Floating Microspheres as Gastro-Retentive Drug Delivery System:
A Review
Sagar Firke*, Ashish Roge, Nitin Ghiware, S.B. Dhoot, S.M. Vadwalkar
CRPS, Nanded Pharmacy College, Nanded, Maharashtra
*Corresponding Author E-mail: sagar1385@yahoo.co.in
ABSTRACT:
Gatsroretentive drug delivery system offers several advantages besides providing better bioavailability to poorly absorbed drugs and a required release profile thus attracting interest of pharmaceutical formulation scientists. A controlled drug delivery system with prolonged residence time in the stomach can be of great practical importance for drugs with an absorption window in the upper small intestine. Various gastroretentive dosage forms are available, including tablets, capsules, pills, laminated films, granules and powders. Floating microspheres is one among the several approaches to gastroretention, like mucoadhesion, flotation, sedimentation, expansion, modified shape systems etc. Floating microspheres have been gaining attention due to the uniform distribution of these multiple-unit dosage forms in the stomach, which results in more reproducible drug absorption and reduced risk of local irritation. Such systems have more advantages over the single-unit dosage forms. The present review briefly addresses the physiology of the gastric emptying process with respect to floating drug delivery systems. The purpose of this review is to bring together the recent literature with respect to the method of preparation, and various parameters affecting the performance and characterization of floating microspheres.
KEYWORDS: Floating microspheres. Emulsion solvent diffusion-evaporation method. Drug delivery system. elease modifiers.
INTRODUCTION:
Among the different routes of drug administration, the oral route has achieved the most attention, partly due to the ease of administration and to the important flexibility in dosage form design. The goal of any drug delivery system is to provide a therapeutic amount of drug at the proper site in the body and then maintain the desired drug concentration. Unfortunately, in most cases, the important variability of the gastrointestinal tract physiology and of its transit time leads to unpredictable bioavailability and non reproducible therapeutic effects1.
Most drugs are well absorbed throughout the entire intestinal tract, but some compounds, usually those that are polar in nature, are poorly absorbed from the large intestine. For such drugs, the main area from which absorption occurs is the small intestine. A major constraint in oral controlled drug delivery is that, not all drug candidates are absorbed uniformly throughout the Gastrointestinal Tract.
Gastric emptying of dosage forms is an extremely variable process and the ability to prolong and control emptying time is a valuable asset for dosage forms that reside in the stomach for a longer period of time than conventional dosage forms. Thus, control of placement of a short period of DDS in a specific region of the GI tract offers numerous advantages, especially for drugs exhibiting an absorption window in the GI tract or drugs with a stability problem. Gastroretentive systems can remain in the gastric region for several hours and hence significantly prolong the gastric residence time of drugs. Prolongation of gastric residence time (GRT) of a rate-controlled oral drug delivery system reduces inter-subject variability and the so-called “peak and valley” effect, leading to increased predictability and bioavailability of the dosage form, especially for molecules with a narrow absorption window2. Moreover, the total gastrointestinal transit time is prolonged, thus, the number of dosage regimen can be reduced and solubility can be improved for drugs that are less soluble in a high pH environment. Floating Drug Delivery Systems (FDDS) first described by Davis (1968), are low-density systems that have sufficient buoyancy to float over the gastric contents and remain in the stomach for a prolonged period. While the system floats over the gastric contents, the drug is released slowly at the desired rate, which results in increased gastro-retention time and reduces fluctuations in plasma drug concentration. Floating microspheres are gastroretentive drug delivery systems based on a non-effervescent approach. Hollow microspheres, microballoons or floating microparticles are terms used synonymously for floating microspheres. Floating microspheres are, in a strict sense, spherical empty particles without a core. These are free-flowing particles, with size ranging from 1 to 1000 µm. This gastrointestinal transit-controlled preparation is designed to float on gastric juice with a specific density of less than one. This property results in delayed transit through the stomach. The drug is released slowly at desired rate, resulting in increased gastric retention with reduced fluctuations in plasma drug concentration3. The objective of the present review is to focus on the method of preparation, and the various parameters affecting the performance and characterization of floating microspheres. The present review is a source of detailed information about the various aspects of floating microspheres.
