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The pure forms of drugs or therapeutic active substances are not administered as same but they are modified as dosage forms with certain non-drug inert components into the body through different routes to provide specific pharmacological functions. However, the functions of formulation additives to ensure solubilize, suspend, thicken, preserve, emulsify, modify dissolution, improve the compressibility and formulate drug substances to form various acceptable dosage forms. The principle objective of the dosage form design is to achieve a predictable therapeutic response to a drug included in a formulation which is capable of large scale manufacturing with reproducible product quality. Therefore, in the ultimate analysis, each and every dosage form irrespective of its final structure and nature is a combination of the drug component and an assortment of different kinds of non-drug components1.
The design of dosage forms should confer a specified type of action pattern which needs an immense amount of scientific skill matched with an equal amount of innovation and imagination. Dosage forms can be designed for administration by all possible delivery routes of administration like oral, topical and parenteral routes to maximize therapeutic response and minimize dose related side effects2.
1.1 Oral drug delivery
The oral route is the most ancient, convenient and commonly used for systemic administration of drugs via various pharmaceutical products like tablets, capsules, solutions, emulsions and suspensions. Oral delivery is the most desirable and preferred method for the development of pharmaceutical formulations mainly because of patient acceptance, convenience in administration, easy of fabrication and cost effective manufacturing process. For many conventional immediate release formulations are clinically effective therapy while maintaining the required balance of pharmacokinetic and pharmacodynamics profiles known to provide a prompt release of drug with acceptable level of safety to the patients. However, the potential for oral dosage form development is limited for therapeutic agents that are poorly absorbed in the gastrointestinal (GI) tract and unstable to various enzymes. The overall process of oral drug delivery is frequently impaired in variable GI conditions such as pH, presence of food, GI transit time and enzymatic activity in the alimentary canal due to several physiological and pharmaceutical functions of drugs3. For improving the oral conventional drug delivery is very challenges and requires some modifications in the manufacturing process. On other hand, manipulation of these problems and improve the therapy is necessary to clear understanding of physicochemical properties of drug and polymer, GI physiology and biochemistry, pharmacokinetics and pharmacodynamics process.
1.2 The anatomy and physiological characteristics of the GI tract
The human gastrointestinal tract (GIT) is a highly specialized region of the body, the primary functions of which involve the processes of secretion, digestion and absorption. The GI lining constituting the absorption barrier allows most nutrients like glucose, amino acids, fatty acids and vitamins to pass rapidly into the systemic circulation but prevents the entry of certain toxins and macromolecular medicaments. The ingested materials, through oral are processed by the GIT first, and then made available for absorption and distributed into different organs and tissues and eliminated from the body and must pass through one or more biological membranes/barriers at various locations4. Thus, the GIT represents a primary barrier for oral absorption of drugs.
The gastrointestinal tract consists of three major anatomical regions: the stomach, the small intestine it includes the duodenum, jejunum, ileum, and the large intestine. As the drug descends through these regions of the GI-tract with respect to pH, enzymes, electrolytes, fluidity and surface features, all of which influence drug absorption. The entire length of the GI mucosa from stomach to large intestine is lined by a thin layer of muco-polysaccharides which normally acts as an impermeable barrier to the particulates such as bacteria, cells or food particles.
Figure 1.1 Schematic representation of the GIT and different sites of drug absorption
The stomach is a bag like structure having a smooth mucosa and thus small surface area. Its acidic pH 1-3 due to secretion of hydrochloric acid favors absorption of acidic drugs; if they are soluble in the gastric fluids they remain unionized to large extent in such a pH. After oral ingestion, materials are presented to the stomach, the primary functions of which are storage, mixing, and reducing all components to slurry with the aid of gastric secretions and then emptying these contents in a controlled manner into the upper small intestine
Small intestine is the major site for absorption of most drugs due to its large surface area. The folds in the intestinal mucosa, called as folds of kerckring, result in 3 fold increase in the surface area. The surface of these folds possess finger like projections called as villi. From the surface of villi protrude several microvilli resulting in 600 times increase in the surface area (approx 285cm). The blood flow to the small intestine is 6 to 10 times that of stomach and the pH range of 5 to 7.5 is most favorable for basic drugs to remain unionized. The peristaltic movement of intestine is slow, transit time is long and permeability is high. The transit time through the small intestine typically takes 3 to 5 hours is fairly constant and unaffected by food status. Hence by prolonging gastric residence, the overall transit time of a dosage form can be extended. If the drug dissolves in the stomach contents, drug solution will then pass in an unimpeded manner to the small intestine for subsequent absorption at the optimal site. Thus, a contribution of all the above factors makes small intestine the best site for absorption of most drugs.
Large intestine having small absorptive area usually plays very little role in the absorption of drugs. The colon may play an important absorptive role for poorly absorbed drugs and sustained release dosage products because of the long residence time (6 to 12 hours).
In view of the differences in the local environment such as pH, nature of luminal contents, length and surface area, absorptive capacity of three sections of the GIT, the duration of transit and residence times in each section, can greatly affects the drug release/absorption from oral drug delivery products. On the other hand, some of the other factors such as drug solubility and dissolution rate, particle size, effective surface area, lipophilicity of the drug, pKa of the drug, polymorphic nature of the drug also influence the drug absorption from oral route.5
1.3 Conventional Oral drug delivery
The goal of any drug delivery system is to promptly provide the required amount of a drug to the proper site in the body and maintain the desired drug concentration in plasma constantly that is the drug delivery system should deliver the drug at a rate as per needs of the body over the entire duration of treatment. This is also possible through administration of a conventional dosage forms in a particular dose and a particular frequency through either oral or parenteral route. Therefore, to achieve as well as maintain the drug concentration within the therapeutically effective range needed for treatment by repeated administration a day. This results fluctuation in plasma-drug level and leads to several dose related toxic effects and reduces patient compliance6. The frequency of administration any drug depends upon its half life or mean residence time and its therapeutic index. In most cases, the drugs administered repeatedly below its biological half-life a number of limitations associated with such a conventional dosage forms.
