Drug administration and Drug Delivery Systems

The oral route of drug administration is the most important method of administering drugs for systemic effects. The parentral route is not routinely used or not possible to self-administration of medication. The topical route of administration has only recently been employed to deliver drugs to the body for systemic effects. It is probable that at least 90 % of all drugs used to produce systemic effects are administered by the oral route. When a new drug is discovered, one of the first questions a pharmaceutical company asks is whether or not the drug can be effectively administered for its intended effect by the oral route. If it cannot, the drug is primarily relegated to administration in a hospital setting or physician’s office. Of drugs that are administered orally, solid oral dosage forms represent the preferred class of product. The reasons for this preference are well known1.

1.1 Novel Drug Delivery System:
Today, a pharmaceutical scientist is well versed with the fact that the overall action of a drug molecule is not merely dependent on its inherent therapeutic activity, rather on the efficiency of its delivery at the site of action. An increasing appreciation of the latter has led to the evolution and development of several drug delivery systems (DDS) aimed at performance enhancement of the potential drug molecules.
A review of the literature has revealed the recent several technical advancements have led to the development of various Novel Drug Delivery Systems (NDDS) that could revolutionize method of drug delivery and hence could provide definite therapeutic benefits 2.
Till date, remedies have been found for most of the diseases; but still research is going on inorder to improve the existing therapy. To bring a new drug molecule in the market, it involves a lot more than investment of time and money. In the pre GATT era the patents of drug molecules/formulations are expiring. The new way of patenting the drug is to use.
‘Novel Drug Delivery Systems’ i.e. NDDS with improved bioavailability (BA). To formulate a drug or to re-formulate it in a form of NDDS is not a Herculean task if one goes methodically and skillfully. This is where the formulation development studies play an important role.

1.2 Oral Controlled Drug Delivery:
Drug absorption at the desired rate means, first to reach the effective plasma level within an acceptable short time period; second, to avoid an overshoot in the case of rapidly absorbed drugs and third to maintain effective plasma levels over the desired time period. Although the intensity of pharmacological effect is related to the drug concentration at the site of action, which is in turn, related to the plasma drug concentration, an ideal situation is obtained when the concentration is continuously maintained between minimum effective and maximum safe levels (Therapeutic Index). Invariably, conventional drug dosage forms do not maintain the drug. Blood levels within the therapeutic range for an extended period of time. To achieve the same, a drug may be administered repetitively using a fixed dosing interval. This causes several potential problems as like saw tooth kinetics characterized by large peaks and troughs in the drug concentration-time curve (Fig.1), frequent dosing for drugs with short elimination half-life, and above all the patient noncompliance. Controlled release drug delievery systems(CRDDS) attempt to sustain drug blood concentration at relatively constant and effective levels in the body by spatial placement or temporal delivery. Thus CRDDS offer various advantages viz. reduce blood level fluctuations, minimize drug accumulation, employ less total drug, improve patient compliance, and minimize local and systemic side effects3-7.

Fig 1.1: Plasma level profiles following conventional and controlled release dosing

Modified release DDS, in general, can broadly divided into four categories:
‘ Delayed release
‘ Site specific release
‘ Receptor release
‘ Sustained release
a) Controlled release
b) Prolonged release
For the oral controlled administration of drug, several research and development activities have shown encouraging signs of progress in the development of programmable controlled release dosage forms as well as in the search for new approaches to overcome the potential problems associated with oral drug administration8.
Drugs that are easily absorbed from the gastrointestinal tract (GIT) and having a short half-life are eliminated quickly from the blood circulation. To avoid this problem, the oral controlled release (CR) formulations have been developed as these will release the drug slowly into the GIT and maintain a constant drug concentration in the serum for a longer period of time1. Oral controlled release dosage forms (CRDFs) are being developed for the past three decades due to their advantages. The design of oral controlled drug delivery systems (CDDS) should primarily be aimed at achieving more predictable and increased bioavailability of drugs. Orally administered
controlled release dosage forms suffer from mainly two adversities:
1.3 Gastroretentive drug delivery system (GRDDS) :
Recent scientific and patent literature shows increased interest in academics and industrial research groups regarding the novel dosage forms that can be retained in the stomach for a prolonged and predictable period of time. One of the most feasible approaches for achieving a prolonged and predictable drug delivery profile in the GI tract is to control the gastric residence time (GRT), using gastroretentive drug delivery system (GRDDS) that will provide us with new and important therapeutic options8. A major constraint in oral controlled drug delivery is that not all drug candidates are absorbed uniformly throughout the GIT. Some drugs are absorbed in a particular portion of the GIT only or are absorbed to a different extent in various segments of the GIT. Such drugs are said to have an absorption window, which identifies the drug’s primary region of absorption in the GIT 11

