The Novel Drug Delivery Systems Biology Essay

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The current interest shown in novel drug delivery systems by both national and international pharmaceutical firms is anything to go by, then the phenomenon is here to stay. Be it the pioneering research to devise new strategies for effective delivery of drugs in the body or the fine tuning of the existing technologies to enhance their efficiency, the current global market for NDDS is touted to be to the tune of more than 80 billion euro's. It is necessary to fathom such keen interest in a phenomenon that has been existent for almost half a century now. The 1950s were the initial stages where the focus was on microencapsulated drug particles. These drug particles were packaged in tiny shells or capsules of dimensions measurable in micrometers and delivered into the body.

A major facelift was brought about with the use of polymers for the manufacture of the capsules or cages in the 1960s. Besides adding to the flexibility and versatility of the process of drug delivery, a few concerns regarding the pulsatile nature of drug delivery were also mitigated. The delivery of drugs to a specific site can be either sustained or pulsatile. The pulsatile mode is however preferred as it closely mimics the in vivo mechanism of release of triggering of repairing agents, as exemplified by the release of hormones. The advent of transepithelial and transdermal delivery strategies in the 1990s has added to the multi dimension nature of the NDDS. The subsequent addition of liposomes at the commencement of this decade has added to the repertoire of existing drug delivery systems. Several strategies are being tried out currently to discover novel carriers for the drugs to be delivered specifically and effectively. Some of the interesting candidates with potential to be deemed as suitable carriers for the novel drugs include Human Serum Albumin (HSA), Silica Gel, Antisense RNA, recombinant DNA and synthetic peptides among others.

Novel drug delivery system refers to the use of a delivery device with the objective of releasing the drug into the patient body at a predetermined rate, or at specific time or with a specific release profile, at a desired area of effect.

The NDDS essentially consists of the drug against the causative agent of the disease being treated and a carrier system into which the drug is loaded and transported to site of action. Efforts are now being made to devise carriers that can transport multiple drugs and release them on command.

The characteristics of a good drug carrier are:

1. Optimum drug quantity can be loaded into it.

2. The release of the drug inside the body is pulsatile in nature.

3. The drug release can be manipulated with.

4. It should not be immunogenic in nature.

5. The manufacturing, production and use should be economically viable.

6. It should be able to transport and release a wide variety of drugs.

7. It should be able to specifically transport the drug to the site of action.

8. The carrier is amenable to fictionalization.

1.2 TYPES OF NOVEL DRUG DELIVERY SYSTEM [2]

There are several types of Novel Drug Delivery System:

Liposomes.

Neosomes.

Nanoparticles.

Microspheres.

Matrix Tablets.

Floating Tablets.

Pellets.

Implants and Inserts.

Transdermal Drug Delivery System.

Ion Exchange Resin Tablets.

1.3 MICROSPHERES [3]

Microspheres can be defined as solid, approximately spherical particles ranging in size from 1 to 1000 mm. They are made of polymeric, waxy, or other protective materials, that is, biodegradable synthetic polymers and modified natural products such as starches, gums, proteins, fats, and waxes. The natural polymers include albumin and gelatin; the synthetic polymers include polylactic acid and polyglycolic acid. The solvents used to dissolve the polymeric materials are chosen according to the polymer and drug solubilities and stabilities, process safety, and economic considerations. Substances can be incorporated within microspheres in the liquid or solid state during manufacture or subsequently by absorption. Microcapsules, where the entrapped substance is completely surrounded by a distinct capsule wall, and micromatrices, where the entrapped substance is dispersed throughout the microsphere matrix. Microspheres are small and have large surface-to-volume ratios. At the lower end of their size range they have colloidal properties. The interfacial properties of microspheres are extremely important, often dictating their activity. In fact, the principle of microsphere manufacture depends on the creation of an interfacial area, involving a polymeric material that will form an interfacial boundary and a method of cross-linking to impart permanency. The methods of manufacturing described later are by no means comprehensive and the reader should bear in mind that if the aforementioned criteria are adhered to, the only limitation to the manufacture of microspheres is the researcher's imagination.

1.3.1 Advantages of Microspheres [2,4]

Very easy to fabricate for a wide range of drugs.

