INTRODUCTION:
The most desirable and convenient method of drug administration is the oral route due to the ease of administration and patient compliance. One limitation for oral delivery is poor bioavailability and for the drug candidates who show absorption window in the proximal gut and is the major obstacle to the development of controlled release formulation. A number of approaches have been developed to increase the residence time of dug formulation. Microsphere carrier systems made from the naturally occurring biodegradable polymers have attracted considerable attention for several years in sustained drug delivery.
Recently, dosage forms that can precisely control the release rates and target drugs to a specific body site have made an enormous impact in the formulation and development of novel drug delivery systems. Microspheres form an important part of such novel drug delivery systems. The problem frequently encountered with controlled release dosage forms is the inability to increase the residence time of the dosage form in the stomach and proximal portion of the small intestine, due to the rapid gastrointestinal transit phenomenon of the stomach which may consequently diminish the extent of absorption of many drugs since almost most of the drug entities are mostly absorbed from the upper part of the intestine, therefore it would be beneficial to develop a sustained release formulation which remain at the absorption site for an extended period of time. Microspheres constitute an important capacity. Microspheres are the carrier linked drug delivery system in which particle size is ranges from 1-1000 μm range in diameter having a core of drug and entirely outer layers of polymer as coating material. However, the success of these microspheres is limited due to their short residence time at site of absorption. It would, therefore be advantageous to have means for providing an intimate contact of the drug delivery system with the absorbing membrane. This can be achieved by coupling bio-adhesion characteristics to microspheres and developing “Muco-adhesive microspheres”. Drug action can be improved by developing new drug delivery system, such as the Muco-adhesive microsphere drug delivery system. Muco-adhesive microspheres remain in close contact with the absorption tissue, the mucous membrane, releasing the drug at site of action leading to a bioavailability increase and both local and systemic effects. The gastro-retentive drug delivery systems can be retained in the stomach for long time and improve the oral bioavailability of drugs that have an absorption window in a particular region of the gastrointestinal tract.
BASIC ANATOMY OF STOMACH AND ITS PHYSIOLOGY:6,7
During past Four decades, the idea of gastro retention is known to researchers and is popularly cultured. Davis, in 1968, 1st described the concept of floating drug delivery systems. To understand the approaches for gastro retention, it is necessary to overview gastric physiology and gastric motility. Human stomach has a resting volume of 25-50ml, which can distend up to 1500 ml following a meal. The stomach is a J-shaped organ. It is located in the upper left hand portion of the abdomen, just below the diaphragm. It occupies a portion of the epigastria and left hypochondria region. The main function of the stomach is to store the food temporarily, grind it and then release it slowly into the duodenum. Since the drugs are absorbed in the upper small intestine, it will be beneficial to develop the dosage forms that reside in that region. It is divided into Three anatomical parts; Fig.1.
a) Fundus:
also called proximal stomach, which acts as food reservoir.
b) Body :
where food is physically and chemically broken down for digestion.
c) Pylorus or antrum:
also called distal stomach, which acts as a site of mixing motions to propel gastric contents for emptying. Pyloric sphincter has a diameter of 12.8±7 mm in humans and serves as a sieve and stricture to passage of large particles.
Fig. 1.Physiology of the stomach
Gastric motility is also a key factor in stomach specific drug delivery. Thorough knowledge of motility is prerequisite for developing a retentive form of drug. Gastric motility differs in fasting and fed states. In fasting states, an Inter-digestive myoelectric motor complex (IMMC), a 2 hours. cycle of peristalsis is generated which progresses to ileocecal junction. It consists of 4 phases.6
Phase I:
also called quiescent period with rare low amplitude contractions, lasting for 30-60 min.
Phase II:
it comprises of intermediate amplitude contractions with bile secretion, lasting for 20- 40 min.
Phase III:
also called Housekeeper waves, it forms of very high amplitude contractions offering maximum pyloric opening and efficient evacuation of stomach contents. It lasts for 10-20 min. with a frequency of 4-5/min.