Figure1. 2: (a) Conventional drug delivery system (b) GRDDS

An absorption window exists because of physiological, physicochemical, or biochemical factors. Drugs having site-specific absorption are difficult to design as oral CRDDS because only the drug released in the region preceding and in close vicinity to the absorption window is available for absorption. After crossing the absorption window, the released drug goes waste with negligible or no absorption (Fig.2a). This phenomenon drastically decreases the time available for drug absorption after its release and jeopardize the success of the delivery system. The GRDDS can improve the controlled delivery of the drugs which exhibit an absorption window by continuously releasing the drug for a prolonged period before it reaches its absorption site, thus ensuring its optimal bioavailability (Fig.2b) 12.

Pharmaceutical aspects of gastroretentive drug delivery system (GRDDS) :
In designing GRDDS, the following characteristics should be sought: convenient intake, retention in the stomach according to clinical demand; ability to load substantial amount of drugs with different physicochemical properties and release them in controlled manner; complete degradation, preferable in the stomach13 .Gastric retention will provide advantages such as the delivery of drug with narrow absorption window in the small intestinal region. Also longer residence time in the stomach could be advantages for local action in the upper part of small intestine; e. g. in the treatment of peptic ulcer disease, further more improved bioavailability is expected for drug that absorbed readily upon release in the GI tract.
1.4 Physiology of Stomach:
The shape of the normal stomach is generally like letter ‘J’. Sometimes the long axis may be slanting from left to right or it may be even horizontal. The junction of the esophageal mucosa with that of the stomach is abrupt. The oesophago-cardiac line of junction is irregular or zigzag and is often referred as the ‘Z’ or ‘ZZ’ line. At the pylorus, the mucous membrane of the stomach makes junction with that of duodenum. The capacity of the average stomach is about 1.12-1.7 lts. The stomach can be subdivided into three parts- the fundus, the body and the pylorus.

Figure 1.3: Stomach anatomy

Each of these contains a particular type of gland. The cardiac area is the zone,1 to 4 cm wide that guards the esophageal orifice, also known as cardiac Fundus Body Pylorus sphincter. The fundic area is the largest area of stomach accounting for 60-80 % of total mucosal surface, interposed between the cardiac and the pyloric areas. The lower part of the fundic area is separated from the pylorus by a sharp angle on the lesser curvature called the incisura angularis. The junction of the pyloric and fundic area is not sharply demarcated and is frequently known as transitional zone.
The pylorus is limited on the left by the incisura and on the right by the pyloric sphincter. The circular fibres of pyloric sphincter guards against back flow of small intestinal contents into the stomach. The pyloric area is about 15 % of the total gastric mucosal area. It is subdivided into two parts: (a) the pyloric antrum which is short, comparatively wider, proximal chamber and (b) the pyloric canal which is narrow tubular passage about 3 cm long, ending in the pyloric sphincter (Fig.3).
Histologically, stomach consists of the same four layers but with characteristic differences. The outer serous coat consists of peritoneum. The muscular coat consists of three layers: the outer longitudinal, the middle circular and the inner oblique layer. Next comes the submucous coat, and then come the layer of muscular is mucosae and a supporting stroma of connective tissue. This layer of muscle also contains of an outer longitudinal and an inner circular layer. Finally comes mucous membrane which is thrown out into the large folds called rugae when the stomach is empty and these folds tend to disappear when distended14.

1.5 Gastric Emptying:
The GIT is always in a state of continuous motility. The process of gastric emptying occurs both during fasting and fed states; however, the pattern of motility differs markedly in the two states. In the fasted state, it is characterized by an interdigestive series of electrical events which cycle both through the stomach and small intestine every 2-3 h. This activity is called the interdigestive myoelectric circle or migrating myoelectric complex (MMC), which is often divided into four consecutive phases13.

Figure1.4: Typical motility patterns in fasting state12

A complete cycle of these 4 phases, as illustrated in Fig. 4, has an average duration of 90-120 minutes. Any CRDDS designed to stay during the fasted state should be capable of resisting the house-keeping action of phase III, if one intends to prolong the GI retention time. The bioadhesive properties added to the GI drug delivery system must be capable of adhering to the mucosal membrane strongly enough to withstand the shear forces produced in this phase15.
The gastroretentive technology of solid dosage forms is thus mainly dependent on the coincidence between dosing time and phase III MMC occurrence. Dosage forms such as tablets, capsules and particles have demonstrated a transit pattern similar to that of nutrients. These forms taken orally in the fasted state empty within 90 min. In fed state, these will have to await the MMC activity occurring at the end of digestion to be cleared from stomach in association with the Phase III cleansing contractions. It is thus the pylorus, and, more particularly, the small diameter of the gastric lumen at the gastroduodenal junction, that has remarkable function of performing the selective retention of the solid particles, depending on their size16.