Limitations of Conventional drug delivery
1. Poor patient compliance: There an increased chances of missing the dose of a drug with short-half life for which frequent administration to be necessary.
2. The concentration of a drug in the blood fluctuates over successive doses of most conventional single unit oral dosage forms. The main reason that the drug to be release immediately after administration (i.e. burst release effect). This causes the drug blood concentration to rise quickly to a high value ("peak") followed by a sudden decrease to a very low level ("valley") as a result of drug elimination.
3. If the dosing interval is not appropriate for the biological half life of the drug, large "peak" and "valleys" in the drug blood level may obtained. The difficulties arise to maintain the steady-state concentration constantly in entire duration of the treatment.
4. The unavoidable fluctuations in the drug concentrations may lead under medication or over-medication leads to raise the peak plasma concentration toxic range or beyond the therapeutic range.
5. Fluctuation in plasma drug concentration may leads that drug levels may swing too high causes precipitation of adverse effects especially, of the drug with small therapeutic index; alternatively drug may fall too low leading to a lack of efficacy.
The above limitations of conventional oral drug delivery can be minimized by the way of developing certain sustained / controlled and targeted drug delivery systems which have more pharmaceutical and clinical superiority over conventional immediate release products.
Figure 1.2: Drug level versus time profile showing differences between zero-order release (controlled release), sustained release (slow first-order), and immediate release (from a conventional tablet or capsule) dosage forms (Jantzen and Robinson, 2002:502).
1. 4 Novel drug delivery systems
The potential drawbacks associated with conventional drug delivery by oral route can be overcome to develop the dosage forms by using novel techniques which are sustaining the rate of drug release and minimize the dose related adverse effects in various physiological conditions. All these advancements have led to the development of several novel drug delivery systems (NDDS) that could improve the method of medication and provide a number of therapeutic benefits.7 At present the drug delivery sector of global pharmaceutical market accounts for novel drug delivery systems was more than US $ 37.9 billion in 2000, US $54.2 billion in 2004 and is reached up to US $ 75 billion in 2005. In 2005, the largest sector of the market consisted of sustained release/implants/transdermal drug delivery systems, more than 50% of the total U.S. market and reached US $64.1 billion.8-9. A survey of the industry experts proves right; the market for new drug delivery systems is reaching over US $54 billion by the year 2007. The global market for advanced drug delivery systems amounted to US 134.3 billion in 2008, and was projected to increasing to US $139 billion in 2009, and is expected to increase US $196.4 billion in 2014.
The drugs are most commonly administered in the form of pills, tablets, capsules and injections. These formulations meet the requirements of therapeutic efficacy but are produces inefficient drug release of drugs. Moreover, the drugs administered systemically in large doses which are have short half-lives, poor aqueous solubility and permeability in membranes precipitates toxic effects10.To overcome these difficulties, to develop certain novel dosage forms by adopting new modes of administration have been focused of a great deal of research in order to improve the bioavailability and pharmacotherapy of diseases.
1.5 Concept of sustained/controlled release drug delivery systems
The idealized objective points of view, two important objectives of sustained/controlled release systems are spatial placement and temporal of a drug. Special placement relates to targeting a drug to a specific organ or tissue, while temporal delivery refers to controlling the rate of drug delivery to target tissue. An appropriately designed sustained or controlled drug release delivery systems can be major advance toward solving these two problems. The general consensus is that controlled release systems which can provide some control, whether this is of a temporal or spatial nature, or both, of drug release in the body. In other words, the system attempts to control drug concentrations in the target tissue followed by zero-order release kinetics in the entire duration of treatment.11
Sustained release products are drug delivery system that achieves slow release of drug over an extended period of time. Normally, the initial therapeutic dose immediately attains the steady state concentration and followed by a constant release of drug. Thus, sustained release products maintain constant plasma drug concentration and minimize the fluctuation. The drug release from these dosage forms is slow either first order fashion or nearer to zero-order.
The term controlled release is the one in which is delivered the drug at predetermined rate locally or systemically for a specified period of time. The release of active ingredients from controlled release drug delivery proceeds at a rate profile not only predictable kinetically but also reproducible from one unit to another. In controlled drug delivery systems the release of a drug from the dosage form is the rate determining step. Controlled release delivery systems provide a uniform concentration of the drug at the absorption site and thus after absorption, allow maintenance of plasma concentrations within a therapeutic range which minimizes side effects and also reduces the frequency of administration.12 The principle advantages of sustained/controlled release drug delivery systems are mentioned below;
1. Maintenance of optimum therapeutic drug concentration in the blood with minimum fluctuation. 2. Predictable and reproducible release rates for extended duration. 3. Enhancement of activity duration for short half-life drugs. 4. Elimination of side effects, frequent dosing and wastage of drug 5. Optimize the therapy and better patient compliance. 6. Economy: In comparisons with conventional dosage forms the average cost of treatment over an extended time period may less and also a decrease in nursing time and hospitalization.
Because of the above advantages, these specialized drug delivery systems are highly applicable to many drugs and in many chronic diseases conditions, such as hypertension, arthritis, diabetes, fertility control, glaucoma, angina pectoris and cancer therapy, etc. there are currently, numerous products in the market formulated for both oral, parenteral, transdermal-through skin, nasal, ocular-through eye, pulmonary through lungs, have been developed for the purpose of the administration of drug to the body to make more effective, easy to administer and prolonged release of drug for entire duration of treatment.13
1.6 Oral sustained/controlled drug delivery
The majority of these oral sustained/controlled drug delivery systems are either tablets or capsules/microspheres although a few liquid products are also available. Sustained release tablet or capsule dosage forms usually consist of two parts; an immediately available portion to establish the blood level quickly and sustaining part that contains several times the therapeutic dose for maintain the steady state plasma concentration within a therapeutic window14. In the exploration of oral sustained/controlled release drug administration, one encounters three areas of potential challenges:
1. Development of a drug delivery system: To develop a viable oral controlled release drug delivery system capable of delivering a drug at a therapeutically effective rate to a desirable site for duration required for optimal treatment.