Multi-particulate drug delivery systems are mainly oral dosage forms consisting of a multiplicity of small discrete units, each exhibiting some desired characteristics. In these systems, the dosage of the drug substances is divided on a plurality of subunit, typically consisting of thousands of spherical particles with diameter of 0.05-2.00 mm. Thus multi-particulate dosage forms are pharmaceutical formulations in which the active substance is present as a number of small independent subunits. To deliver the recommended total dose, these subunits are filled into a sachet and encapsulated or compressed into a tablet. Floating multi-particulate systems include: hollow microspheres (micro-balloons), low density floating micro-pellets and floating micro-beads. Hollow microspheres are in strict sense, spherical empty particles without core4,5. The term microcapsule is defined as a spherical particle size 50nm to 5 nm, containing core substance.
Figure 1: Rationale for the use of GRDDS
Basic gastrointestinal tract physiology
Anatomically, the stomach is divided into three regions: fundus, body, and antrum (pylorus). The proximal part made of fundus and body acts as a reservoir for un-digested material, whereas the antrum is the main site for mixing motions and acts as a pump for gastric emptying, through propelling actions. Gastric emptying occurs during fasting as well as in fed states. The pattern of motility is, however, distinct in the two states. During the fasting state, an interdigestive series of electrical events takes place, cycling through both stomach and intestine every two to three hours. This is called the interdigestive my-loelectric cycle or migrating myloelectric cycle (MMC), which is further divided into the following four phases, as described by Wilson and Washington (1989)6.
1. Phase I (basal phase) lasts from 40 to 60 minutes with rare contractions.
2. Phase II (preburst phase) lasts for 40 to 60 minutes with intermittent action potential and contractions. As the phase progresses, the intensity and frequency also increases gradually.
3. Phase III (burst phase) lasts for four to six minutes. It includes intense and regular contractions for a short period. It is due to this wave that all the undigested material is swept out of the stomach down to the
small intestine. It is also known as the housekeeper wave.
4. Phase IV lasts for zero to five minutes and occurs between phases III and I of two consecutive cycles.
After the ingestion of a mixed meal, the pattern of contractions changes from fasted to that of fed state. This is also known as digestive motility pattern and comprises continuous contractions as in phase II of the fasted state. These contractions result in reduced size of food particles (to less than 1 mm), which are then propelled toward the pylorus in a suspension form. During the fed state, onset of MMC is delayed, resulting in slowdown of gastric emptying rate. Scintigraphic studies determining gastric emptying rates have revealed that orally administered controlled-release dosage forms are subject to basically two complications, namely short gastric residence time and unpredictable gastric emptying rate7.
Approaches to gastric retention
Over the last three decades, various approaches have been pursued to increase the retention of an oral dosage form in the stomach, including floating systems, swelling and expanding systems, bioadhesive systems, modified-shape sys-terms, high-density systems, and other delayed gastric emptying devices8. FDDS or hydrodynamically balanced systems have a bulk density lower than gastric fluids and thus 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 a desired rate from the system. After the release of drug, the residual system is emptied from the stomach. This results in an increase in the GRT and a better control of fluctuations in plasma drug concentrations in some cases. Swelling type dosage forms are such that after swallowing, these products swell to an extent that prevents their exit from the stomach through the pylorus. As a result, the dosage form is retained in the stomach for a long period of time. These systems may be referred to as ‘plug type systems’ since they exhibit a tendency to remain lodged at the pyloric sphincter. Bioadhesive systems are used to localize a delivery device within the lumen and cavity of the body to enhance the drug absorption process in a site-specific manner9.
Factors affecting gastric retention.
