PRESENTATION ON

“Route of administration of biotech product: parenteral

route mentioning particulate carrier system

and soluble carrier system.”

BIOTECH PRODUCTS

Biotechnology products are product which are manipulating and modifying by organisms, usually at molecular level.Biotechnology products in medicine are manufactured by using recombinant DNA technology, which entails genetic manipulation of cells, or a monoclonal antibody.Examples of biotech product: Acetone Biohydrogen Biopolymer

Biohydrogen Biopolymer Polyamide

ROUTE OF ADMINISTRATION OF BIOTECH PRODUCT:

Routes of administration of biotech products are:

Oral route. Parenteral route. Nasal route. Transmucosal route.

PARENTERAL ROUTE

Parenteral mode of delivery has been the major route of choice for proteins and peptides, owing to their poor absorption and metabolic instability when given by other alternative routes.

Potent nature of these peptides/ proteins demands their targeting to specific receptors to improve therapeutic index of a drug.

PARENTERAL DRUG DELIVERY SYSTEMS:

These systems include those intended for IV, IM, intra-arterial, subcutaneous, intraperitoneal and intrathecal use.

The drug carrier systems used for defined and controlled delivery of drug through this route can be:

1. Particulates2. Soluble carriers (Macromolecules)3. Others

PARTICULATES

There are different types of particulate carrier systems .These are: Microspheres Microcapsules Nanoparticles Aquasomes Liposomes Emulsions Cellular carriers Replication defective viruses.

MICROSPHERES Microspheres are solid

particles in the particle size range of few tenths of a micrometer up to several hundreds micrometer .They contain dispersed drug in either solution or microcrystalline form. They are prepared by various polymerization and encapsulation processes.

An example is targeting of microspheres to the RES (1-7µm particles) and to the lung capillaries (7-12 µm particles). The microspheres conjugating receptor specific moieties, such as monoclonal antibodies incorporating magnetic particles, or based on a combination of two could be used for active peptide(s) or protein targeting.

The advantages of microspheres include:

Can be prepared cheaply if the correct encapsulation method is optimized and chosen, and

Can be administered subcutaneously, IM or intraperitoneally and thus implantation is not necessary.

Their disadvantages include:

High molecular weight compounds have limited and restricted loading and their release may be difficult,

May successfully pass through biological barriers (like blood, endothelium, RES) and cellular barriers before and they can be effective.

May be interact or complex with the blood components.

MICROCAPSULES Microcapsules carrier

system holds immense potential for controlled release of peptide moieties from mammalian cells and tissues.

The microcapsules are polymeric in nature and prepared employing interfacial polymerization, or interfacial coacervate phase separation of capsules wall forming polymers.

The capsule membrane serves as a permeability barrier. The polymers conventionally used include PVA, polyvinyl acetate, nylon, polyurethane, gelatin, polyacrylonitrile etc.

NANOPARTICLES Nanoparticles are very much similar to

microspheres but their particle size which is in the nanometer range (10-1000nm).

They can also be used for targeted delivery. Owing to their small size they can pass through the sinusoidal spaces in the bone-marrow and spleen.

Targeting moieties like monoclonal antibodies can be attached to Nanoparticles to enhance their specificity.

Polycyanoacrylate and glycolic acid co-lacted based Nanoparticles have been discussed as an effective adjuvant version that demonstrated effective aduvanticity.

The better adjuvanticity is attributed to the effective presentation of antigens by Nanoparticles.

The typical constitutive polymers include cyanoacrylate, polymethacrylate, polystyrene poly co-glyco-lactide, albumin and acrylic resins.

The methods employed for preparation are conventional solution, desolvation, in situ micellar polymerization etc.

AQUASOMES Aquasomes are self-assembling

nanoconstructs comprising of a solid ceramic core and a glassy polyhydroxyl oligomeric surface coating.

The system has been studied for the immobilization of various bioactive molecules.

These include insulin, antigen for Epstein-Barr virus, HIV, Mussel adhesive protein, hemoglobin etc.

For example, aquasome-delivered insulin showed 149.31-156.99 mg/dL fall in blood glucose concentration.

LIPOSOMES Liposomes are spherical vesicles formed when

phospholipids are allowed to hydrate in an aqueous media. They consist of one or more concentric bilayers surrounding aqueous phases.

Protein and proteinaceous drug(s) are incorporated in liposomes using dehydration rehydration vesicle (DRV) and reverse phase evaporation methods.