2. Modulation of gastrointestinal transit time: To modulate the GI transit time so that the drug delivery system developed can be transported to a target site or to the vicinity of an absorption site and reside there for prolonged period of time to maximize the delivery of a drug dose.
3. Minimization of hepatic first pass metabolism: If the drug to be delivered is subjected to extensive hepatic first pass metabolism, preventive measures should be devised to either bypass or minimize the extent of hepatic metabolic effect.
Generally, most of the oral sustained/ controlled release systems are able to release the drug slowly by dissolution, diffusion, or a combination of both mechanisms. When the dosage form enter into the GI-tract and the fluid slowly penetrate through the outer layer of polymer matrix system which induces the dissolution, swelling and formation of thick hydrodynamic layer. Further, drug diffusion occurs from a region of higher concentration to a region of lower concentration. This concentration difference is the driving force for drug diffusion out of the system. The inside of the system should have lower water content initially than the surrounding medium to control the diffusion of a drug effectively in a sustained manner, finally, the diffused drug partition between the body fluid and enters through plasma15 . Based on the above principle several approaches are summarized below;
A. Dissolution controlled release systems
Dissolution-controlled release can be obtained by slowing the dissolution rate of a drug in the GI medium, incorporating the drug in an insoluble polymer, and coating drug particles or granules with polymeric materials of varying thicknesses. The rate-limiting step for dissolution of a drug is the diffusion across an aqueous boundary layer. The solubility of the drug provides the source of energy for drug release, which is countered by the stagnant-fluid diffusional boundary layer.
i) Matrix (Monolith) dissolution controlled systems
Matrix systems are also called as monoliths since the drug is homogeneously dispersed throughout a rate controlling medium. Generally, waxes such as beeswax, carnauba wax, hydrogenated castor oil are employed, which control drug dissolution by controlling the rate of dissolution fluid penetration into the matrix by altering the porosity of tablet, decreasing its wettability or itself dissolved slower rate. The wax embedded drug is generally prepared by dispersing the drug in molten wax by congealing and granulating techniques. The mechanism of drug release from the system is often followed to first order kinetics.
ii) Encapsulation/coating dissolution controlled systems
The drug particles are coated or encapsulated by microencapsulation techniques with slowly dissolving materials like sodium alginate, cellulose, poly ethylene glycols, polymethacrylates, waxes etc. The resulting pellets or microbeads may be filled as such in a hard gelatin capsules or compressed into tablets. The dissolution rate of the formulation depends upon the solubility and thickness of the coating polymeric matrices.
B. Diffusion controlled release systems
In these types of systems, the rate controlling step is the diffusion of dissolved drug through a polymeric barrier. The diffusion path was controlled by using swellable or non-swellable or insoluble matrix material. The drug release rate is never zero-order since the diffusional path length increases with time as the insoluble matrix is gradually depleted of insoluble drug16. The diffusion controlled systems are:
i) Matrix diffusion controlled systems
In these types of systems, the drug is dispersed in rigid non-swellable hydrophobic or swellable hydrophilic polymeric materials such as polyvinyl chloride, beeswax, carnauba wax, guar gum, sodium alginate, chitosan, xanthan, gellan gum etc. granulated together any organic solvent and compressed into tablets.
The release of drug from matrix system such initially dehydrated polymeric matrix involves simultaneous absorption and desorption of drug via a swelling controlled diffusion mechanism. As the polymeric matrix swells, the drug diffuses out from the diffusion layer followed by Fickian first-order under equilibrium conditions.
ii) Reservoir type diffusion system
These systems are hollow containing an inner core of drug surrounded in a water insoluble polymer membrane fabricated by coating or microencapsulation techniques. The drug release mechanism across the membrane involves its partitioning into the membrane with subsequent release into the surrounding fluid by diffusion. The rate of drug release is controlled by concentration of polymer in coating, thickness of coating membrane and mechanical strength of microcapsules.
iii) Dissolution and diffusion controlled release systems
In such systems, the drug core is encapsulated or enclosed in a partially soluble membrane. Dissolution part of the membrane permits to entry of aqueous medium into the core and drug dissolution and allow diffusion of dissolved entrapped drug out of the system through pores in the polymer outer coat. The drug release from the system depends on the fraction of soluble polymer in the coat.
C. Ion exchange resin complexes
It is an attractive technique for oral sustained release drug delivery of ionizable acidic and basic drugs can be obtained by complexing them with insoluble nontoxic anion exchange and cation exchange resins respectively. The drug loaded formulations prepared by mixing the respective resins with drug solution and then converted as granules or spheres. When a high concentration of an appropriately charged ion is in contact with the ion exchange group, the drug molecule is exchanged and diffuses out of the resin to the bulk solution according to the following scheme.
A cationic drug forms a complex with an anionic ion-exchange resin e.g. a resin with a SO3- group. In the G.I tract Hydronium ion (H+) in the gastrointestinal fluid penetrates into the system and that activates the release of cationic drug from the drug resin complex
H+ + Resin - SO3- Drug+ Resin - SO3- H+ +drug+
An anionic drug forms a complex with a cationic ion exchange resin, e.g. a resin with a [N (CH3)3+] group. In the GI tract, the Chloride ion (Cl-) in the gastrointestinal fluid penetrates into the system and that activates the release of anionic drug from the drug resin complex.