There are several factors that can affect gastric emptying (and hence GRT) of an oral dosage form. These factors include density, size, and shape of dosage form, associated intake of food and drugs such as anticholinergic agents (e.g., atropine, propantheline), opiates (e.g., codeine) and prokinetic agents (e.g., metoclopramide, cisapride), and biological factors such as gender, posture, age, body mass index, and disease states (e.g., diabetes, Crohn’s disease). The rate of gastric emptying depends mainly on viscosity, volume and on the caloric content of meals. Nutritive density of meals helps determine gastric emptying time. The prolongation of the GRT by food is expected to maximize drug absorption from a FDDS. This may be rationalized in terms of increased dissolution of drug and longer residence at the most favorable sites of absorption. The resting volume of the stomach is 25 to 50 mL. Volume of liquids administered affects gastric emptying time. When volume is large, emptying is faster. Fluids taken at body temperature leave the stomach faster than colder or warmer fluids. Studies have revealed that gastric emptying of a dosage form in the fed state can also be influenced by its size. Concern regarding the role of food in the prolongation of the GRT has also provided insights into other determinants of gastric retention. For instance, studies have shown that the GRT of a dosage form in the fed state can also be influenced by its size. Small-size tablets are emptied from the stomach during the digestive phase, while larger-size units are expelled during the housekeeping waves10. In order to pass through the pyloric valve into the small intestine, particle size should be within the range of 1 to 2 mm6. The pH of the stomach in fasting state is ~1.5 to 2.0 and, in fed state, it is 2.0 to 6.0. A large volume of water administered with an oral dosage form raises the pH of stomach contents above 4.
Studies have shown that the gastric residence time can be significantly increased under the fed conditions, since the MMC is delayed11. Several formulation parameters can affect gastric residence time. More reliable gastric emptying patterns are observed for multiparticulate formulations, as compared to single-unit formulations, which suffer from the “all or none concept.” As the units of multiparticulate systems are distributed freely throughout the gastrointestinal tract, their transport is affected to a lesser extent by the transit time of food, when compared to single-unit formulations12. Size and shape of dosage unit also affect gastric emptying. The density of a dosage form also affects the gastric emptying rate. A buoyant dosage form having a density of less than that of the gastric fluids will float. Since it is away from the pyloric sphincter, the dosage unit is retained in the stomach for a prolonged period. Posture and nature of the meal also have an effect on gastric emptying.
Advantages of floating microspheres
1. Bioavailability enhances, despite first pass effect, because fluctuations in plasma drug concentration are avoided, and a desirable plasma drug concentration is maintained by continuous drug release.
2. Superior to single-unit floating dosage forms, as such microspheres release drugs uniformly and there is no risk of dose dumping.
3. Enhanced absorption of drugs that solubilise only in stomach.
4. Site-specific drug delivery to the stomach can be achieved.
5. Avoidance of gastric irritation, due to sustained release effect.
6. Better therapeutic effect of short half-life drugs can be achieved.
Suitable drug candidates for floating drug delivery system
In general, appropriate candidates for floating drug delivery system are the molecules that have poor colonic absorption but are characterized by better absorption properties at the upper parts of the GIT [15].
1. Drugs with narrow absorption window in GI tract, e.g., Para aminobenzoic acid, furosemide, riboflavin in a vitamin deficiency and Levodopa.
2. Drugs which are primarily absorbed from stomach and upper part of GIT, e.g., Calcium supplements, Chlordiazepoxide and Scinnarazine.
3. Drugs that act locally in the stomach, e.g., Antacids and Misoprostol.
4. Drugs that degrade in the colon, e.g., Ranitidine HCl and Metronidazole.
5. Drugs that disturb normal colonic bacteria, e.g. Amoxicillin trihydrate.
Methods of preparation of hollow microspheres
Hollow microspheres are prepared through the solvent diffusion and evaporation method to create the hollow inner core. The solvent is evaporated either by increasing the temperature under pressure or by continuous stirring. Sato et al. prepared the floating microspheres by the emulsion solvent diffusion method, utilizing enteric acrylic polymers dissolved with drug in a mixture of dichloromethane and ethanol13. The above solution was introduced in the aqueous solution of polyvinyl alcohol at 40 ºC with constant stirring to form an oil-in-water (o/w) emulsion. After agitating the system for 1 hour, the resulting polymeric particulate systems were sieved between 500 and 1000 mm and then dried overnight at 40ºC to produce hollow microspheres. Jain et al. used the emulsion solvent diffusion technique with a modification. The drug was adsorbed on a porous carrier (calcium silicate). The drug-adsorbed porous carrier was added into the polymer solution (Eudragit S) in the mixture of ethanol and dichloromethane (2:1) and sonicated using a probe sonicator. The resulting suspension was poured into an aqueous solution of polyvinyl alcohol (0.75% w/v) at 40 ºC. The emulsion was stirred at 500 rpm employing a propeller-type agitator for 3 hours. The microspheres were separated by filtration, washed with water and dried at room temperature in the desiccators for 24 hours14.
