SECTION 1.1: ORAL DRUG DELIVERY SYSTEM
A drug delivery system is defined as a formulation or a device that can be introduce the therapeutic or pharmaceutical substance in to the body and improves the efficacy and safety of substance by controlling the time, rate and place of drug release in the body. Drug delivery system is an interface between the patient and the drug. It may be a formulation of drug to administer it for a therapeutic or medical reason or a device used drug delivery. Oral drug delivery system is most desirable, preferable and suitable route for the administration of therapeutic and pharmaceutical agents for administration. Historically the oral route of drug administration has been the one used most for both conventional as well as the novel drug delivery. The reasons for this preference are obvious because of ease of administration. Oral drug delivery is the most desirable, suitable and preferred method of administering therapeutic agents for their systemic effects. The oral medication is mostly considered as the first investigation in the development and discovery of new drug molecules and pharmaceutical preparations, mainly because of acceptance by the patients, convenience, and cost effective manufacturing process. For many drug substances conventional immediate release formulations provide clinically and therapeutically effective therapy while maintaining the required level of pharmacodynamic and pharmacokinetic profiles with acceptable level of safety to the patient. Multiple unit dosage forms such as microspheres or micro beads have gained in popularity as oral drug delivery systems because of high uniformity of the drug distribution in the gastrointestinal tract, better drug absorption, minimized local irritation and elimination of unwanted intestinal retention of polymers and other excipients, when compared to non-disintegrating single unit dosage form.2
SECTION 1.2: CONTROLLED DRUG DELIVERY SYSTEM
A wide variety of newer oral drug delivery systems like sustained/controlled release dosage forms are designed and evaluated in order to overcome the limitations of conventional therapy. These products are able to maintain steady drug plasma levels for extended periods of time as a result the variations of the drug levels in the blood are prevented and minimized drug related side effects.3 The controlled release drug delivery systems are aimed at controlling the rate of drug delivery, sustaining the time period of therapeutic activity and targeting the drug delivery to a tissue. Drug release from these systems should be at a desired rate, predictable and reproducible. Among the various approaches for controlled systems, microencapsulation process and microcapsules have gained good acceptance as a process to achieve controlled release and drug targeting.4
The goal in designing sustained or controlled delivery system is to reduce the frequency of dosing or to increase the effectiveness of the drug by localization at the site action, reducing the dose required, or providing uniform drug delivery.5 Of growing interest generally in the world of oral drug delivery is colon-targeted delivery for treatment of both local and systemic conditions. It is recognised that this region of the Gastrointestinal tract offers advantages over the stomach and small intestine, e.g. milder pH, lower enzymatic activity, lower bile salt concentrations, longer residence time and slower turnover of the mucus layer. For biopharmaceutical delivery, it also appears to offer the benefit of allowing greater functioning of absorption enhancers, thus allowing reasonable bioavailability of drugs such as peptides which would normally be poorly absorbed from the GI tract.6
Controlled release systems are used in the improvement of the effectiveness of drug therapy. These systems modify several parameters of the drug: the release profile and capacity to cross biological carriers (depending on the size of the particle), biodistribution, clearance, and stability (metabolism), among others. In other words, the pharmacokinetics and the pharmacodynamics of the drug are modified by these formulations. Controlled release offers numerous advantages over conventional dosage forms. This approach increases therapeutic activity and decreases side effects, thus reducing the number of drug dosages required during treatment. Controlled release methods offer an appropriate tool for site-specific and time-controlled drug delivery. There are two main situations in which the distribution and time-controlled delivery of a drug can be beneficial-
When the natural distribution of the drug causes major side effects due to its interaction with other tissues.
When the natural drug distribution does not allow it to reach its molecular site of action due to degradation.
Many different kinds of drugs can benefit from distribution or time-controlled delivery, such as anti-inflammatory agents, antibiotics, chemotherapeutic drugs, immunosuppressants, anesthetics and vaccines.7
1.2.1: Advantages of oral controlled release formulations
Oral controlled drug delivery has been widely preferred in research because of its large number of benefits over conventional dosage forms, some of which are as follows:
The frequency of dosing is less due to drug being released for a longer duration of time than conventional dosage form.
This is highly valuable for the patients with chronic disease and illnesses which required to maintaining the plasma concentrations of a drug within the range of therapeutic effects to avoid breakthrough symptoms.