Cl- + Resin - [N (CH3)3+] Drug Resin - [NCH3)3+] Cl- + Drug-
D. Osmotic pressure controlled release systems
In this type of drug delivery systems, to activate the release of drug depends on the osmotic pressure developed within the system. A tablet containing a core of an osmotically active drug or a core of an osmotically inactive drug in combination with an osmotically active salt (potassium chloride or manitol) is surrounded by a rigid semipermeable membrane coating with cellulose ester. When the tablet is exposed to GI fluids, water flows through the semipermeable membrane into the tablet due to osmotic pressure difference which dissolves the drug and diffuse it out through the orifice in a controlled manner. The drug release from the system depends on orifice diameter, membrane thickness, osmotic pressure gradient, drug solubility and membrane permeability16
E. Altered Density Systems
The transit time of GI contents is usually less than 24 hours. This is the major limiting factor in the design of oral controlled release formulations which can reduce the frequency of dosing to a time period little more than the residence time of drug. This can be achieved by altering the density of drug particles or increasing the adhesive of dosage form by using mucoadhesive polymers.
High density pellets: The density of GI fluids is around 1.4g/cc. The drug combined with heavy inert core or encapsulates with high density polymer and then covered by a diffusion controlled membrane. The formed pellets or beads ensures the prolonged GI residence that is unaffected by food.
Low Density Pellets: The pellets or beads having density less than that of GI fluids, float on the gastric juice for an extended period of time while slowly releasing the drug.
A prodrug is a compound formed by the chemical modification of the biologically active compound that will liberate the active compound in vivo, by enzymatic or hydrolytic cleavage. The primary purpose of employing prodrugs for oral administration is to increase intestinal absorption and reduce local side effects.
1.7 Selection of drug candidates for controlled drug delivery
The design of oral sustained/controlled drug delivery systems is subject to several variables like route of administration, type of delivery system, the disease being treated, and the length of therapy. The rate of drug release from the system is mainly depends upon the physicochemical properties of the drug and its biopharmaceutical characteristics.17 The desired physicochemical and biopharmaceutical properties of a drug to be used in an oral sustained / controlled drug delivery system are mentioned in table 1.7.1
Table 1.1: Properties of drug candidates for the design of CDDS
Properties of drug candidates
A. Biopharmaceutical properties
Partition coefficient (K o/w)
Dissociation constant pKa
Ionization at physiological pH
Stability in GI tract
B. Pharmacokinetic Properties
Absorption rate constant Ka
Elimination half-life ( t1/2)
C. Pharmacodynamic Properties
Less than 600 Daltons
More than 0.1mg/ml, pH independent
pKa> 2.5 ( Acidic drugs), pKa< 11.0 basic drugs)
Not more than 95%
Stable at both gastric and intestinal pH
Not too high or high first-pass
Maximum 1.0 g
1.8 Microencapsulation techniques in drug delivery
Microencapsulation is a process whereby small discrete solid particles or small liquid droplets are surrounded and enclosed, by an intact shell. The concept of microencapsulation was initially utilized in carbonless copy paper. More recently it has received increasing much attention in pharmaceutical and biomedical applications. The first research leading in the development of microencapsulation procedures for pharmaceuticals was published by Bungenburg de Jong and Kass in 1931 and dealt with the preparation of spheres by the use of gelatin coacervation process for coating.18 Now a days, the pharmaceutical industries and researchers are involved to develop newer drug delivery systems by using several coating materials for the microencapsulation of oral products. Thus microencapsulation provides the means of converting liquids to solids, altering colloidal and surface properties, enrolling environmental protection and of controlling the release characteristics depending on physicochemical properties of coating materials.19. Several of these properties can be attained by micro-packaging techniques or microparticulate techniques.
The microparticles are small discrete particles with a diameter of 1-1000Âµm, irrespective of the precise interior or exterior structure are generally formulated by encapsulation process whereby an active ingredient may be dispersed in a protective matrix or it may be surrounded by a coating membrane or shell. In other words, microparticles are micron size particles formulated by homogeneous mixture of polymer and active core that solid, liquid or gas.20
Microparticles are can be divided into two broad groups. The first is aggregate type of particles which have the active ingredient dispersed uniformly throughout a continuous polymeric matrix. The matrix may be a solid or swellable gel with solvent is known as microcapsules. The second is mononuclear microparticles are similar to an egg shape, in which solid, liquid core surrounded by polymeric flexible membrane. This type of mononuclear micron size spheres has less than 1000Âµm in diameter and more spherical in shape. Generally, they termed as microspheres or microbeads.21
The optimization of microencapsulation technology is an important to develop the products in reproducible manner because no single microencapsulation process is adaptable to all products applications. Several manufacturing difficulties arises such as incomplete coating, inadequate stability or shelf-life of sensitive drugs, non reproducible and unstable release characteristics of coated materials, clumping of microcapsules and economic limitations often are encountered in the attempt to selection of particular microencapsulation methods.22 Thus appropriate combination of starting materials and synthesis methods can be chosen to produce microencapsulated products with a wide variety of compositional and morphological characteristics.