1.5.1. Factors Affecting Gastric Retention 10, 12:
Gastric residence time of an oral dosage form is affected by several factors. The pH of the stomach in fasting state is ~1.5 to 2.0 and in fed state is 2.0 to 4.0. A large volume of water administered with an oral dosage form raises the pH of stomach contents from 6.0 to 9.0. Stomach doesn’t get time to produce sufficient acid when the liquid empties the stomach; hence generally basic drugs have a better chance of dissolving in fed state than in a fasting state.
To pass through the pyloric valve into the small intestine the particle size should be in the range of 1 to 2 mm.. In the case of elderly persons gastric emptying is slowed down. Generally females have slower gastric emptying rates than males. Stress increases gastric emptying rates while depression slows it down. Studies have revealed that gastric emptying of a dosage form in the fed state can also be influenced by its size. Small-size tablets leave the stomach during the digestive phase while the large-size tablets are emptied during the housekeeping waves. The effect of size of floating and nonfloating dosage forms on gastric emptying and concluded that the floating units remained buoyant on gastric fluids12. These are less likely to be expelled from the stomach compared with the nonfloating units, which lie in the antrum region and are propelled by the peristaltic waves.
It has been demonstrated using radiolabeled technique that there is a difference between gastric emptying times of a liquid, digestible solid, and indigestible solid. It was suggested that the emptying of large (91 mm) indigestible objects from stomach was dependent upon interdigestive
migrating myoelectric complex. Indigestible solids larger than the pyloric opening are propelled back and several phases of myoelectric activity take place when the pyloric opening increases in size during the housekeeping wave and allows the sweeping of the indigestible solids. Size and shape of dosage unit also affect the gastric emptying. Garg and Sharma15 reported that tetrahedron- and ring-shaped devices have a better gastric residence time as compared with other shapes. The diameter of the dosage unit is also equally important as a formulation parameter. Dosage forms having a diameter of more than 7.5 mm show a better gastric residence time compared with one having 9.9 mm.
Floating units away from the gastroduodenal junction are protected from the peristaltic waves during digestive phase while the nonfloating forms which stay close to the pylorus and are subjected to propelling and retropelling waves of the digestive phase. It is also observed that of the floating and nonfloating units, the floating units had a longer gastric residence time for small and medium units while no significant difference was seen between the 2 types of large unit dosage forms. When subjects are kept in the supine position it was observed that the floating forms could only prolong their stay because of their size; otherwise the buoyancy remained no longer an advantage for gastric retention. A comparison was made to study the affect of fed and non-fed stages on gastric emptying. For this study all subjects remaining in an upright position were given a light breakfast and another similar group was fed with a succession of meals given at normal time intervals. It was concluded that as meals were given at the time when the previous digestive phase had not completed, the floating form buoyant in the stomach could retain its position for another digestive phase as it was carried by the peristaltic waves in the upper part of the stomach10.

1.6 Gastroretentive technologies (GRT) :
A number of systems have been used to increase the GRT of dosage forms by employing a variety of concepts. These systems have been classified according to the basic principles of gastric retention (Fig.5).

Figure 1.5: Classification of gastroretentive drug delivery system

1. Floating DDS (FDDS), with low density providing sufficient buoyancy to float over the gastric contents.
2. Bioadhesive systems, the localized retention of the system in the stomach.
3. Swelling and expanding systems, preventing transit from the gastric sphincter.
4. High density systems, remaining in the stomach for longer period of time, by sedimenting to the folds of stomach. Fig.5 illustrates the mechanistics of these systems in stomach.

A number of other methods like use of passage-delaying agents and modified shape systems have also been used for gastroretention purpose.

1.6.1 Floating Drug Delivery System (FDDS) :
Floating dosage form is also known as hydrodynamically balanced system (HBS). FDDS have a bulk density less than gastric fluids and so remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time while the system is floating on the gastric contents, the drug is released slowly at the desired rate. After release of drug, the residual system is emptied from the stomach. It is formulation of a drug (capsule or tablet) and gel forming hydrocolloids meant to remain buoyant on stomach contents. This not only prolongs GI residence time but also does so in an area of the GI tract that would maximize drug reaching its absorption site in solution and hence ready for absorption. Drug dissolution and release from the capsule retained in stomach fluids occur at the stomach, under fairly controlled condition. The retentive characteristics of the dosage form in gastric content are most significant for drugs which are insoluble in intestinal fluid, that acts locally and that exhibits sitespecific absorption16, 17.