Phase IV:
transitional phase between phase III and I of two consecutive cycles. It lasts for less than 5 min. In fed states, motility is induced 5-10 min after ingestion and persists as long as food remains in stomach, typically 3-4 hours. Activity is same as phase2 of IMMC. Gastro retentivity of drug is required to increase the bioavailability of drug and to reduce the undesirable effects caused by exposure of drug to other regions of Gastrointestinal Tract.
Fig 2. Schematic Representation of Inter Digestive Gastric Motility Pattern
GASTRO-RETENTIVE DRUG DELIVERY SYSTEM:8,9,10
The relatively short gastric emptying time in humans, which normally averages 2–3 hours through the major absorption zone (stomach or upper part of intestine), can result in incomplete drug release from the drug delivery system leading to diminished efficiency of the administered dose. Thus, localization of a drug delivery system in a specific region of the gastrointestinal tract offers numerous advantages, especially for drugs having narrow absorption window. The intimate contact of the dosage form with the absorbing membrane has the potential to maximize drug absorption and may also influence the rate of drug absorption. These considerations have lead to the development of oral sustained release dosage forms possessing gastric retention potential.
The primary concern in the development of once daily oral sustained release dosage form is not just to prolong the delivery of drugs for 24 hours but to prolong the presence of dosage forms in the stomach or somewhere in the upper small intestine. Gastro-retentive dosage forms through local drug release will greatly enhance the pharmacotherapy of the stomach leading to high drug concentrations at the gastric mucosa, which are sustained over a long period of time. Gastro-retentive dosage form can be used as potential delivery system for drugs with narrow absorption windows; these substances are taken up only from very specific sites of the gastrointestinal tract, often from the stomach and the proximal region of the intestine. Conventional sustained release dosage forms pass the absorption window although they still contain a large fraction of the drug which is consequently lost and not available for absorption.
Advantages of Gastro-retentive Drug Delivery Systems:11
1. The bioavailability of therapeutic agents can be significantly enhanced.
2. For drugs with relatively short half-life, sustained release may result in reduced frequency of dosing with improved patient compliance.
3. They also have an advantage over their conventional system as it can be used to overcome the adversities of the gastric retention time and the gastric emptying time.
4. Gastro-retentive drug delivery can produce prolong and sustain release of drugs from dosage forms which avail local therapy in the stomach and small intestine. Hence, they are useful in the treatment of disorders related to stomach and small intestine.
5. The controlled, slow delivery of drug form Gastro-retentive dosage form provides sufficient local action at the diseased site, thus minimizing or eliminating systemic exposure of drugs. This site-specific drug delivery reduces side effects.
6. Gastro-retentive dosage forms minimize the fluctuation of drug concentrations and effects.
7. Gastrointestinal side effects that are associated with high drug concentrations can be minimized by using Gastro-retentive dosage form.
8. The sustained mode of drug release from Gastro-retentive doses form enables extension of the time over a critical concentration and thus enhances the pharmacological effects and improves the chemical outcomes.
Disadvantages of Gastro-retentive Drug Delivery System:12,13,14
1. Need for increased level of fluids in the stomach.
2. Unsuitable for such drugs as:
· Problematic with solubility in gastric fluid
· Causing G.I irritation
· Inefficient in acidic environment
3. Drugs intended for selective release in the colon.
4. Unpredictable adherence owing to state of constant renewal of mucus wall of stomach.
5. GRDDS is fed into the system after the meal as time of stay in stomach depends on digestive state.
6. The ability of the drug to remain in the stomach depends upon the subject being positioned upright.
7. Hydrogel based swelling system takes longer time to swell.
8. Upon multiple administrations, size increasing drug delivery systems pose the threat to life owing to possible hazard of permanent retention in stomach.