Research to find new or to improve microencapsulation techniques to fabricate certain newly discovered active medicaments by using nontoxic, inert polymeric materials and solvents is much important progress because of the limitations of the current pharmacopeia. Besides of this, the regulatory authorities, such as the U.S. Food and Drug Administration (FDA), are restricting to greater degrees the amounts of additional components allowed such as organic solvents or tensioactive molecules. For these reasons, in designing of new techniques one must take into account several new requirements; The physical and chemical stability of the drug should not be affected during the microencapsulation process, the formulated spheres or beads with high yield and drug encapsulation efficiency, good mechanical strength and should not exhibit aggregation or adherence. The drug release from the formulation is a reproducible manner with specified time limit and the process should be usable at an industrial scale and the residual level of organic solvent should be lower than the limit value.23
Reasons for microencapsulation:
Microencapsulation of materials is resorted to ensure that the encapsulated material reaches the area of action without getting adversely affected by the environment through which it passes24.The principal reasons for encapsulation are: i) Separation of incompatible components ii) Conversion of liquids to free flowing solids iii) Protection of the encapsulated materials against oxidation or deactivation due to reaction in the environment and improve the stability iv) Masking of odor, taste of encapsulated active materials or the dosage forms v) Control the release of active compounds in a sustained manner vi) Targeted release of the encapsulated active material vii) The ability to incorporate reasonably high concentrations of the drug viii) Controlled particle size and dispersability in aqueous vehicles for injection. ix) Reduce GI-disorders of acidic drugs x) Improve the bioavailability of water in-soluble drugs and patient compliance.
Although a variety of techniques have been reported for microencapsulation, they can broadly be divided into two main categories mentioned in table 1.2
Table1.2 Various processes of microencapsulation techniques
Coacervation and phase separation
Ionotropic gelation technique
Fluidized bed coating
Single emulsion technique
Double emulsion technique:
Vibrational Nozzle process;
Emulsion cross-linking technique
Rotational suspension separation
Polymerization at liquid gas
Air suspension process
Layer-by-layer adsorption Process;
Coaxial ultrasonic technique
Table 1.3 Different types polymers used in microencapsulation
Collagen, casein, fibrinogen, albumin, gluten and gelatin
Sodium alginate, carrageenan, agar, gellan gum, locust been gum, xanthan gum, chitosan, scleroglucan, guar gum, xyloglucan, curdlan, Pullulan, taragum, rosin
Ethylcellulose, methylcellulose, corboxymethylcellulose, hydroxypropylmethylcellulose [HPMC], hydroxypropylcellulose [HPC] cellulose acetate
Polyurethanes, silicon resins, polyesters, polycaprolactone, polyamides, polysterene, polyacrylamides, methacrylic copolymers, polyacrylic acid, polysine etc.
Waxes and lipids
Paraffin, Carnauba, Spermaceti, Beeswax, Stearic acid, Stearyl alcohol, Glyceryl stearates.
Shellac, cellulose acetate phthalate, Zein.
Ionotropic gelation technique
Microencapsulation by ionotropic gelation is one of the widely used technique for developing the oral solid microparticles to control the drug release, reduce the dose related adverse effects especially drug with small therapeutic range and improve the bioavailability of poor water soluble drugs. Ionic-gelation may be defined as a physicochemical process of micro-droplet hardening by chelation of polyelectrolyte with polyvalent ions. Such a chelation results in cross-linking of the polyelectrolyte molecules while forming a shell in the form of a polymeric gel. The most widely used system is based on gelation of aqueous sodium alginate, gellan, carrangeenan, pectin and chitosan solutions by the addition of divalent cations such as calcium chloride, tripolyphosphate, aluminum chloride, barium chloride; potassium chloride induces the cross-linking of the polymers, and instantaneously the formation of discrete solid microparticles.25 In this method strong spherical shape and narrow particle size with high yield microparticles are formed which are used for the carriers of many NSAIDs to minimize the dose related adverse effects and prolong the drug release potential.
The ionic gelation mechanism of alginates with divalent calcium ion has widely used for the preparation of calcium alginate microbeads which are recently used as a vehicle for oral controlled drug delivery system of many therapeutic agents such as NSAIDs, hypertensive, antibiotics, anticancer drugs, antihistamines, cardiovascular agents, vitamins, tranquilizers etc.
Sodium alginate is a natural polysaccharide used to develop sustained release products because of its ability to form cross-linked gels with calcium salts. It is a salt of alginic acid is composed of D-mannuronic acid and L-guluronic acid residues at varying proportions of GG-, MM- and MG-blocks. Cross-linking takes place only between the carboxylate residues of GG-blocks and Ca2+ ions via egg-box model to give a tight gel network structure. It has been stated that when a drop of alginate solution comes in contact with calcium ions, gelation occurs instantaneously. As Ca2+ ions penetrate into interior of droplets water is squeezed out of the interior, resulting in the formation of spherical beads.26 Ionotropic gelation method has much attracted considerable attention than other microencapsulation techniques because ease of manufacture, improve swelling properties of products and are susceptible to environmental pH conditions.27
1.9 Solid micro-emulsification (SME) in oral sustained drug delivery
Many new potential therapeutic active compounds under investigation possess high lipophilicity, poor water solubility, and low oral bioavailability. To improve the aqueous solubility and oral bioavailability of such type of drugs through emulsions are used as vehicles for the administration of drugs. Microemulsion is homogeneous, transparent mixture of water, oil, surfactant and co-surfactant and thermodynamically stable dispersion28. The formation of microemulsion is spontaneous and does not involve the input of external energy. One theory considers negative interfacial tension while another considers swollen micelles. The surfactant and the co-surfactant alternate each other forming a mixed film at the interface contributing to the stability of the microemulsion.32 Microemulsion is a potential drug delivery systems for poorly water soluble drugs due to their ability to solubilize the drugs in the oil phase, thus increasing their dissolution rate.29
Oral sustained delivery systems designed for poorly water-soluble drugs include micelles with surfactants, micro-emulsions, self-emulsifying/micro-emulsifying drug delivery systems, solid dispersions, and cyclodextrin inclusion complexes. These delivery systems have been shown to enhance oral bioavailability and therapeutic effects of poorly water-soluble drugs mainly by improving the aqueous solubility.30 The various attractive advantages of microemulsion; nanosized (<200 nm), ease of scale-up and manufacturing, long shelf life, ability to improve dissolution rate and lymphatic transport of hydrophobic drugs over other novel delivery systems such as liposome's, dendrimers and polymeric microspheres and nanoparticles31.