Can offer a sustained and controlled action of drug to desired area of effect.

Suitable for biodegradable and non - biodegradable polymers.

Easy to carry because of its light weight.

Drug release rates can be tailored for the desired therapy.

Fragile drugs can be protected.

Increased patient compliance.

Increased bioavailability of active ingredient.

Increased residence time of drugs in case of mucoadhesive microspheres.

1.3.2 Disadvantages of Microspheres [2,4]

Difficulty of large scale manufacturing.

Maintenance of drug stability is low.

Control of drug release rates is troublesome.

Difficulty of removal from the site of action.

Low drug loading tendencies in case of controlled release parenterals.

Possible drug degradation within the microspheres.

Changes in drug crystallinity or polymorphic form during microsphere processing.

Expensive, not economical.

1.4 MECHANISM OF DRUG RELEASE FROM THE MICROSPHERES [2]

Drug release from microspheres takes place by the following three mechanisms:

Liberation of drug due to polymer erosion or degradation.

Self diffusion from the pore.

Drug release from the surface of the polymer.

Drug release may take place due to the combination of more than one of the above factors.

1.5 PHYSICO-CHEMICAL CHARACTERIZATION OF MICROSPHERES

The most important physicochemical characteristics that may be controlled in microsphere manufacture are:

Particle size and distribution.

Polymer molecular weight.

Ratio of drug to polymer.

Total mass of drug and polymer.

Each of these can be related to the manufacture and rate of drug release from the systems. The following discussion presents methods of manufacture of coated or encapsulated systems, referred to as microcapsules, and matrix systems containing homogeneously distributed drug, referred to as micromatrices.

1.6 PREPARATION METHODS OF MICROSPHERES

1.6.1. Emulsification Technique

The aqueous protein or drug solution is dispersed in a lipophilic organic continuous phase. The continuous phase is generally consisted of the polymer solution that eventually encapsulates of the protein or drug contained in dispersed aqueous phase. The primary emulsion is then subjected to the homogenization or the sonication before addition to the aqueous solution of the poly vinyl alcohol (PVA). The emulsion is then subjected to solvent removal either by solvent evaporation or by solvent extraction process. [6]

1.6.2. Coacervation Phase Separation

This technique is used to microencapsulate water-soluble drugs. The core material (drug) is suspended in a nonaqueous polymer solution (coating material), and the polymer is made to form a uniform coat by various approaches, such as temperature change, addition of an incompatible polymer, addition of a nonsolvent, or addition of a salt. [7]

1.6.3. Emulsion Phase Separation

Water-soluble drugs are fabricated in the form of microcapsules by this method. An aqueous phase containing dissolved drug and an organic phase containing polymer are emulsified. Then polymer is phase separated using the techniques such as temperature change, addition of salts, etc. A nonsolvent then is used to harden the microspheres. [7]

1.6.4. Solvent Evaporation

This is the most commonly used method for microencapsulation of the drugs that are soluble or suspended in the organic phase. In this method, a solution or suspension of drug in an organic solvent containing dissolved polymer is emulsified to form o/o or o/w dispersion, possibly with the aid of a surfactant. The organic phase is then evaporated by heating or applying vacuum, leaving microspheres.

1.6.5. Spray Drying

Microencapsulation by spray drying [7] is an ideal method for poorly water-soluble drugs. The drug is dispersed in polymer (coating) solution, and then this dispersion is atomized into an airstream. The air, usually heated, supplies the latent heat of vaporization required to remove the solvent and forms the microencapsulated product. This technique is employed most commonly when microcapsules are intended for oral use because the resulting microspheres are porous in nature, and large batch sizes are required.

1.6.6. Pan Coating and Fluidized Bed Coating

Pan coating employ heat-jacketed coating pans in which the solid drug core particles are rotated and into which the coating material is sprayed. The core particles are in the size range of micrometers up to a few millimeters. The coating material is usually sprayed at an angle from the side into the pan. The process is continued until an even coating is completed. Microspheres can be prepared with different coating thicknesses and mixed to achieve specific controlled release patterns.