Table 1: List of recently marketed drug formulation utilizing FDDS
Sr. No |
Dosage Form |
Drug |
Polymer |
Method |
1 |
Multiparticulate FDDS |
Zolpidem tartarate |
(Eudragit® NE 30D) |
Gas generation technique |
2 |
Floatingmicrospheres |
Cephalexin |
Ethyl Cellulose (EC) |
Emulsion solvent evaporation |
3 |
Hollowmicrospheres |
Ranitidine HCl |
Eudragit RLPO |
Solvent evaporation method |
4 |
Floatingmicroparticles |
Metoprolol succinate |
Polymethacrylate (Eudragit S100, RSPO, RLPO) |
Non-aqueous emulsion solvent evaporation method |
5 |
Drug-loaded beads |
Pantoprazole |
Alginate, Sterculia gum |
Ionotropic gelation |
6 |
Floating matrixtablets |
Acyclovir |
Hydroxypropylmethylcellulose 4000 |
Gas generation technique |
7 |
Cinnarizine-loaded EMG beads |
Cinnarizine |
HPMC K4M, HPMCK100M |
Emulsion-gelation method |
8 |
Floating alginatebeads |
Levofloxacin Hemihydrate |
Methyl cellulose |
Gas generation technique |
9 |
Floating microspheres |
Aceclofenac |
Eudragit RS 100 |
Emulsification solvent evaporation technique |
10 |
Floating microspheres |
Aceclofenac |
Eudragit S 100 (ES):Eudragit RL 100 |
Emulsion solvent diffusion technique |
11 |
Self-emulsifying floating pellet |
Tetrahydrocurcumin |
Glyceryl behenate andsodium starch glycolate |
---- |
12 |
Floating matrix tablets |
Antiretroviral drug |
Hydroxypropylmethylcellulose |
Gas generation technique |
13 |
Gas generation technique |
Verapamil HCl |
Carbopol |
Gas generation technique |
14 |
Sustained-release matrices |
Metoprololsuccinate |
Gelucire 43/01 andGelucire 44/14 |
Melt-solidification technique |
15 |
Floating matrix tablets |
Antiretroviraldrug |
Hydroxypropylmethylcellulose |
Gas generation technique |
Method of preparation of floating microspheres
Wide ranges of developmental techniques are available for the preparation of Gastro retentive floating microspheres. However, solvent evaporation technique and ionotropic gelation method have been extensively employed by large number of scientific investigators worldwide to explore the different vistas of floating microspheres. During the preparation of floating controlled release microspheres, the choice of optimal method has utmost relevance for the efficient entrapment of active constituents. Selection of fabrication technique generally depends upon the nature of the polymer, the drug, and their intended use. Characteristic features of materials and the process engineering aspects strongly influence the properties of microspheres and the resultant controlled release rate.15,16
1. Solvent evaporation technique
This technique is widely employed by large number of pharmaceutical industries to obtain the controlled release of drug17.This approach involves the emulsification of an organic solvent (usually methylene chloride) containing dissolved polymer and dissolved/dispersed drug in an excess amount of aqueous continuous phase, with the aid of an agitator. The concentration of the emulsifier present in the aqueous phase affects the particle size and shape. When the desired emulsion droplet size is formed, the stirring rate is reduced and evaporation of the organic solvent is realized under atmospheric or reduced pressure at an appropriate temperature. Subsequent evaporation of the dispersed phase solvent yields solid polymeric micro particles entrapping the drug. The solid micro particles are recovered from the suspension by filtration, centrifugation, or lyophilisation. For emulsion solvent evaporation, there are basically two systems which include oil-in-water (o/w) and water-in-oil (w/o) type.