The reduction or avoidance of side effects due to high plasma drug concentrations or ‘dose dumping’.
Improvement of the patient compliance because of reduced dosing.
Better control on the concentration of therapeutic drug in body.
Cost effective manufacturing as the amount of dose required per patient would be reduced as compared to its conventional dosage form.8
SECTION 1.3: COATING OF FORMULATION
Coating is defined as a process by which dosage form is covered with an essentially dry, outer layer of coating material by applying it on the surface of a formulation or dosage form for specific benefits that broadly ranges from improving product identification to modifying the release of the drug from the formulation. After making a good formulation, one must often coat it for many benefits.
There are five reasons for putting such a coating on a pharmaceutical formulation:
Protection of active pharmaceutical ingredients, from the acidic environment of the stomach (e.g. enzymes and certain antibiotics).
To prevent gastric distress or nausea from a drug due to irritation (e.g. sodium salicylate ).
For the delivery of drugs that are optimally absorbed in the small intestine to their primary absorption site in their most concentrated form.
To provide a delayed/sustained release of drug substance for repeat action.
Required for minimizing first pass metabolism of drugs.19
1.3.1: Coating material
The coating material should be capable of forming a film that is cohesive with the materials required for coating, should be chemically compatible with the material and must be non reactive with the core material and provide the desired coating properties such as strength, impermeability, optical properties stability and flexibility. When coating is done by microencapsulation techniques the size of thickness of coating is in microscopic units.
A number of different substances both non-biodegradable and biodegradable have been investigated for the formulation of microcapsules. These materials include the polymers of synthetic natural and origin and also modified natural substances. Some of the polymers used in the preparation of the microcapsules are classified and listed.
1.3.2: Ideal properties of an enteric coating material
Resistance from the gastric fluids
Permeable/Susceptible to the intestinal fluid
Should be compatibility with the most components of coating solution and the substrates of the drug
Formation of uniform and continuous film
Cheap, nontoxic and easy to apply
Provide ability in readily printed19
1.3.3: EUDRAGIT S100
Eudragit S100 is anionic copolymers based on methacrylic acid and methyl methacrylate. The IUPAC name of edragit S100 is Poly(methacrylic acid-co-methyl methacrylate). Eudragit S100 contains 30% of methacrylic units and dissolves at pH values higher than 7.0. Eudragit S100 is suitable coating agent for controlled and colon targeted drug delivery system.10 Eudragit S100 is an effective and stable enteric coating agent with fast dissolution in upper bowl. It is generally accepted that pH7 is not normally reached until at least the distal small bowel/ileocaecal region; thus drug release from formulations coated with Eudragit S100 is likely to commence at the junction between the small intestine and colon, continuing into the colon.6
SECTION 1.4: NON-STEROIDAL ANTIINFLAMATORY DRUGS
Non-steroidal anti-inflammatory drugs (NSAIDs) are considered to be the first-line drugs in the symptomatic treatment of rheumatoid arthritis, ankylosing spondilytis and osteoarthritis. Aceclofenac is one of the emerging NSAID molecules for the treatment of arthritis. Aceclofenac is a new derivative of diclofenac and has less gastrointestinal complications. All drugs grouped in this class have analgesic, antipyretic antiinflammatory action in different measures. They do not depress CNS, do not produce the physical dependence, are weaker analgesics and have no abuse liability. They are more commonly employed and many are over-the-counter drugs.21
Aceclofenac is a non-steroidal anti-inflammatory drug, widely used in the management of osteoarthritis, ankylosing, rheumatoid arthritis and spondylitis. Usual therapeutic dose is 100 mg twice daily and half life is 3-4 hrs; thus it is necessary to be administered frequently in order to maintain the desired concentration.