9. Superporous systems having drawback like problematical storage of much easily hydrolysable, biodegradable polymers
Drug Characteristics Required for Gastro-retentive Drug Delivery System:15,16
The properties of drug candidates that make them suitable or not-suitable for incorporation into Gastro-retentive Delivery System are shown below...Drug Candidates for Gastro-retentive Drug Delivery System
|
Potential Drug Candidates for Gastro-retentive Drug Delivery |
Drug Candidates not suitable for Gastro-retentive Drug Delivery |
|
Drugs that locally act in the stomach, e.g., antacids and drugs for H. Pylori therapy, viz., misoprostol |
Drugs that have very limited acid solubility, e.g., phenytoin |
|
Drugs that disturb normal colonic bacteria, e.g. amoxiciline |
Drugs with solubility problem in stomach |
|
Drugs having narrow absorption window in GI tract, e.g., riboflavin, levodopa, cyclosporin, methotrexate |
Drugs which undergo extensive first pass metabolism |
|
Drugs which are primarily absorbed from stomach and upper part of GI tract, e.g., calcium supplements, chlordiazepoxide, cinnarazine. |
Drugs with irritant effect in the stomach |
|
Drugs those are poorly soluble at alkaline pH. e.g. furosemide, diazepam, verapamil. |
Drugs that suffer instability in the gastric environment, e.g. erythromycin |
Why there is need of Gastro-retentive Drug Delivery System?:17,18
There occurs a quick elimination of certain drugs, that have been absorbed from the gastrointestinal tract (usually having short half-lives), from circulatory system due to which frequent dosing is required. To sort out this matter, innovative method Gastro-retentive Drug Delivery Systems are incorporate. They have efficient plasma drug concentration thereby reduce dosing frequency. Another highlight of this system is that it effectively reduces variations in plasma drug concentration by delivering the drug in a controlled and reproducible fashion 10. The rationale for the use of GRDDS is shown in Figure 4.
Fig 4: Rational For The Use Of GRDDS
Approaches to Gastro-retentive Drug Delivery System:19, 20
1. High-density (sinking) systems
2. Low-density (floating) systems
3. Expandable systems
4. Superporous hydrogel systems
5. Muco-adhesive (bio-adhesive) systems
6. Magnetic systems
Fig. 5 Gives Diagrammatic Representation of Approaches To Gastro-retentive Drug Delivery System.
Muco-adhesive (Bio-Adhesive) Systems:21, 22
Bio-adhesive drug delivery systems are used to localize a delivery device within the human to enhance the drug absorption in a site-specific manner. In this approach, various bio-adhesive polymers are used and they can adhere to the epithelial surface in the stomach. Thus, they increase Gastro-Retentive Time of the dosage forms. The basis of muco-adhesion in that a dosage form can stick to the mucosal surface by different mechanism. These mechanisms are:-
i. The wetting theory, which is based on the ability of bio-adhesive polymers to spread and develop intimate contact with the mucous layers.
ii. The diffusion theory, which proposes physical entanglement of mucin strands the flexible polymer chains, or an interpenetration of mucin strands into the porous structure of the polymer substrate.
iii. The absorption theory, suggests that bio-adhesion is due to secondary forces such as Vander Waal forces and hydrogen bonding.
iv. The electron theory, which proposes attractive electrostatic forces between the lycoprotein mucin net work and the bio adhesive material. Gastric muco-adhesion does not tend to be strong enough to impart to dosage forms the ability to resist the strong population forces of the stomach wall. The continuous production of mucous by the gastric mucosa to replace that is lost through peristaltic contractions and the dilution of the stomach content also seems to limit the potential of muco-adhesion as a gastro-retentive force. The major challenge for bio-adhesive drug delivery systems is the high turnover rate of the gastric mucus in the GIT and resulting limited retention times. Furthermore, it is very difficult to target specifically the gastric mucus with bio-adhesive polymers. Materials commonly used for bio-adhesion are poly acrylic acid, polylactic acids, cholestyramine, HPMC, sodium CMC, chitosan, sodium alginate, sucralfate, tragacanth, dextrin, gliadin, lectin etc.
Mechanism of Muco-adhesion:23
A complete understanding of how and why certain macromolecules attach to a mucus surface is not yet available, but a few steps involved in the process are generally accepted, at least for solid systems. A General Mechanism of Muco-adhesion Drug Delivery system has shown in Fig. 6.