Classification of FDDS:
Based on the mechanism of buoyancy, floating systems can be classified into two distinct categories viz. non-effervescent and effervescent systems.

A. Non-Effervescent systems:
1. Colloidal gel barrier systems:
Hydrodynamically balanced system (HBS) of this type contains drug with gel forming or swellable cellulose type hydrocolloids, polysaccharides and matrix forming polymers. They help prolonging the GI residence time and maximize drug reaching its absorption site in the solution form ready for absorption. These systems incorporate high levels (20 to 75 % w/w) of one or more gel forming highly swellable cellulose type hydrocolloids e.g. hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC) hydroxypropyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (NaCMC) incorporated either in tablets or capsules. When such a system comes in contact with the gastric fluid, the hydrochloride in the system hydrates and forms a colloidal gel barrier around its surface (Fig.6).

Figure1. 6: Hydrodynamically Based System (HBS) 18

The HBS must comply with following three major criteria
1. It must have sufficient structure to form cohesive gel barrier.
2. It must maintain an overall specific density lower than that of gastric contents.
3. It should dissolve slowly enough to serve as reservoir for the delivery system.

Figure 1.7: Intragastric Floating Tablet

Intragastric floating tablet that were hydrodynamically balanced in the stomach for an extebded period of time until all the drug- loading dose was released. Tablets were comprised of an active ingredient, 0-80 % by weight of inert material, and 20-75 % by weight of one or more hydrocolloids such as methylcellulose, hpc, hydroxypropylmethylcellulose, and sodium caboxymethylcellulose, which upon contact with gastric fluid provided a water impermeable colloid gel barrier on the surface of tablets. (as shown in fig 7)

Figure 1.8: Bilayer Intra-Gastric Floating Tablet

A bilayer tablet can also be prepared to contain one immediate release and other sustained release layer. (Fig.8) Immediate release layer delivers the initial dose whereas sustained release layer absorbs gastric fluid and forms a colloidal gel barrier on its surface. This results in system with bulk density lesser than that of gastric fluid and allows it to remain buoyant in the stomach for an extended period of time19. A multi-layer, flexible, sheath-like device buoyant in gastric juice showing sustained release characteristics have also been developed. The device consists of at least one dry self-supporting carrier film made up of water insoluble polymer matrix having a drug dispersed/dissolved therein, and a barrier film overlaying the carrier film.
2. Micro- porous compartment system:
This technology is comprised of encapsulation of a drug reservoir inside a micro porous compartment with pores along its top and bottom surfaces. The peripheral walls of the drug reservoir compartment are completely sealed to prevent any direct contact of gastric mucosal surface with undissolved drug. In stomach, the floatation chamber containing entrapped air causes the delivery system to float over the gastric contents. Gastric fluid enters through the pores, dissolves the drug and carries the dissolved drug for continuous transport across the intestine for absorption. The micro porous compartment system is shown in (Fig.9).

Figure 1.9: Floating drug delivery device with microporous membrane and floatation chamber
Micro porous intra-gastric floating drug delivery device 19:
Intra-gastric floating and sustained release granules of Diclofenac sodium were developed using hydroxypropyl cellulose, ethyl cellulose and calcium silicate as floating carriers which had a characteristically porous structure with numerous pores and a large individual pore volume. The coated granules acquired floating ability from the air trapped in the pores of calcium silicate when they were coated with a polymer.

3. Alginate beads:
Multiple unit floating dosage forms have been developed from freeze-dried calcium alginate. Spherical beads of approximately 2.5 mm in diameter were prepared by dropping a sodium alginate solution into aqueous solution of calcium chloride, causing a precipitation of calcium alginate. These beads were then separated; snap frozen in liquid nitrogen and freeze-dried at ‘ 40”C for 24 hrs. leading to formation of porous system that maintained floating force for over 12 hrs. They were compared with non-floating solid beads of same material. The latter gave a short residence time of 1 hr., while floating beads gave a prolonged residence time of more than 5.5 hrs10.

4. Hollow Microspheres:
Hollow microspheres (microballoons), loaded with ibuprofen in their outer polymer shells were prepared by novel emulsion solvent diffusion method. The ethanol: dichloromethane solution of the drug and an enteric acrylic polymer were poured into an agitated aqueous solution of PVA that was thermally controlled at 40oC. The gas phase was generated in dispersed polymer droplet by evaporation of dichloromethane and formed an internal cavity in microsphere of polymer with drug (Fig.10).