The drawbacks of these systems mainly produce the chemical instabilities of drugs and GI-irritation is observed due to high surfactant concentrations more than (30-60%). Conventionally, microemulsion drug delivery system (MEDDS) is filled in hard or soft gelatin capsules for ease of administration. However, certain problems such as leaking, leaching of components from the capsule shell, and interaction of microemulsion with capsule shell components resulting in the precipitation of the lipophilic drugs are often observed for such liquid-filled capsules.32 Solidification of liquid systems has been a challenge that has attracted wide attention due to handling difficulties and stability problems that are often encountered with liquids.
Many literature reports explains the blending liquid systems with selected powder excipients or adsorbents produce free-flowing using several techniques such as spray drying, solvent evaporation and extrusion spheronization. Generally, lactose, natural gums and microcrystalline cellulose were used as solidifying aids. But in all these studies, to obtain solids with suitable processing properties, the required ratio of solidifying excipients to MEDDS was very high, and it seems to be practically infeasible for drugs having limited solubility in oil phase and shows less drug content uniformity.33
In recent years, there is a growing trend to formulate solid-MEDDS by adsorbing liquid microemulsion pre-concentrates onto suitable solid carriers which can convert into spheres or nanosized particles and are easily filled in hard gelatin capsules for oral administration34. Such systems require the solidification of liquid microemulsifying (ME) ingredients into powders/ microparticles to create various solid dosage forms such as tablets or capsules and ME pellets. Thus, S-MEDDS combine the advantages of liquid MEDDS which are enhances the solubility and bioavailability, low production cost, convenience of process control, high stability and reproducibility and better patient compliance.
1.10 Matrix tablets in oral sustained drug delivery
Matrix systems are also called as monoliths since the drug is homogeneously dissolved or dispersed throughout a soluble swellable hydrophilic or insoluble erodible or non-swellable hydrophobic rate controlling materials. Matrix tablets are an interesting option when developing an oral controlled release formulations manufactured by direct compression or wet-granulation techniques of active drug, retardants and other additives to form tablets. The release of the drug from the tablets by dissolution controlled as well as diffusion/erosion controlled mechanisms35. To control the release of the drugs, which are having different solubility properties, the drug is dispersed in swellable hydrophilic substances, an insoluble matrix of rigid non-swellable hydrophobic materials or plastic materials. The three classes of retardant materials used to formulate matrix tablets, each are demonstrating a different approach to the matrix concept was summarized in table 1.4.
The first class consists of retardant materials such as insoluble or inert polymers. In this concept the insoluble or inert polymers such as polyethylene, polyvinyl chloride, and acrylate copolymers formed insoluble or skeleton matrices. A wet-granulation method used to formulate the tablets using mixtures of the active drug and methylcellulose used as the matrix former [granulating agent dissolved with ethanol]. The rate limiting step in controlling release from these formulations is liquid penetration into the matrix depends on the percentage of wetting agents are included to promote permeation of the polymer matrix by water, which allows drug dissolution and diffusion from the channels created in the matrix.
The drug bioavailability, which is mainly dependent on the drug: polymer ratio, degree of penetration, formation of matrix and swellability of insoluble polymer in different pH environment. These forms of matrix tablets are not useful for high potency formulations in which the polymer content would be insufficient to form a matrix, or for highly water-insoluble drugs in which dissolution in the matrix would become rate limiting. Release of water soluble drugs, however, should be unaffected by the amount of liquid, pH-level, enzyme content, and other physical properties of digestive fluids.36
The second class represents water insoluble materials that are potentially erodible such as certain waxes, lipids, and related materials form matrices that control release through both pore diffusion and erosion. Release characteristics are therefore more sensitive to digestive fluid composition than to the total insoluble polymer matrix. Total release of the drug from the wax-lipid matrices is not possible, since a certain fraction of the dose is coated with impermeable wax films. Release is more effectively controlled by the addition of surfactants in the form of hydrophilic polymers, which promotes water penetration and subsequent matrix erosion.
Table 1.4 Different types of drug release retardants used in matrix drug delivery systems
Insoluble / inert
Polyethylene, Polyvinyl chloride Methylacrylate-Methacrylatecopolymer, Ethylcellulose, Polyvinyl acetate
Insoluble / Erodable
Carnauba wax, Stearyl alcohol, Stearic acid, Polyethylene glycol, Castor wax, Polyethylene glycol monostearate, Triglycerides
Methylcellulose, Hydroxyethylcellulose (HMC) Hydroxypropylmethylcellulose (HPMC)
Sodium alginate, Guar gum, Gellan gum, Xanthan gum, Pectin, Carrageenan, Locust bean gum, Chitosan etc
Three methods are used to disperse drug and additives in the retardant base or lipid based polymers.
a). Solvent Evaporation Technique; In this technique, a solution or dispersion of drug and other additives is incorporated into the molten wax phase. The solvent is removed by evaporation. The formed dry matrix mixture prepared as tablets.
b) Slugging method: In this blends the dry polymer, active drug and other additives to prepare the uniform size distribution granules, compressed into tablets.
c). Fusion technique: In this method drug and additives are blended into the molten wax matrix at temperature slightly above the melting point. The molten material may be spray congealed, solidified and milled and screened to form uniform sized granules. Carnauba wax in combination with stearyl alcohol has been utilized as a retardant base for many controlled release matrix formulations. A novel approach to the development of a lipid matrix utilizes pancreatic lipase and calcium carbonate as additives, with triglycerides as retardants. The lipase is activated on contact with moisture and thus promotes erosion independent of intestinal fluid composition. The release profile is controlled by the calcium carbonate, since calcium ions function as lipase accelerator37.