Fig 6. Mechanism of Muco-adhesion
Several theories have been proposed to explain the fundamental mechanism of adhesion.
a. Electronic Theory:
According to this theory, electron transfers occur upon contact of adhesive polymer with a mucus glycoprotein network because of difference in their electronic structures. This results in the formation of electrical double layer at the interface e.g.–interaction between positively charged polymers chitosan and negatively charged mucosal surface which becomes adhesive on hydration and provides an intimate contact between a dosage form and absorbing tissue.
b. Absorption Theory:
According to this theory, after an initial contact between two surfaces, the material adheres because of surface force acting between the atoms in two surfaces. Two types of chemical bonds resulting from these forces can be distinguished as primary chemical bonds of covalent nature and Secondary chemical bonds having many different forces of attraction, including electrostatic forces, Vander Walls forces, hydrogen and hydrophobic bonds.
c. Diffusion Theory:
According to this theory, the polymer chains and the mucus mix to a sufficient depth to create a semi permanent adhesive bond. The exact depth to which the polymer chain penetrates the mucus depends on the diffusion coefficient and the time of contact. The diffusion coefficient in terms depends on the value of molecular weight between cross linking and decreases significantly as the cross linking density increases.
d. Wetting Theory:
The wetting theory postulates that if the contact angle of liquids on the substrate surface is lower, then there is a greater affinity for the liquid to the substrate surface. If two substrate surfaces are brought in contact with each other in the presence of the liquid, the liquid may act as an adhesive among the substrate surface.
e. Cohesive Theory:
The cohesive theory proposes that the phenomena of bio-adhesion are mainly due to intermolecular interaction amongst like molecule. Based upon the above theories, the process of bio-adhesion can broadly be classified into two categories namely chemical (electron and absorption theory) and physical (wetting, diffusion and cohesive theory).
Methods of Preparation Of Muco-adhesive Microspheres:24,25
Muco-adhesive Microspheres can be prepared by using different techniques like:
1. Complex Coacervation
2. Hot Melt Microencapsulation
3. Emulsification-Internal Gelation Technique
4. Double Emulsion Method
5. Solvent Removal
6. Ionotropic Gelation
7. Phase Inversion Method
8. Spray Drying
1. Complex Coacervation:
Principle of this method is under suitable conditions when solutions of two hydrophilic colloids are mixed, result into a separation of liquid precipitate. In this method the coating material phase, prepared by dissolving immiscible polymer in a suitable vehicle and the core material is dispersed in a solution of the coating polymer under constant stirring. Microencapsulation is achieved by utilizing one of the methods of phase separation, that is, by changing the temperature of the polymer solution; by changing the pH of the medium, by adding a salt or an incompatible polymer or a non-solvent to the polymer solution; by inducing a polymer polymer interaction. Generally coating is hardened by thermal cross linking or desolvation techniques, to form a self sustaining microsphere.
2. Hot Melt Microencapsulation:
Microspheres of polyanhydride copolymer of poly bis(p-carboxy phenoxy) propane anhydride with sebacic acid are firstly prepared by this method19. In this metod the polymer is firstly melted and then the solid drug particles are added to it with continuous mixing. The prepared mixture is then suspended in a non-miscible solvent like silicone oil with stirring and heated at the temperature above the melting point of the polymer with continuous stirring so as to get stabilized emulsion. The formed emulsion is cooled to solidify polymer particles followed by filtration and ishing of the microspheres with petroleum ether.
3. Emulsification-Internal Gelation Technique:
The polymeric solution prepared by dissolving polymer in distilled water in distilled water stirred magnetically with gentle heat and sonicated for 15min to remove air bubbles. The drug and cross-linking agent are added to the polymer solution and mixed thoroughly by stirring magnetically to form a viscous dispersion which is then extruded through a syringe with a needle of size no. 23 into light liquid paraffin containing 1.5% span 80 and 0.2% glacial acetic acid being kept under magnetic stirring at 100 rpm. The microspheres are retained in the light liquid paraffin for 30 min to produce rigid discrete particles. They are collected by decantation and the product thus separated is ished with chloroform to remove the traces of paraffin oil. The microspheres are dried at 400C under vacuum for 12 hours.