2. Oil in water emulsion solvent evaporation technique
In this process, both the drug and the polymer should be insoluble in water while a water immiscible solvent is required for the polymer. In this method, the polymer is dissolved in an organic solvent such as dichloromethane, chloroform, or ethyl acetate, either alone or in combination18. The drug is either dissolved or dispersed into polymer solution and this solution containing the drug is emulsified into an aqueous phase to make an oil-in water emulsion by using a surfactant or an emulsifying agent. After the formation of a stable emulsion, the organic solvent is evaporated either by increasing the temperature under pressure or by continuous stirring. Solvent removal from embryonic microspheres determines the size and morphology of the microspheres. It has been reported that the rapid removal of solvent from the embryonic microspheres leads to polymer precipitation at the o/w interface. This leads to the formation of cavity in microspheres, thus making them hollow to impart the floating properties.
Figure 2: Preparation technique (emulsion-solvent diffusion method) and mechanism of ‘microballoon’ Formation.
3. Oil in oil emulsification solvent evaporation technique
This oil-in-oil (sometimes referred as water-in-oil) emulsification process is also known as non aqueous emulsification solvent evaporation. In this technique, drug and polymers are co dissolved at room temperature into polar solvents such as ethanol, dichloromethane, acetonitrile etc. with vigorous agitation to form uniform drug–polymer dispersion. This solution is slowly poured into the dispersion medium consisting of light/heavy liquid paraffin in the presence of oil soluble surfactant such as Span. The system is stirred using an overhead propeller agitator at 500 revolutions per minute (rpm) and room temperature over a period of 2–3 h to ensure complete evaporation of the solvent. The liquid paraffin is decanted and the micro particles are separated by filtration through a Whitman filter paper, washed thrice with n-hexane, air dried for 24 h and subsequently stored in desiccators.[33-37] Span 60 is generally used which is non ionic surfactant. Span 60 has an HLB value of 4.3 and acts as a droplet stabilizer and prevents coalescence of the droplets by localizing at the interface between the dispersed phase and dispersion medium.19
4. Ionotropic gelation method
In this method, cross linking of the polyelectrolyte takes place in the presence of counter ions to form gel matrix. This technique has been generally employed for the encapsulation of large number of drugs. Polyelectrolyte such as sodium alginate having a property of coating on the drug core and acts as release rate retardant contains certain anions in their chemical structure. These anions forms meshwork structure by combining with polyvalent cations and induce gelation. Microspheres are prepared by dropping drug loaded polymeric solution using syringe into the aqueous solution of polyvalent cations. The cations diffuses into the drug loaded polymeric drops, forming a three dimensional lattice of ionically cross linked moiety. Microspheres formed left into the original solution for sufficient time period for internal gelification and they are separated by filtration. Natural polymers such as alginates can be used to improve drug entrapment and are widely used in the development of floating microspheres.20
Figure 03: Ionotropic gelation method
5. Emulsion solvent diffusion method
In this method solution of polymer and drug in ethanol methylene chloride is poured into an agitated aqueous solution of poly (vinyl alcohol). The ethanol rapidly partitions into the external aqueous phase and the polymer precipitates around methylene chloride droplets. The subsequent evaporation of the entrapped methylene chloride leads to the formation of internal cavities within the micro particles.21
6. Single emulsion technique
In this method, micro particulate carriers of natural polymers i.e. those of proteins and carbohydrates are prepared by single emulsion technique. The natural polymers are dissolved or dispersed in aqueous medium followed by dispersion in non-aqueous medium like oil with the help of cross linking agent.22
7. Double emulsion technique
This method involves the formation of the multiple emulsions or the double emulsion such as w/o/w. This method can be used with the natural as well as synthetic22.