Third group of matrix formers represents the biodegradable hydrophilic materials form the gel like matrix. Drug release is controlled by penetration of water through a gel layer produced by hydration of the polymer and diffusion of drug through the swollen, hydrated matrix causes the erosion of the gelled layer. The extent to which diffusion or erosion controls release depends on the polymer nature as well as the drug: polymer ratio in the formulation. The process used to prepare formulations for compression into tablets either wet-granulation or a direct compression method depends on the polymer and drug: polymer ratio. With high drug: polymer ratios a wet granulation process. Low-potency formulations may be directly compressed or granulated using alcohol.
The hydrophilic polymers are commonly used in several oral sustained release dosage forms to control the release of drug in extended period of time. These hydrophilic polymers achieve special properties such as good compression characteristics, high drug loading, adequate swelling properties that allows rapid formation of an thick hydrodynamic gel layer which retards or plays a major role in controlling drug release.38
1.11 Nonsteroidal anti-inflammatory drugs (NSAIDs)
Arthritis is a term that includes a group of disorders that affect the joints and muscles. Arthritis symptoms include joint pain, inflammation and limited movement of joints. The most common types of arthritis are osteoarthritis, rheumatoid arthritis, septic arthritis, juvenile idiopathic arthritis; ankylosing, spondylitis and inflammatory bowel disease39. The formation of arthritis in various parts of joints summarized in the figure 1.3
Figure 1.3 Arthritis formations in various parts of joints
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed categories of drugs worldwide owing in their efficacy as anti-inflammatory, anti-thrombotic, anti-pyretic and in the treatment of pain and inflammation in many conditions. During the past 30 years, there has been a substantial increase in the number of clinically available NSAIDs. They annually account for 70 million prescriptions and 30 billion over-the-counter (OTC) medications sold in the worldwide. Population studies have shown that 10-20% of peoples who are 60 years or older either are currently receiving a prescription for NSADs drugs. Due to the competitions among pharmaceutical companies the number of new drugs and marketing of NSAIDs has dynamically increased in the past four decades. Today more than 100 preparations are in the market or under clinical investigation40
The history of analgesic and anti-inflammatory substances started with the use of decocted salicylate-containing plants by ancient Greek and Roman physicians. Over the past 140 years other substances have been introduced for therapy, collectively termed as nonsteroidal anti-inflammatory drugs (NSAIDs), after PS Hench discovered the anti-inflammatory properties of glucocorticoids in 1949. In the past few years there have been significant advances in explaining the mechanism of action of NSAIDs.
In the 1930s, Gold blatt and Von Euler showed that human seminal fluid contained a component that reduced blood pressure, the effects of which could not be classified among the tissue hormones known at the time. Von Euler termed these new, unknown substances 'prostaglandins' (PGs) and are an important group of chemical mediators which are responsible for producing changes, symptoms and signs of inflammation. PGs are paracrine secretions (local hormones) they are released from cells and bring about changes in neighboring cells that carry specific PG receptors in their membranes. PG was released by damaged cells and nearby macrophages and one of their effects is to stimulate pain receptors (nociceptors). At the same time they intensify the effects of other chemical mediators such as histamine and bradykinin. Acting in concert these substances can bring about vasodilatation and an increase in the permeability of capillaries supplying the damaged area, encouraging the migration of phagocytes from the blood through capillary walls into the damaged tissue. As a result of these changes, the blood supply to the area increases, the tissues swell, and pain occurs, signs of inflammation.
Another milestone was leading to inflammatory changes discovered by Vane and coworkers the analgesic, antipyretic and anti-inflammatory properties of acetylsalicylate were based on the inhibition of prostaglandin synthesis. Vane showed that the acidic anti-inflammatory analgesics decreased pro-inflammatory prostaglandin concentrations by inhibiting cyclooxygenases (COX).This finding made sense because the PGs characterized in the 1960s were found to be substantially involved in bringing about and maintaining inflammatory processes by increasing vascular permeability and amplifying the effects of other inflammatory mediators such as kinins, serotonin and histamine and also involved in the induction of fever, inflammation and pain. In 1971 Vane and co-workers discovered that aspirin and some NSAIDs prevented the synthesis of prostaglandins from arachidonic acid by inhibiting the activity of the cyclooxygenase (COX) enzyme41. The different types of NSAIDs are summarized in the table 1.5
Table 1.5 Different types of non-steroidal anti-inflammatory drugs (NSAIDs)
Non-steroidal anti-inflammatory drugs
Salicylates [aspirin, diflunisal]
Pyrazolone derivatives [phenylbutazone, oxyphenbutazone]
Indole derivatives [indomethacin, etodolac, sulindac]
Propionic acid derivatives[ibuprofen, ketoprofen, flurbiprofen, dexibuprofen, naproxen, fenoprofen,]
Anthranilic acid derivatives [ mefenamic, meclofenamic]
Aryl-acetic acid derivatives [diclofenac, aceclofenac, fenclofenac]
Oxicam derivatives[piroxicam, tenoxicam. sudoxicam, isoxicam, meloxicam]
Pyrrolo-pyrrole derivatives [ ketorolac]
Preferential COX-2 inhibitors
Nimesulide, Meloxicam and Nabumetone
Selective COX-2 inhibitors
Celecoxib, Rofecoxib and Valdecoxib
Paracetamol, Propyphenazone and Nefopam Mechanism of NSAIDs
All NSAIDs share a common mode of action of inhibiting the synthesis of PGs from arachidonic acid. Arachidonic acid is released from membrane phospholipids as a response to inflammatory stimuli. This mechanism was found to be responsible for the therapeutic anti- inflammatory effects of NSAIDs probably as a result of suppressing the synthesis of certain physiologically important prostaglandins. Prostaglandins are an important group of chemical mediators which are responsible for producing changes, symptoms and signs of inflammation. Flow chart of the mechanism of NSAIDs represented in the figure 1.4
Figure 1.4 Flowchart of the mechanisms of NSAIDs
From: M.J. Neal, Non-steroidal anti-inflammatory drugs (NSAIDs) Medical Pharmacology at a glance (66), 1985.