Figure1. 10: Mechanism of microballoon formation by emulsion-solvent diffusion

Figure 1.11: Microballoon
These microballoons floated continuously over surface of acidic solution media that contained surfactant, for greater than 12 hrs. in vitro. The drug release was high in pH 7.2 than in pH 6.8.

B. Effervescent systems:
A drug delivery system can be made to float in the stomach by incorporating a floating chamber, which may be filled with vacuum, air or inert gas. The gas in floating chamber can be introduced either by volatilization of an organic solvent or by effervescent reaction between organic acids and bicarbonate salts.

1. Volatile liquid containing systems:
These devices are osmotically controlled floating systems containing a hollow deformable unit that can be converted from a collapsed to an expanded position and returned to collapse position after an extended period.

Figure1. 12: Gastro inflatable drug delivery device16.

A deformable system consists of two chambers separated by an impermeable, pressure responsive, movable bladder. The first chamber contains the drug and the second chamber contains volatile liquid. The device inflates and the drug is continuously released from the reservoir into the gastric fluid. The device may also consist of bioerodible plug made up of PVA, polyethylene, etc. that gradually dissolves causing the inflatable chamber to release gas and collapse after a predetermined time to permit the spontaneous ejection of the inflatable system from the stomach (Fig.12). Intra-gastric, osmotically controlled drug delivery system consists of an osmotic pressure controlled drug delivery device and an inflatable floating support in bioerodible capsule.

Figure 1.13: Intragastric osmotic controlled drug delivery system16.
2. Gas generating systems:
These buoyant delivery systems utilize effervescent reaction between carbonate/bicarbonate salts and citric/tartaric acid to liberate CO2 which gets entrapped in the jellified hydrochloride layer of the system, thus decreasing its specific gravity and making it float over chyme. These tablets may be either single layered wherein the CO2 generating components are intimately mixed within the tablet matrix or they may be bilayer in which the gas generating components are compressed in one hydrocolloid containing layer, and the drug in outer layer for sustained release effect. Multiple unit type of floating pills (Fig.1.14) that generates CO2, have also been developed. These kinds of systems float completely within 10 minutes and remain floating over an extended period of 5-6 hrs.

Figure-1.14: The multiple units floating drug delivery system using gas generation technique Advantages of floating drug delivery system19:
An FDDS offers numerous advantages over conventional DDS:
1. The gastroretensive systems are advantageous for drugs absorbed through the stomach. E.g. Ferrous salts, antacids.
2. Acidic substances like aspirin cause irritation on the stomach wall when come in contact with it. Hence HBS formulation may be useful for the administration of aspirin and other similar drugs.
3. Administration of prolongs release floating dosage forms, tablet or capsules, will result in dissolution of the drug in the gastric fluid. They H2O e) Drug d) dissolve in the gastric fluid would be available for absorption in the small intestine after emptying of the stomach contents. It is therefore expected that a drug will be fully absorbed from floating dosage forms if it remains in the solution form even at the alkaline pH of the intestine.
4. The gastroretensive systems are advantageous for drugs meant for local action in the stomach. e.g. antacids.
5. When there is a vigorous intestinal movement and a short transit time a might occur in certain type of diarrhea, poor absorption is expected. Under such circumstances it may be advantageous to keep the drug in floating condition in stomach to get a relatively better response.
6. Sustained Drug Delivery:
HBS systems can remain in the stomach for long periods and hence can release the drug over a prolonged period of time. The problem of short gastric residence time encountered with an oral CR formulation hence can be overcome with these systems. These systems have a bulk density of 100 , swell to equilibrium size within a minute, due to rapid water uptake by capillary wetting through numerous interconnected open pores. Moreover, they swell to a large size (swelling ratio of approx. 100 or more) and are intended to have sufficient mechanical strength to withstand pressure by gastric contraction.

Figure 1.17: High Density System

1.6.5. Superporous hydrogel:
Although these are swellable systems, they differ sufficiently from the conventional types to warrant separate classification. With pore size ranging between 10 nm and 100 nm, absorption of water by conventional hydrogel is a very slow process and several hours may be needed to reach an equilibrium state during which premature evacuation of the dosage form may occur. Superporous hydrogels, average pore size >100 , swell to equilibrium size within a minute, due to rapid water uptake by capillary wetting through numerous interconnected open pores. Moreover, they swell to a large size (swelling ratio of approx. 100 or more) and are intended to have sufficient mechanical strength to withstand pressure by gastric contraction.

1.6.6. Incorporation of passage delaying food agents:
The food excipients like fatty acids, e.g. salts of myristic acid change and modify the pattern of the stomach to a fed state, thereby decreasing gastric emptying rate and permitting considerable prolongation of release. The delay in the gastric emptying after meals rich in fats is largely caused by saturated fatty acids with chain length of C10-C1416, 18.