4. Double Emulsion Method:
This method is firstly described by Ogawa Y et al. in year 1988, and is the most widely used method of microencapsulation . In this method an aqueous solution of drug and polymer is added to the organic phase with vigorous stirring to get primary water-in-oil emulsion. This emulsion is then poured to a large volume of water containing an emulsifier like polyvinyl alcohol or polyvinyl pyrrolidone, under stirring, to get the multiple emulsions (w/o/w); and stirring is continued until most of the organic solvent evaporates, leaving solid microspheres. The microspheres are then ished and dried.
5. Solvent Removal:
This is a non-aqueous method of microencapsulation and is most suitable for water labile polymers such as the poly-anhydrides. The method involves dissolving the polymer into volatile organic solvent and the drug is dispersed or dissolved in it, this solution is then suspended in the silicone oil containing span 85 and methylene chloride under stirring, then petroleum ether is added and stirred until solvent is extracted into the oil solution. The obtained microspheres are then subjected for vacuum drying.
6. Ionotropic Gelation :
This method is developed by Lim F and Moss RD. Using this method Microspheres are formed by dissolving the gel-type polymers, such as alginate, in an aqueous solution followed by suspending the active ingredient in the mixture and extruding the solution through needle to produce micro droplets which fall into a hardening solution containing calcium chloride under stirring at low speed. Divalent calcium ions present in the hardening solution crosslink the polymer, forming gelled microspheres.
7. Phase Inversion Method:
The method involves addition of drug into dilute polymeric solution, in methylene chloride; and resultant mixture is poured into an unstirred bath of strong non-solvent, petroleum ether, in a ratio of 1: 100. Microspheres produced are then clarified, ished with petroleum ether and air dried.
8. Spray Drying
This method involves dissolving/dispersing of the drug into the polymer solution which is then spray dried. By this method the size of microspheres can be controlled by manipulating the rate of spraying, feeding rate of polymer drug solution, nozzle size, and the drying temperature.
EVALUATION OF CONTROLLED RELEASE MUCO-ADHESIVE MICROSPHERES:
The prepared muco-adhesive microspheres are evaluated by following parameter:
Percentage Yield:26,27
The prepared muco-microspheres of all batches are accurately weighed. The measured weight of prepared muco-adhesive microspheres are divided by the total amount of all the excipients and drug used in the preparation of the muco-adhesive microspheres, which give the total percentage yield of muco-adhesive microspheres. It is calculated by using following equation,
Actual weight of product
% Yield
= X 100
Total weight of excipients and drug
Particle Size Determination: 26
Muco-adhesive Microsphere size is determined by using optical microscopic method with the help of ocular and stage micrometer. The sizes of around 100 particles are measured and their average particle size is determined.
Determination of Particle Size Distribution And Zeta Potential: 28-29
Controlled release muco-adhesive microspheres are dispersed in 10ml Methanol, at 25+0.5ºC. The resultant muco-adhesive microspheres are prepared by gentle agitation for 10min using magnetic stirrer. The particle size of control release muco-adhesive microspheres is a crucial factor of determines the rate and extent of drug release, as well as the stability of the muco-adhesive microsphere formed. The poly-dispersity index (PDI) reflects the uniformity of particle diameter and can be used to depict the size distribution of the muco-adhesive microsphere population. PDI varies from 0.0 to 1.0. ZP measurement is used to identify the charge of the droplets. It has been suggested that ZP may serve as a partial indicator for the physical stability of the emulsion being formed. High absolute ZP values (±30 mV) should preferably be achieved in most of the muco-adhesive microspheres prepared in order to ensure the creation of a high-energy barrier against coalescence of the particle size distribution, polydispersity index and zeta potential of the resultant muco-adhesive microsphere is determined immediately using, Nano Malvern droplet analyzer (UK) and zeta potential analyzer. Wavelength scattering angle 90º at 25ºC, average hydrodynamic diameter of the muco-adhesive microsphere is derived from cumulative analysis by the auto measure software.
Micromeritic Studies: 30-34
The prepared muco-adhesive microspheres are characterized by their micromeritics properties such as, bulk density, tapped density, Carr’s compressibility index, Hausner’s ratio and angle of repose.