NSAIDs are heterogeneous group of compounds that are selectively by inhibiting both Cyclooxygenase enzymes (COX 1 and COX 2) which are responsible for the biosynthesis of the prostaglandins (PGs) and thramboxanes from its precursor arachidonic acid. COX-1 enzyme present constitutively in almost all types tissues including thrombocytes and those present in kidney, stomach and vascular endothelium and convert arachidonic acid to PGs. These PGs in turn to stimulate physiological functions, such as stomach mucous production and kidney water excretion, as well as platelet formation. This is a housekeeping enzyme involved in the production of prostaglandins which help to keep the stomach and blood vessels clean by making prostacyclin. Therefore, the location of the COX-1 enzyme dictates the functions of PGs. In contrast, COX-2 enzymes which are not normally present or in minute quantities induced by cytokines and other signal molecules at the site of inflammation. The induction of COX-2 has been observed in macrophages and monocytes, endothelial cells, chondrocytes and osteoblasts. Inhibition of COX-2 is therefore thought to be responsible for at least some of the analgesic anti-inflammatory and antipyretic properties of NSAIDs whereas inhibition of COX-1 is thought to produce some of their toxic effects particularly those on the gastrointestinal tract.42
Prostaglandins are paracrine secretions they are released from cells and bring about changes in neighboring cells that carry specific prostaglandin receptors in their membranes. They are rapidly degraded locally, and generally do not reach the blood stream. COX-1 enzyme influences the functions of PGs depends upon the type of tissue they are acting upon directly or as a result of modifying the actions of other signaling molecules. Prostaglandins were released by damaged cells and nearby macrophages and stimulate pain receptors (nociceptors). At the same time they intensify the effects of other chemical mediators such as histamine and bradykinin. Acting in concert these substances can bring about vasodilatation and an increase in the permeability of capillaries supplying the damaged area, encouraging the migration of phagocytes from the blood through capillary walls into the damaged tissue. As a result of these changes, the blood supply to the area increases, the tissues swell, and pain occurs.43
Action of NSAIDs on Cyclooxygenase
The two forms of cyclooxygenase have equal molecular weights and are very similar in structure. However, the attachment site of COX-1 is smaller than the attachment site of COX-2. Therefore, it accepts a narrower range of structures as substrates. The cyclooxygenase active site lies at the end of a long, narrow, hydrophobic tunnel or channel. Three of the alpha helices of the membrane-binding domain lie at the entrance to this tunnel. In various ways, they all act by filling and blocking the tunnel, preventing the migration of arachidonic acid to the active site at the back of the tunnel. They act temporarily blocking the attachment site for arachidonic acid on the cyclooxygenase enzyme, thereby preventing it from converting arachidonic acid to prostaglandin 44
Pharmacokinetics of NSAID (ADME)
Most of the NSAIDs show short biological half-lives and hence have administered 3 to 4 times a day. This leads to patient noncompliance and fluctuations in blood level drug concentration. NSAIDs are also associated with the development of upper GI damage including lesions, ulcers and hemorrhage. Accumulation of NSAIDs compounds occurs particularly in inflamed tissue, GI mucosa, renal cortex and bone marrow because of their acidic nature (pKa 3-5.5) more capacity to binding with proteins. With non-acid, neutral (paracetamol) or weakly basic (phenazone and derivatives) analgesics that do not accumulate in damaged tissue but reach relatively high concentrations in the central nervous system. According to above findings thus, that paracetamol and phenazone are weak inhibitors of prostaglandin synthesis in the periphery whereas paracetamol interferes with prostaglandin synthesis in the central nervous system.45
The most of NSAIDs are high binding with plasma proteins (above 90%) and metabolized into inactive products in the liver. The metabolism of NSAIDs phase-I metabolism produces more polar metabolites and are not efficient COX inhibitors because they have high lipophilic properties more compete with arachidonic acid and prevent its binding to COX. The NSAIDs are mostly excreted as phase-II glucouronides and in a few cases as sulfate conjugates. In addition, small percentages of NSAIDs are excreted unchanged in urine.
When comparing the absorption, distribution, metabolism of the different NSAIDs, similarities as well as differences may be found in their effectiveness. Following oral administration, the drugs are rapidly and almost completely absorbed from the GI tract. Plasma peak drug concentration (t max) may be obtained within 0.5-6 hours.
Adverse effects of NSAIDS;
Most of NSAIDs are associated with extensive side effects like gastric-irritation, dyspepsia, peptic ulceration, esophagitis, constipation, sodium and water retention, chronic renal failure, interstitial nephritis. CNS effects etc, apart from these side effects GI-disorders are the main side effects caused by repeated administration of NSAIDs especially with COX-1 inhibitors. The great therapeutic value of these drugs has made it neÂcessary to develop strategies for avoiding the gastrointestinal risks. Alternatively, co-administer gastric mucosal protectors or develop different novel controlled drug delivery systems to minimize their dose related side effects.46
This chapter gives a brief background on mechanism, adverse effects and pharmacokinetics of NSAIDs especially new molecules such as aceclofenac sodium and dexibuprofen in the treatment of inflammation and pain therapy. It explains the research problems associated with conventional dosage problems over sustained/controlled drug delivery. Further, also explains brief background history of certain new techniques such as microencapsulation, microemulsification and polymeric matrices involved in the formulation of NSAIDs to minimize dose related adverse effects and improve the pharmacotherapy of arthritis.