1.6.7. Modified- shape systems:
These are non-disintegrating geometric shapes molded from silastic elastomer or extruded from polyethylene blends which extend the GRT depending on size, shape and flexural modulus of the drug delivery system23.

Figure 1.18: Modified shape systems24
1.7 Criteria for selection of drug candidate for GRDF:
‘ Drugs that are easily absorbed from the gastrointestinal tract (GIT) and having a short half-life are eliminated quickly from the blood circulation.
‘ Absorption from upper GIT: Drugs have a particular site for maximum absorption, e.g. Ciprofloxacin, whose maximum absorption is in the stomach only. The absorption of Metformin HCL is confined to the small intestine only and the conventional sustained release dosage forms may be poorly BA since absorption appears to diminish when the dosage form pass into large intestine.
‘ Drugs insoluble in intestinal fluids (acid soluble basic drugs):e.g. Chlordiazepoxide, chlorpheniramine, cinnarizine, diltiazem.
‘ Local action is seen in the treatment of Helicobacter pylori by Amoxicillin24.
‘ The BA of drugs that get degraded in alkaline pH can be increased by formulating gastro-retentive dosage forms, e.g. Doxifluridine, which degrades in small intestine.
‘ Drug that are erratically absorbed due to variable gastric emptying time.
‘ Drug which get metabolized in the colon or having high first pass metabolism.

1.8 Floating microspheres:
Floating microspheres are gastro-retentive drug delivery systems based on non-effervescent approach. Hollow microspheres are in strict sense, spherical empty particles without core. These microspheres are characteristically free flowing powders consisting of proteins or synthetic polymers, ideally having a size less than 200 micrometer. Solid biodegradable microspheres incorporating a drug dispersed or dissolved throughout particle matrix have the potential for controlled release of drugs 25. As the exterior surface of the dosage form dissolves, the gel layer is maintained by the hydration of the adjacent hydrocolloid layer. The air trapped by the swollen polymer lowers the density and confers buoyancy to the microspheres. However a minimal gastric content needed to allow proper achievement of buoyancy26. Hollow microspheres of Acrylic resins, Eudragit, PMAA, Polyethylene oxide, and Cellulose acetate; Polystyrene floatable shells; polycarbonate floating balloons and gelucire floating granules are the recent developments27.

1.8.1 Method of preparation for floating microspheres9, 25,27,28,29:
Floating microspheres should satisfy certain criteria, they are:
1. The ability to incorporate reasonably high concentration of drug.
2. Stability of the preparation after synthesis with a clinically acceptable shelf-life.
3. Release of active agent with good control over a wide time scale.
4. It must maintain specific gravity lower than gastric content (1.004-1.01 g/cc)
5. Biocompatibility with a controllable biodegradability.
6. Susceptibility to chemical modification.
Selection of excipients is an important strategic consideration for designing a dosage forms with consistence and controlled residence in the stomach. High molecular weight and less hydrophilic polymers are expected to improve floating properties of delivery system. The polymer studied for the development of such systems include cellulose acetate, chitosan, eudragit acrycoat, methocil, polyacrylate, polyvinylacetate, carbopol, agar, polyethylene oxide, and polycarbonate. Various methods are employed for the preparation of the floating microspheres is:

1. Solvent diffusion and Evaporation methods:
Hollow microspheres are prepared by solvent diffusion and evaporation methods to create the hollow inner core. The polymer is dissolved in an organic solvent and the drug is either dissolved or dispersed in the polymer solution. The solution containing the drug is then emulsified into an aqueous phase containing polyvinyl alcohol to form an oil-in water emulsion. After the formation of a stable emulsion, the organic solvent is evaporated either by increasing the temperature under pressure or by continuous stirring. The solvent removal leads to polymer Precipitation at the o/w interface of the droplets, forming the cavity and thus making them hollow to impart the floating properties.

2. Solvent evaporation method:
In this method drug and polymers (HPMC and Ethylcellulose) were dissolved in a mixture of ethanol and dichloromethane at room temperature (Table I). This was poured into 250 mL water containing 0.01% Tween 80 maintained at a temperature of 30’40 ”C and subsequently stirred at ranging agitation speed for 20 min to allow the volatile solvent to evaporate. The microspheres formed were filtered, washed with water and dried in vacuum.

