and then dispersing the solution homogeneously in a lipophilic polymer to form thousands of unreachable, microscopic spheres of drug reservoirs. This thermodynamically unstable dispersion is stabilized quickly by immediately cross-linking the polymer in situ by using cross linking agents.

DRUG TARGETING USING DENDRIMERS

Dendrimers are comprised of highly branched monodispersive macromolecules. These structures are generally prepared by one of two methods: divergent or convergent reactions. In the divergent preparation, polymer branches grow outwards from a multifunctional core. The core molecule first interacts with a monomer molecule containing on reactive and two non-reactive groups, which allows for additional monomers to attach. This process is repeated a number of times until a starburst formation has occurred with a multitude of branches to create a dendrimer .

In the convergent preparation, the dendrimer is constructed piece by piece, starting from the outside sections and working inwards. Polymeric branches are grown originally independent of the core center until

they are large enough to be attached to the multifunctional core molecule . Because the convergent pathway allows for specific polymer attachment, it introduces a method of engineering by precise placement of functional groups at the periphery of the macromolecule . For this reason, dendrimers provide an optimal possibility as a site specific drug transporter targeting tumors. Drugs can be loaded into the interior or coat the outside of dendrimers, while the remaining branches can be engineered with targeting ligands or moieties to ensure specificity of interaction (on tumors) to apply treatment (Figure 2)

Drug delivery properties Dendrimers, which are capable of interacting specifically with cancerous tumor tissue, are an excellent option as a drug transporter within the body. Various polymers and other highly branched structures lack consistency of functional groups, monodispersive nature, and uniform molecular weight distribution.

Dendrimers also have an exceptionally high drug loading capacity, which provides a greater accumulation of drug at the tumor site. Considering that dendrimers can be prepared with a predetermined, specific number of monomers and polymer branches, as well as peripheral functional group specific, they are the ideal macromolecule to enter the highly permeable vasculature of tumor sites and remain localized at the site to deliver an immense amount (within cytotoxic levels) of drug to the specific tissue. The surface of dendrimers can be modified with functional groups so that drugs will be physically entrapped, encapsulated,or conjugated by covalent bonds, ionic interactions, or hydrogen bonds. With the increase of molecular weight of the drug, due to the dendrimer-drug interaction, the hydrodynamic volume increases causing longer circulation time and slower elimination of drug so cytotoxicity levels are lowered and dosage can be decreased Lastly, dendrimers have the ability to solubilize some insoluble anti-cancer drugs. Increased solubility results in higher loading efficiency, which prevents nonspecific interactions and negative side effects of the drug. Folate conjugated dendrimers Dendrimers can be conjugated with a ligand specific for targeting tumor sites. Ligands can be recognized by the appropriate cell surface receptor and thus internalized where it can deposit the therapeutic agent. One such ligand being tested for use is folate. Folate appears to be an excellent ligand because many cancerous tumor cells overexpress

folate receptors; therefore, folate conjugated dendrimers can be effective drug deliverers having high affinity for these cancer cells. Other properties of folate conjugated dendrimers are that they must be hydrophilic and a have a high lipid solubility to enter the cell via endocytosis. Upon entering the cell, the folate conjugates remain functional for some time. The endocytosed vesicle is then signaled to release the conjugated moiety into the cytoplasm and the folate receptor returns to the cell surface.

Glycodendrimers Glycodendrimers find use as a targeted anticancer drug vehicle because of the relationship of glycosylation on cancer cell surfaces. Glycodendrimers can be used in a similar manner by being introduced to the tumor site and acting as an antigen to promote the accumulation of monoclonal antibodies, which then selectively affect tumor cells. Glycodendrimers closely resemble the natural carbohydrate ligands, which add to the selective localization of the drug to the specific site. The formation of these dendrimers can occur in three ways: fully coated dendrimers with carbohydrates, carbohydrate moieties at the periphery, and carbohydrates at the center of the dendrimer PEGylated dendrimers Polyethylene glycol (PEG) dendrimers are non-toxic and avoid detection by the immune system, protein adsorption, and show tissue specificity. By inserting drugs into PEGylated dendrimers, there is an improved efficiency of delivery to the tumor site of that drug and an increase in the half-life because of the prevention of deterioration due to non-specific interactions.

Peptide dendrimers Peptide dendrimers consist of amino acids as the core molecules with the outer polymers made up of peptide moieties or amino acids. These dendrimers are effective as drug vehicles because peptides can trigger apoptosis and inhibit the growth of epithelial tissues.