8. Phase separation coacervation technique
It is based on the principle of decreasing the solubility of the polymer in organic phase to affect the formation of polymer rich phase known as co-acervates. The drug particles are dispersed in a solution of the polymer and an incompatible polymer is added to the system which makes first polymer to phase separate and engulf the drug particles23
9. Polymeriztion technique
The polymerization techniques conventionally used for the preparation of the microspheres are mainly classified as:
1. Normal Polymerization
It is carried out using different techniques as bulk, suspension, precipitation, emulsion and micellar polymerization processes. Bulk polymerization has an advantage of formation of pure polymers.
2. Interfacial Polymerization
It involves the reaction of various monomers at the interface between the two immiscible liquid phases to form a film of polymer that essentially envelops the dispersed.22,23
10. Spray drying and spray congealing
These methods are based on the drying of the mist of the polymer and drug in the air. 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 evaporates instantaneously leading the formation of the microspheres in a size range 1-100 μm. Depending upon the removal of the solvent or cooling of the solution, the two processes are named spray drying and spray congealing respectively.22,23
11. Hot melt encapsulation method
Lin WJ and Kang WW compared the performance of Indomethacin micro particles and their release properties after coating with chitosan and gelatin, respectively. Here the poly (epsilon-caprolactone) (PCL) micro particles were prepared by the hot-melt encapsulation method. This method is having a disadvantage that thermo-labile substances cannot be used24.
Characterization/evaluation of floating microspheres
Particle size
Size is measured using an optical microscope, and mean particle size is calculated by measuring 200–300 particles with the help of a calibrated ocular micrometer.
Different sizes of microspheres and their distribution in each batch are measured by sieving in a mechanical shaker, using a nest of standard sieves (ASTM) and the shaking period of 15 minutes. Particle size distribution is determined and the mean particle size of microspheres is calculated by using the following formula25.
Mean particle size = Σ(mean particle size of the fraction× weight fraction)/Σ(weight fraction)
Tapped density and compressibility index
The tapping method is used to determine the tapped density and percentage compressibility index, as follows 26.
where V and Vo are the volumes of the sample after and before the standard tapping, respectively.
Surface morphology
The external and internal morphology of the microspheres is studied by scanning electron microscopy (SEM).
Percent Yield
The yield was calculated from the following equation.
Percentage of drug content / drug loading amount(%)
A fixed amount of microspheres containing a drug are dissolved in a suitable solvent such as ethanol, methanol, etc. by ultrasonication. The solution is then filtered through a 5 μm membrane filter. Finally, drug concentration is determined by the UV, spectrophotometrically. Drug content is calculated according to following equation:
Percentage of drug entrapment
The percentage of drug entrapment can be calculated by the following equation.
Floating behavior
The floating test on the microspheres is carried out using the dissolution method II apparatus, specified in the USP XXII. The microspheres are spread over the surface of the dispersing medium (900 ml), which is agitated by a paddle rotated at 100 rpm. Disintegration test solution No. 1 (pH 1.2), containing Tween 20 (0.02%, w/v), was used as a dispersing medium to simulate gastric fluid. After agitation for a previously determined interval, the hollow microspheres that floated over the surface of medium and those that settled to the bottom of the flask were recovered separately. After drying, each fraction of the hollow microspheres was weighed. The buoyancy of the hollow microspheres was represented by the following equation21.
In vivo buoyancy
The in vivo transit behavior of the floating and non floating microspheres was monitored using 12 one-year-old male albino rabbits. These rabbits were divided into two groups, i.e., group I and group II. In order to standardize the conditions of GI motility, the animals were fasted for 12 hours prior to the commencement of each experiment. Floating microspheres (100 mg) were orally administered in suspension form to the animals in group I and non-floating microspheres were administered to group II, followed by a sufficient volume of drinking water. The location of the formulation in the stomach was monitored by keeping the subjects in front of a gamma camera. In between the gamma scannings, the animals were freed and allowed to move and carry out normal activities, but were not allowed to ingest any food or water until the formulation had emptied the stomach completely14.