3. Spray drying method:
In Spray Drying the polymer is first dissolved in a suitable volatile organic solvent such as dichloromethane, Acetone, etc. The drug in the solid form is then dispersed in the polymer solution under high-speed homogenization. This dispersion is then atomized in a stream of hot air. The atomization leads to the formation of the small droplets or the fine mist from which the solvent, evaporate instantaneously leading the formation of the microspheres in a size range 1-100 ”m. Micro particles are separated from the hot air by means of the cyclone separator while the trace of solvent is removed by vacuum drying. One of the major advantages of process is feasibility of operation under aseptic conditions. This process is rapid and this leads to the formation of porous microparticles.
Selection of excipients is an important strategic consideration for designing a dosage forms with consistence and controlled residence in the stomach. High molecular weight and less hydrophilic polymers are expected to improve floating properties of delivery system. The polymer studied for the development of such systems include cellulose acetate, chitosan, eudragit acrycoat, methocil, polyacrylate, polyvinylacetate, carbopol, agar, polyethylene oxide, and polycarbonate. Various methods are employed for the preparation of the floating microspheres is:

1.8.2 Advantages of floating microspheres24:
‘ Improves patient compliance by decreasing dosing frequency.
‘ Bioavailability enhances despite first pass effect because fluctuations in plasma drug concentration is avoided, a desirable plasma drug concentration is maintained by continuous drug release.
‘ Better therapeutic effect of short half-life drugs can be achieved.
‘ Gastric retention time is increased because of buoyancy.
‘ Drug releases in controlled manner for prolonged period.
‘ Site-specific drug delivery to stomach can be achieved.
‘ Enhanced absorption of drugs which solubilize only in stomach.
‘ Superior to single unit floating dosage forms as such microspheres releases drug uniformly and there is no risk of dose dumping.
‘ Avoidance of gastric irritation, because of sustained release effect, floatability and uniform release of drug through multiparticulate system.
‘ During the process of an gastric emptying, a proportion of the floating microspheres adheres to stomach wall (as shown in fig. 19) to provide a gastroretention and sustained drug release for drugs like PPI’s drugs which having short elimination half-life.

Fig.1. 19: (A) Microspheres Float on Stomach Contents (B) &(C) Micropsheres
Adheres To Stomach Wall during Gastric Emptying30

1.8.3 Disadvantages11:
‘ This requires sufficiently high levels of fluids in the stomach, for enabiling the system to float and to work efficiently.
‘ Floating microspheres are not suitable candidates for drugs with stability or solubility problem in the stomach.eg nifedipine.
‘ A drug with irritant effect on gastric mucosa also limits the applicability of floating microspheres.

1.8.4 Characterization of Floating Microspheres31, 32:
Floating microspheres are characterized for micromeritic properties, surface morphology, in-vitro buoyancy, drug entrapment efficiency and in-vitro drug release. Micromeritic properties such as particle size, tapped density, compressibility index, true density and flow properties including angle of repose. The particle size is determined by optical microscopy; true density is determined by liquid displacement method; tapped density and compressibility index are calculated by measuring the change in volume using a bulk density apparatus; angle of repose is determined by fixed funnel method. The hollow nature of microspheres is confirmed by scanning electron microscopy.33, 34, 35 Floating behavior of hollow microspheres is studied in a dissolution test apparatus by spreading the microspheres on a simulated gastric fluid (pH 1.2) containing tween 80 as a surfactant; the media is stirred and a temperature of 37’C is maintained throughout the study. After specific intervals of time, both the fractions of the microspheres floating and settled are collected; the buoyancy of the floating microspheres can be calculated using the data.
The in-vitro drug release studies are performed in a dissolution test apparatus using 0.1N hydrochloric acid as dissolution media. X-ray photography of hollow microspheres loaded with barium sulphate in the stomach of beagle dogs.

1.8.5 Application of floating microspheres:
1. Floating microspheres are especially effective in delivery of sparingly soluble and insoluble drugs.
2. For weakly basic drugs that are poorly soluble at an alkaline pH, hollow microspheres may avoid chance for solubility to become the rate-limiting step in release by restricting such drugs to the stomach.
3. Drugs that have poor bioavailability because of their limited absorption to the upper gastrointestinal tract can also be delivered efficiently thereby maximizing their absorption and improving the bioavailability.
4. The floating microspheres can be used as carriers for drugs with so-called absorption windows, these substances, for example antiviral, antifungal and antibiotic agents (Sulphonamides, Quinolones, Penicillins, Cephalosporins, Aminoglycosides and Tetracyclines).
5. For more effective oral use of peptide and protein drugs such as Calcitonin, Erythropoietin, Vasopressin, Insulin, low-molecular-weight Heparin, and LHRH.
6. Hollow microspheres of non-steroidal anti-inflammatory drugs are very effective for controlled release as well as it reduces the major side effect of gastric irritation; for example floating microspheres of Indomethacin are quiet beneficial for rheumatic patients.