Bulk Density:-
The bulk density is defined as the mass of powder divided by bulk volume. Bulk density is measured by pouring the pre-weight muco-adhesive microspheres into a graduated cylinder. The bulk volume (Vb) of the blend is determined. The bulk density is calculated by dividing the weight of the samples in grams by the bulk volume in cm3. The bulk density is calculated by using the following formula,
Mass of microspheres
Bulk density =
Volume of microspheres before tapping
Tapped Density:-
Tapped density is the volume of powder determined by tapping by using a measuring cylinder containing weighed amount of sample. The measuring cylinder containing a known mass of muco-adhesive microspheres are tapped for a fixed time, and the minimum volume occupied in the cylinder is measured.
The tapped density is calculated by using the following formula,
Mass of microspheres
Tapped density =
Volume of microspheres after tapping
Carr’s Compressibility Index:
It is one of method for determining flow properties and also called as % consolidation index. It is indirectly related to the relative flow rate, cohesiveness and particle size. It is simple, fast and popular method of predicting powder flow characteristics. This is an important property in maintaining uniform weight. It is calculated using following equation,
Tapped density – Bulk density
% Compressibility Index
= X 100
Tapped density
Hausner ratio:-
A similar index like percentage compressibility index has been defined by Hausner. Values less than 1.25 indicate good flow, where as greater than 1.25 indicates poor flow. Added glidant normally improve flow of the material under study. Hausner’s ratio can be calculated by formula,
Tapped density
Hausner’s ratio =
Bulk density
Angle of Repose (θ):-
Good flow properties are critical for the development of any pharmaceutical tablet, capsules or powder formulation. It is essential that an accurate assessment of flow properties be made as early in the development process as possible so that an optimum formulation can be quickly identified. Interparticle forces between particles as well as flow characteristics of powders are evaluated by angle of repose. Angle of repose is defined as the maximum angle possible between the surface and the horizontal plane. The angle of repose of each powder blend is determined by glass funnel method. Powders are weighed accurately and passed freely through the funnel so as to form a heap. The height of funnel is so adjusted that the tip of the funnel just touched the apex of the heap. The diameter of the powder cone so formed is measured and the angle of repose is calculated using the following equation,
tan Ө = h/r
Ө = tan-1 (h/r)
Where, θ = angle of repose
h = height of the pile and,
r = radius of the powder cone respectively.
Angle of repose affects particle size distribution, as larger the particle size, it will flow freely and vice-versa. It is a helpful parameter to monitor quality of powdered or granular pharmaceutical formulations. For good flowing materials the angle of repose should be less than 300.
Drug Entrapment Efficiency: 35 -37
Entrapment efficiency of muco-adhesive microspheres are evaluated by deriving percent drug entrapment. The drug content of drug loaded muco-adhesive microspheres is determine by dispersing 10 mg of muco-adhesive microspheres in 10 ml ethanol followed by agitation with magnetic stirrer for about 30 min to extract the drug and dissolved completely. After filtration through Whatman filter paper the 1ml of this filtrate is pipetted out and diluted upto the mark in 10 ml volumetric flask. Drug concentration in ethanol phase is recorded by taking absorbance of this solution spectrophotometrically at lamda max of drug. The drug concentration is calculated. Thus, the total drug encapsulated in total yielded muco-adhesive microspheres from the procedure is calculated. It is express in percentage called as “percent drug entrapment”. The amount of drug loaded and entrapped in the muco-adhesive microspheres is calculated by the following formula,
Amount of drug actually present
% Drug entrapment = X
100
Theoretical drug load expected
Scanning Electron Microscopy (SEM): 38-41
The surface, morphology, size, shape, etc., are determined by using Scanning Electron Microscope. Dry muco-adhesive microspheres are placed on an electron microscope brass stub that is coated with gold (thickness 200 nm) in an ion sputter. Pictures of muco-adhesive microspheres are taken by random scanning of the stub under the reduced pressure (0.001 torr).