Kawashima et al. (1991) prepared hollow microspheres made with Eudragit S, containing barium sulfate as a contrast agent for the radiographical in vivo test. The study was carried out with two healthy male volunteers, free of detectable gastrointestinal diseases or disorders. Each subject, having fasted overnight, had a light Japanese breakfast (one rice ball and one cup of soup). After 30 minutes, each subject ingested two hard-gelatin capsules packed with hollow microspheres (1000 mg), together with 100 ml of water. The intragastric behavior of the hollow microspheres after dosing was observed by taking a series of X-ray photographs at suitable intervals.
In vitro release studies
In vitro dissolution studies can be carried out in a USP paddle type dissolution assembly. Microspheres equivalent to the drug dose are added to 900 ml of the dissolution medium and stirred at 100 rpm at 37 ± 0.5 °C. Samples are withdrawn at a specified time interval and analyzed by any suitable analytical method, such as UV spectroscopy or HPLC, etc27.
In vivo studies
In vivo studies are generally conducted in healthy male albino rabbits weighing 2-2.5 kg. The animals are fasted for 24 hours before the experiments; however, they are given free access to food and water during the experiments. Blood samples (2 mL) are collected from the marginal ear vein into heparinized centrifuge at an appropriate time interval27
CONCLUSION:
Gastro retentive multiparticulates have emerged as an efficient means of enhancing the bioavailability and controlled delivery of many drugs. Multiparticulate drug delivery systems provide several all the advantages including greater flexibility and adaptability of microparticulate dosage forms which gives clinicians and those engaged in product development powerful new tools to optimize therapy. The increasing sophistication of delivery technology will ensure the development of increasing number of gastroretentive drug delivery systems to optimize the delivery of molecules that exhibit narrow absorption window, low bioavailability and extensive first pass metabolism. It is little wonder therefore, that such systems are growing rapid in popularity. The control of gastro intestinal transit could be the focus of the next decade and may result in new therapeutic possibilities with substantial benefits for patient.
REFERENCES:
1. Hilton, A.K.; Deasy, P.B. In vitro and in vivo evaluation of an oral sustained-release floating dosage form of amoxycillin trihydrate. Int. J. Pharm., v.86, 1992:79-88.
2. Groning, r.; heun, g. Oral dosage forms with controlled gastrointestinal transit. Drug dev. Ind. Pharm., v.10, 1984: 527- 539.
3. Holt, S.; Cervantes, J.; Wilkinson, A.A.; Wallace, J.H.K. Measurement of gastric emptying rate in humans by real-time ultrasound. Gastroenterology, v.89, 1985:752-759.
4. Dhole AR, Gaikwad PD, Bankar VH, Pawar SP. A Review on Floating Multiparticulate Drug Delivery System- A Novel Approach to Gastric Retention. IJPSRR. 6(2); 2011:205-211.
5. Somwanshi SB, Dolas RT, Nikam VK, Gaware VM, Kotade KB, Dhamak KB and Khadse AN. Floating Multiparticulate Oral Sustained Release Drug Delivery System. J.Chem.Pharm Res. 3(1); 2011:536-547.
6. Wilson CG, Washington N. The stomach: its role in oral drug delivery. In: Rubinstein, MH, editors. Physiological Pharmaceutical: Biological barriers to drug absorption. Chichester, U.K.: Ellis Horwood. 1989:47-70.
7. Christmann, V.; Rosenberg, J.; Seega, J.; Lehr, C.M. Simultaneous in vivo visualization and localization of solid oral dosage forms in the rat gastrointestinal tract by magnetic resonance imaging (MRI). Pharm. Res., v.14, 1997:1066-1072.
8. Shah S.H, Patel J.K and Patel N.V. Stomach Specific Floating Drug Delivery System: A review. Inter. J PharmTech Res. 1(3); 2009:623-633.
9. El Gamal SS, Naggar VF, Allam AN. Optimization of acyclovir oral tablets based on gastroretention technology: Factorial design analysis and physicochemical characterization studies. Drug Development and Industrial Pharmacy;37(7); 2011:855-67.
10. Sharma N, Agarwal D, Gupta MK and Khinchi MP. A Comprehensive Review on Floating Drug Delivery System. IJRPBS. 2(2); 2011:428-441.