1.4.2: MECHANISM OF ACTION
Aceclofenac drug acts as non selective inhibitor of cyclooxygenase enzyme(COX). It inhibits both cyclooxygenase-1(COX-1) and cyclooxygense-2 (COX-2) isoenzymes. COX catalyses the formation of prostaglandin and thromboxane from archidonic acid. Prostaglandins act like messenger molecules in the process of pain and inflammation. Aceclofenac also have antipyretic activity and be used in treatment of pyrexiya. The reason of fever is the elevation in the levels of PGE2. Aceclofenac inhibits the biosynthesis of PGE2 within the hypothalamus to reduce the fever. Archidonic acid is precursor substrate for COX which helps to lead the production of prostaglandins F, D and E.22
SECTION 1.5: MICROENCAPSULATION
Microencapsulation is a rapidly expanding technology for the preparation of formulatios in which drug is present as core material covered by polymer. As a process, it is a means applying relatively a thin coating to small solid particles or liquids droplets and dispersions. Microencapsulation is arbitrarily differentiated from macro-coating techniques in that the farmer involves the coating of particles is in the range between several tenths of a micron to 5000 microns in size.23
Microencapsulation is process by which thin coating can be applied reproducibly to small solids particles or liquid droplets or dispersions or even gases are encapsulated into micro sonic particles. Particle size range dimensionally from 1 µm to 1000 µm.9
Particulate drug delivery system are gaining more prominence in recent years because they uniformly distribute in the GIT there by improve the bioavailability of the drugs and also reduces the local irritation. Due to attractive properties and wider applications of microparticles, their application in controlled release formulation is appropriate.
Microencapsulation is a rapidly expanding technology. Microencapsulation helps in converting the liquids into the solids, altering colloidal and surface properties of formulation, in providing environmental and external protection and in controlling the release behaviour or availability of coated materials.
1.5.1: Applications of microencapsulation
In the development and the design of controlled and sustained release dosage form.
Alteration in site of absorption.
To mask the taste of bitter drugs.
To provide the protection to the core material from atmospheric effects.
To minimize gastric and other GIT irritation.
In the preparation of free flowing powder formulations from drugs in liquid forms.
Stabilization of drugs which are sensitive to moisture, light or oxygen.
In the elimination of incompatibilities among drugs.
Prevention of volatile drugs from vaporization.
Reduction of toxicity.
To reduce hygroscopicity.
Alteration in site of absorption.
1.5.2: MICROENCAPSULATION BY IONOTROPIC GELATION METHOD
Alginates have ability to form gels by reaction with calcium salts. Alginic acid is composed of D-mannuronic acid and L-gluronic acid residues at varying proportions of GG-, MM- and MG- blocks. When suspension of alginate is added drop by drop to the solution of calcium salt, crosslinking takes place between the carboxylate residue of GG- blocks and Ca+2 ions via egg-box model to give a tight gel network structure. This method is called ionotropic gelation method because in this process the anion of alginate and cation of calcium salt (mostly Ca+2ion) crosslinked to form a gel. These gels resemble a solid retaining their shape, resisting stress and consist of almost 100% water.
It has been suggested that the cross-links are caused by simple ionic bridging of two carboxyl groups on adjacent polymer chain via calcium ions or by chelating of single calcium ions by hydroxyl and carboxyl groups on each a pair of polymer chains.24
In this method strong spherical beads with a narrow range particle size distribution and lower friability could be prepared. Beads formed by this method have high yield and drug content. The flow properties of micronized of needle like drug crystals can be improved by the help of agglomeration technique as compared to the non-agglomerated drug crystals. The ionic character of the polymers results from pH dependent disintegration of the beads.
SECTION 1.6: GEL BEADS
Gel beads are defined as spherical structure in which drug is present in the core of beads. Different types of gel beads can be prepared by using various techniques. Gel beads help in the slow dissolution of drug hence slowdown the release of drug, thus results in improvement of bioavailability of drug.
1.6.1: APPLICATIONS GEL BEADS
Stomach specific drug delivery using floating alginate gel beads
A multiple unit type oral floating dosage form of many drug have been developed in recent years. Drugs like riboflavin, ranitidine, diclofenac sodium were formulated to prolong the gastric residence time and increase bioavailability.
Beads of various drugs have been formulated and further coated with enteric polymers for colon targeting.
Protein drug delivery
In recent years many formulations have been prepared for protein drug molecules for site specific release of protein in the intestine.
Microbeads as inoculants and carriers for plant growth-promoting bacteria
Beads of various bacteria are developed in recent years to promote the growth of plants. The release of bacteria from the microbeads depends on its type (wet or dry) and the time of incubation (the longer the incubation time, the smaller the extent of bacteria released with time).
Enzymes are immobilized by formation ofdehydrated gel beads for use in non-aqueous enzymatic reactions by having an average particle size of 5 to 150 microns.