In Fluidized bed coating, [8,9] the solid core particles are fluidized by air pressure and a spray of dissolved polymer material is applied from the perforated bottom of the fluidization chamber parallel to the air stream and onto the solid core particles. Alternatively, the coating solution can be sprayed from the top or the sides into an upstream of fluidized particles. This process allows the coating of small particles. The fluidized-bed technique produces a more uniform coating thickness than the pan-coating methodology.

1.6.7. Hot-Melt Microencapsulation

In the hot-melt microencapsulation process, the drug, encapsulated as solid particles, was mixed with melted polymer. The mixture was suspended in a non-miscible solvent that was heated to 5°C above the melting point of the polymer and stirred continuously. Stirring was done using an overhead stirrer and a four-blade impeller. Once the emulsion was stabilized, it was cooled until the core material solidified. The solvent used in this process was silicon or olive oil. In some cases the drug can be used without sieving but, in general, a particle size of less than 50 µm was found to be optimum and substantially improved the drug distribution within the microspheres. After cooling, the microspheres were washed by decantation with petroleum ether to give a free-flowing powder. They were then sieved, dried, and stored in a freezer. Size distribution can be controlled by the stirring rate; the yield is 70-90%. The process was quite reproducible with respect to yield, size, and loading distribution, if the same molecular weight of polymer was used. Less than 5% error was observed. [10]

1.6.8. Ionic Cross-linking Technique

Dropping or spraying a sodium alginate solution into a calcium chloride or barium chloride solution produces microcapsules. [11]The divalent calcium or barium ions cross-link the alginate, formed gelled droplets. Variations on this method with different polymers have been developed. Chitosan is a preferred polymer, because it has a better biocompatibility than alginate. However, the droplets were relatively large, because the drops do not fall until they reach a critical mass. Smaller droplets can be formed by using a pump to force the alginate through the pipette a vibration system to help remove the drops from the end of the pipette and an air atomization method.

1.6.9. Freeze Drying

This technique involves the freezing of the emulsion the relative freezing points of the continuous and dispersed phases are important.[13] The continuous-phase solvent is usually organic and is removed by sublimation at low temperature and pressure. Finally, the dispersed phase solvent of the droplets is removed by sublimation, leaving polymer-drug free-flowing particles.

1.6.10. Chemical and Thermal Cross-Linking

Water in oil emulsion is prepared, where the water phase is a solution of the polymer (gelatin, albumin, starch, and dextran) that contains the drug to be incorporated. The oil phase is a suitable vegetable oil or oil-organic solvent mixture containing an oil-soluble emulsifier. Once the desired water-oil emulsion is formed, the water soluble polymer is solidified by some kind of cross-linking process. This may involve thermal treatment or the addition of a chemical cross-linking agent such as glutaraldehyde [14] to form a stable chemical cross-link.

1.8 COLON SPECIFIC DRUG DELIVERY SYSTEM

1.8.1 Introduction

Historically, oral ingestion has been the most convenient and commonly used method of drug delivery. For sustained release as well as controlled release systems, the oral route of administration has received the most attention. This is because of greater flexibility in dosage form design for the oral rather than the parenteral route. Patient acceptance of oral administration of drugs is quite high. It is a relatively safe route of drug administration compared with most parenteral forms, and the constraints of sterility and potential damage at the site of administration are minimal. Colon-specific drug-delivery systems offer several potential therapeutic advantages. [20] In a number of colonic diseases such as colorectal cancer, Crohn's disease, and spastic colon, it has been shown that local is more effective than systemic delivery. Colonic drug delivery can be achieved by oral or by rectal administration. Rectal delivery forms (suppositories and enemas) are not always effective because a high variability is observed in the distribution of drugs administered by this route. Suppositories are effective in the rectum because of the confined spread and enema solutions can only be applied topically to treat diseases of the sigmoid and the descending colon. Therefore, the oral route is preferred. Absorption and degradation of the active ingredient in the upper part of the gastrointestinal tract is the major obstacle with the delivery of drugs by the oral route and must be overcome for successful colonic drug delivery. Drugs for which the colon is a potential absorption site (for example, peptides and proteins) can be delivered to this region for subsequent systemic absor

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