Muco-adhesive Property of Microspheres:
The muco-adhesive properties of the microspheres are evaluated employing the method described by Lehr with slight modification. The Muco-adhesiveness of microspheres is compared with that of a non bio-adhesive material, ethyl cellulose microspheres. The test is performed at both simulated gastric fluid (0.1 M HCl, pH 1.2) and simulated intestinal fluid (phosphate buffer, pH 7.4). The freshly excised pieces of intestinal mucosa (2 × 3 cm) from goat are mounted onto glass slides (3 × 1 inch) with cyanoacrylate glue. About 50 microspheres are spread onto each wet rinsed tissue specimen and immediately thereafter the slides with suitable support are hung onto the arm of a USP tablet disintegrating test machine. When the disintegrating test machine is operated, the tissue specimen is given a slow, regular up and down movement in the test fluid at 370C contained in a 1-liter vessel. At different time intervals up to 12 h the machine is stopped and the number of muco-adhesive microspheres still adhering to the tissue is counted.
In Vitro Drug Release Study: 41,42
A USP paddle apparatus is used to study in-vitro drug release from muco-adhesive microspheres. It is perform as per USP. In the present study, drug release is studied using a USP dissolution apparatus type II at 50 rpm 0.1N HCL as dissolution medium (900 ml) maintained at 37±0.50C. Withdrawn samples (5ml) are analyzed spectrophotometrically at lambda max using Shimadzu 1800 spectrophotometer. The volume is replenished with the same amount of fresh dissolution fluid each time to maintain the sink condition. The cumulative % drug release is calculated and a graph of % Cumulative Drug release Vs. Time is plotted.
Kinetics of Drug Release: 43, 44
In vitro dissolution has been recognized as an important element in drug development. To analysis the mechanism for the release and release rate kinetics of the formulated dosage form, the data obtained from conducted studies is fitted into Zero order, First order, Higuchi matrix, Korsmeyer-Peppas and Hixson Crowell model. In this by comparing the r-values obtained, the best-fit model is selected.
Stability Studies: 45, 46
Stability of a drug has been defined as the ability of a particular formulation, in a specific container, to remain within its physical, chemical, therapeutic and toxicological specifications. A drug formulation is said to be stable if it fulfills the following requirements:
Ø It should contain at least 90 % of the stated active ingredient.
Ø It should contain effective concentration of added preservatives, if any.
Ø It should not exhibit discoloration or precipitation, nor develops foul odour.
Ø It should not develop irritation or toxicity.
The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, light and enables recommended storage conditions, re-test periods and shelf lives to be established.
International Conference on Harmonization (ICH) specifies the length of study and storage conditions:
Long term testing: 250C ± 20C / 60 % RH ± 5 % for 12 months. Accelerated testing: 400C ±20C / 75 % RH ± 5 % for 6 months.
REFERENCES
1. Capan, Y., Jiang, G., Giovagnoli, S. and DeLuca, P. P., Preparation and of poly (D,L- lactide-co-glycolide) microsphere for controlled release of human growth hormone, AAPS PharmSciTech, 2003,4, E28.
2. Carvalho, F. C., Bruschi, M. L., Evangelista, R. C., Gremio, M. P. D., Muco-adhesive drug delivery system, Brazilian J Pharma Sci., 2010, 46(1), 1-17.
3. Castellanos, M. R., Zia, H., Rhodes, C. T., Mocoadhesive drug delivery systems, Drug Dev lnd Pharm, 1993,19, 143.
4. Hardenia, S. S., Jain, A., Patel, R., Kaushal, A., Formulation and evaluation of Muco-adhesive microspheres of ciprofloxacin. Journal of Advanced Pharmacy Education and Research, 2011, 1(4), 214-224.
5. S.D. Pande , Pranita V. Vaidya, Priyanka N. Gulhane, Floating Drug Delivery System (FDDS): A New Way For Oral Drug Delivery System. International Journal of Pharmaceutical and Clinical Science 2013; 3(1): 1-13.
6. S. Shukla, A. Patidar, “A review on: recent advancement of stomach specific floating drug delivery system”, International Journal Pharmaceutical Biological Archive, 2011, (2) 1561–1568.
7. Brahmankar D.M. and Jaiswal S.B., “Biopharmaceutics and Pharmacokinetics a Treatise”, (1st Edn) Vallabh Prakashan, Delhi, 2002, 335-337.