The protein(s) bearing liposomes can further be surface modified in order to endow them with long circulatory character.

PEG, pullulan coating, GM coating etc are used as surface modifier.

The advantages of liposomes are: Flexible in size, shape and structure. Relatively nontoxic deposition. Ability to encapsulate both hydrophilic and

lipophilic peptide and proteins.

The drawbacks of liposomes are: The constituent phospholipids have an inherent

tendency to interact with peptides and proteins. Their capacity as adjuvants.

EMULSIONS Colloid sized emulsion

droplets can be utilized for parenteral delivery of peptides.

This delivery system can be of great significance and utility in protecting hydrophilic or hydrophobic drugs from direct contact with body fluids and also in delivering the drugs over a prolonged period of time.

Advantages of emulsion system:

Large clinical acceptability. The amenability to large

scale production.

Disadvantage is of this system:

It is rather limited use but investigations are in progress to utilize their potential for delivery of peptides.

CELLULAR CARRIERS Enzymes and other

proteinaceous pharmaceuticals can be encapsulated in erythrocytes to achieve a prolonged release or targeting of the same.

Some of the methods of encapsulation include hemolysis, dialysis and electric field breakdown.

The release of drug occurs by simple diffusion or by a specific transport system.

Advantages of erythrocytes include:

 Biodegradability. Non-immunogenicity. Large circulation life (up to 4 months). Easy availability. Large quantities of material can be entrapped in small

volume of cells (about 20-80%) extracellular concentration.

Afford enzymatic and immunological protection.

Drawbacks include:

Long term storage is problematic. Permeable to a large number of drugs. Only those drugs that are not susceptible to irreversible

denaturation under hypotonic conditions can be used.

REPLICATION DEFECTIVE VIRUSES

Retroviral gene delivery systems have been developed to assist in entry of genes into the cells. This system consists of an RNA copy of a gene package into a viral particle.

The basic concept of gene therapy is that functionally active genes are delivered into the somatic cells of a patient with genetic defect.

SOLUBLE CARRIERS (MACROMECULES)

Soluble carrier systems include : conjugates. chemically modified drugs and hybrid proteins.The peptide/protein drugs can be conjugated

with a polymer/macromolecule.

Polymer modifications bring with it the following changes:

Masking of antigenic determinants. Masking of protease- susceptible sites. Masking of immunogenic recognition

signals. Masking of clearance recognition

signals. Allow free access to low molecular

weight substrates. Alter optimum pH by changing

microenvironment.

Protein molecules can themselves act as carriers for targeting of other peptides/proteins.

The four basic mechanisms involved in targeting:

Interaction with surface receptor. Facilitated uptake and interaction of intact

molecules with intracellular target site. Facilitated uptake and intracellular release of

warhead moiety. Facilitated uptake and release of a suicide

warhead, which is activated only after interacting with its target.

Fig: Schematic representation of mechanisms for targeting peptide drugs.

OTHERS On-demand systems Self-regulated system Temper sensitive systems Pumps Mechanical pumps Osmotic pumps Controlled- release micropumps

ON-DEMAND SYSTEMS

It is beneficial to have externally augmented delivery on-demand as in delivery of insulin to patient with diabetes mellitus.

Magnetically modulated systems have been designed to achieve this end.

The release rate is influence by the position, orientation and strength of the embedded magnets , the amplitude and frequency of the applied magnetic field and the mechanical properties of polymer matrix .

SELF-REGULATED SYSTEM The self-regulated systems are of great importance to

deliver insulin in response to blood glucose concentration for diabetic patients.

the pH of the microenvironment within the membrane is lowered and the amine groups in the membrane are protonated, due to this, the membrane swells and its permeability to the insulin held in a continuous reservoir increases.

TEMPERATURE SENSITIVE SYSTEMS

Some polymers like polyacrylamide derivatives have inherent thermosensitive swelling behavior.

This leads to a temperature-dependent release pattern that can be exploited in pulsatile delivery of peptides/proteins.

PUMPS

Mechanical pumps: Most of the portable pumps for insulin delivery are syringe driven, either lead screw or direct drive.

Osmotic pumps: Osmotic pumps have been used extensively for delivery of a large number of preptides and protein drugs in animals. Some of the representative examples include insulin, ACTH, calcitonin, LHRH, growth hormone, neutrotensin, vasopressin.

Controlled- release micropumps: The concentration difference between the drug reservoir and the delivery site causes diffusion of the drug to the delivery site to provide basal delivery.