11. Mojaverian, P.; Ferguson, R.K.; Vlasses, P.H.; Rocci, M.R.J.R.; Oren, A.; Fix, J. A.; Caldwell, L.J.; Gardner, C. Estimation Of Gastric Residence Time Of The Heidelberg Capsules In Humans: Effect Of Varying Food Composition. Gastroenterology, V.89, 1985:392-397.
12. Bechgaard, H.; Ladefoged, K. Distribution Of Pellets In Gastrointestinal Tract. The Influence On Transit Time Exerted By The Density Or Diameter Of Pellets. J. Pharm. Pharmacol., V.30; 1978 :690-692,.
13. Sato, Y.; Kawashima, Y.; Takeuchi, H.; Yamamoto, H. In Vitro And In Vivo Evaluation Of Riboflavin-Containing Microballoons For A Floating Controlled Drug Delivery System In Healthy Humans. Int. J. Pharm.V.275; 2004:97-107.
14. Jain, S.K.; Agrawal, G.P.; Jain, N.K. A Novel Calcium Silicate Based Microspheres Of Repaglinide: In Vivo Investigations. J. Control. Release, V.113, P.111-116, 2006
15. Okada H, Toguchi H. Critical Reviews In Therapeutics Drug Carrier Systems, 12(1); 1995:1-99.
16. Vyas. In: Jain N.K. Pharmaceutical Product Development, CBS Publishers, New Delhi, 2006:112-138.
17. Li M, Rouaud O, Poncelet D. Microencapsulation by solvent evaporation: State of the Art for Process Engineering Approaches, International Journal of Pharmaceutics, 363(1-2); 2008:26-39.
18. Gupta, P.K.; Sau-Hung, S.; Robinson, J. Bioadhesive/ mucoadhesive in drug delivery to the gastrointestinal tract. In: LENAERTS, V.; GURNEY, R. (Eds.). Bioadhesive drug delivery system. Boca Raton: CRC Press, 1990: 65-92.
19. Shivakumar HN, Patel R, Desai BG. Formulation optimization of propranolol hydrochloride microcapsules employing central composite design. Indian Journal of Pharmaceutical Sciences, 70(3); 2008: 408-413.
21. Kawashima Y, Niwa T, Takeuchi H, Hino T. Preparation of multiple unit hollow microspheres (microballoons) with acrylic resin containing tranilast and their drug release characteristics (in-vitro) and floating behaviour (in-vivo), J. Con. Rel. 16; 1991:279-290.
22. Vyas SP, Khar RK. Targeted and Controlled Drug Delivery Novel Carrier System. New Delhi, CBS Publishers and Distributors, 2004, pp. 417-457.
23. Alagusundaram M, Madhusudana CC, Umashankari K. Microspheres as A Novel Drug Delivery Sysytem-A Review, International Journal of Chemical Technology and Research 1(3); 2009: 526-534.
24. Mathew TS, Devi SG, Prasanth VV, Vinod B. NSAIDs as Microspheres. The Internet Journal of Pharmacology, 6(1); 2008:101-105.
25. Badri, V.N.; Thomas, P.A.; Pandit, J.K.; Kulkarni, M.G.; Mashelkar, R.A. Preparation Of Non-Porous Microspheres With High Entrapment Efficiency Of Proteins By A (Water-In-Oil)-In-Oil Emulsion Technique. J. Control. Release, V.58; 1999:9-20.
26. Sinko, P.J. Micrometrics. In: Martin, A. (Ed.) Martin’s Physical Pharmacy And Pharmaceutical Science. 5. Ed. Philadelphia: Lippincott Willians And Wilkins/A Wolters Kluwer Company, 2006:553-559.
27. Wei, Y.; Zhao, L. In Vitro And In Vivo Evaluation Of Ranitidine Hydrochloride Loaded Hollow Microspheres In Rabbits. Arch. Pharm. Res., V.31; 2008:1369-1377.
Received on 29.09.2013 Modified on 15.10.2013
Accepted on 19.10.2013 © RJPT All right reserved
Research J. Pharm. and Tech. 6(12): Dec. 2013; Page 1452-1458