Need for the study:
Oral drug delivery is the most desirable and preferred method of administering therapeutic agent for their systematic effect such as patient acceptance, convenience in administration and cost effective manufacturing process. Thus wide variety of approaches of drug delivery system has been investigated for oral application. However development process is precluded by several physiological difficulties, such as inability to restrain & localize drug delivery system within desired region of GIT tract and highly variable nature of gastric emptying process. For example relatively brief gastric emptying time can result in incomplete drug release from drug delivery devices leading to diminished efficacy of administered dose.
Floating drug delivery system is noted orally applicable drug delivery system for prolongation of gastric emptying time. The bulk density of floating drug delivery system is lower than that of gastric fluid and thus it remains buoyant on stomach content for long time in the drug releasing process. Hence it is useful for obtaining sufficient bioavailability for long time and effective plasma level. Microspheres provide a constant & prolonged therapeutic effect which will reduce dosing frequency.36, 37 it was reported that microspheres prepared with proton pump inhibitor effective in reducing gastric acid level and allowing acid related disease to heal.36, 37

The aim of presented work is to develop the floating microspheres of Repaglinide by solvent evaporation method.
1. To develop the floating microspheres of Repaglinide by using Sodium alginate, HPMC K100, Sodium bicarbonate in different ratios.
2. To characterize prepared microspheres by Fourier Transform Infrared (FTIR) Spectroscopy.
3. Surface morphology of prepared microspheres can be studied by Scanning Electron Microscopy (SEM).
4. To evaluate the prepared floating microspheres for micrometric properties (particle size, bulk density, tapped density, compressibility index, hausners ratio and angle of repose), practical yield, drug incorporation efficiency, In- vitro buoyancy, In ‘vitro drug release study.

1. Literature Review
2. Selection of drug and polymers
3. Procurement of Drug and polymers
4. Construction of standard graph in 0.1 N HCL
5. Drug and excipent compatibility studies
6. Preparation of Floating Microspheres
7. Determination of flow properties of Floating microspheres.
‘ Angle of repose
‘ Bulk density
‘ Tapped density
‘ Carr’s index
‘ Hausners ratio
8. Characterisation of Floating microspheres
‘ Drug content
‘ Drug Entrapment Efficiency
‘ Percentage Yield
‘ In vitro buoyancy studies
‘ In vitro dissolution
9. Select the best formulaton
10. Application drug release kinetics of optimised formula.
List of Materials used:

S.No List of Chemicals Manufacturing Company
1 Repaglinide Procured from Aurobindo Pharma, Provided by Sura Labs, Hyderabad
2 Sodium alginate S.D. fine chemicals Pvt. Ltd., Mumbai
3 HPMC K100 S.D. fine chemicals Pvt. Ltd., Mumbai
4 Ethanol Merk specialities Pvt Limited,Mumbai
5 Dichloromethane Merk specialiities Pvt Limited,Mumbai
6 Tween 80 Merk specialities Pvt Limited,Mumbai
7 Hydrochloric acid Merk specialities Pvt Limited,Mumbai
8 Sodium bicarbonate Merk specialities Pvt Limited,Mumbai

Table 6.1: List of Materials used
List of Equipments used:
S.No Instruments/Equipments Manufacturer/Supplier
1 Electronic weighing balance Sartorious
2 Mechanical stirrer Remi Laboratories
3 UV-Visible spectrophotometer Lab India, India
4 Dissolution Apparatus Lab India, Lab India
5 Compound microscope Conation technologies
5 Ultrasonic cleaner Remi Laboratories
6 FT’IR Spectrometer Bruker

Table 6.2: List of Equipments used
Formulation Studies :
6.1 Preparation of 0.1N Hydrochloric acid:
8.5 ml of concentrated hydrochloric acid was diluted with distilled water and volume was made up to 1000ml with distilled water.
6.2 Preparation of calibration curve in 0.1N HCL :
10mg of Repaglinide pure drug was dissolved in 10mL of methanol (stock solution 1). 1mL of solution was taken and made up with 10mL of 0.1N HCL (100”g/ml) stock-2. From this 1mL was taken and make up with 10 mL of 0.1N HCL (10”g/ml) stock-3. The above stock-II solution was subsequently diluted with 0.1N HCL to obtain series of dilutions containing and 2, 4, 6, 8 and 10”g/mL of solution. The absorbance of the above dilutions was measured at 220 nm by using UV-Spectrophotometer taking 0.1N HCL as blank. Then a graph was plotted by taking Concentration on X-Axis and Absorbance on Y-Axis which gives a straight line Linearity of standard curve was assessed from the square of correlation coefficient (R2) which determined by least-square linear regression analysis.

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