8. Parmar, H., Bakliwal, S., Gujarathi, N., Rane, B., Pawar, S., Different method of formulation and evaluation of Muco-adhesive microsphere, Int J Applied Biology Pharma Technol, 2010, 1(3), 1157-1167.
9. Singh, B., Kim, K., Floating drug delivery systems: An approach to oral controlled drug delivery via gastric retention, J Control Release, 2000, 63, 235-59.
10. Woo, B. H., Jiang, G., Jo, Y. W. And DeLuca, P. P., Preparation and characterization of a composite PLGA and poly (acryloyl hydroxymethyl starch) microsphere system for protein delivery, Pharm Res, 2001, 18, 1600-1606.
11. Hoffman, A., Pharmacodynamic aspects of sustained release preparation, Adv Drug Delivery Rev, 1998, 33, 185-99.
12. Pandey A, Kumar G, Kothiyal P and Barshiliya Y: A Review on current approaches in gastro retentive drug delivery system. Asian Journal of Pharmacy and Medical Science 2012; 2: 60-77.
13. Makwana A, Sameja K, Parekh H and Pandya Y: Advancements in controlled release gastro-retentive drug delivery system: A review. Journal of Drug Delivery and Therapeutics 2012; 2:12-21.
14. Nayak KP and Upadhyay P: Gastro-retentive drug delivery systems and recent approaches: A review. Journal of Pharmaceutical Research and Opinion 2012; 2: 1-8.
15. Nayak AK, Maji R, Das B. Gastro-retentive drug delivery systems: A review. Asian J Pharm Clin Res. 2010; 3(1): 2-10.
16. Vyas SP, Khar RK. Controlled drug delivery: concepts and advances. New Delhi: Vallabh Prakashan. 2006.
17. Swetha S, Allena RT and Gowda DV: A comprehensive review on gastro-retentive drug delivery systems. International Journal of Pharmaceutical and Biomedical Research 2012; 3:1285-1293.
18. Kawatra M, Jain U and Ramana J: Recent advances in floating microspheres as gastro-retentive drug delivery system: A review. International Journal of Recent Advances in Pharmaceutical Research 2012; 2:5-23.
19. Bardonnet, P. L., Faivre, V., Pugh, W. J., Piffaretti, J. C. and Falson, F., Gastro-retentive dosage forms: overview and special case of Helicibacter pylori, J Control Release, 2006, 111, 1-18.
20. Deshpande, A. A., Rhodes, C. T., Shah, N. H., Malick, A. W., Controlled-release drug delivery systems for prolonged gastric residence: An overview, Drug Develop Ind Pharm , 1996, 22, 31-9.
21. Huang, Y., Leobandung, W., Foss, A., Peppas, N. A., Molecular aspects of muco- and bio-adhesion: tethered structures and site-specific surfaces, J Control Release, 2000, 65(1- 2), 63-71.
22. Ito, R., Machida, Y., Sannan, T., Nagai, T., Magnetic granules: a novel system for specific drug delivery to oesophagal mucosa, Pharm Res., 1996, 13(11), 1716-1719.
23. Jain, N. K., Controlled and Novel Drug Delivery, Muco-adhesive drug delivery. First edition, 353.P.L. Soo, L. Luo , D. Maysinger, A (2002).
24. Eisenberg . Incorporation and release of hydrophobic probes in biocompatible polycaprolactone-block-poly (ethylene oxide) micelles: implications for drug delivery, Langmuir. (1997). 18, 9996-10004.
25. G.S. Asane, Muco-adhesive gastro intestinal drug delivery system: An overview, Vol. 5 issue 6,(2007). http// www.pharmainfo.net. Accessed on 06/07/2010.
26. Meena, K. P., Dangi, J. S., Samal, P. K., Namedo, K. P., Recent advances in microsphere manufacturing technology, Int J Pharm Technol, 2011, 3(1), 854-855.
27. Gadad A., Naval C., Patel K., and Dandagi P, Formulation and evaluation of floating microspheres of Captopril for prolonged gastric residence time, Indian Journal of Novel Drug Delivery, 3(1),pp-17-23,2011.
28. Elsheikh MA, Elnaggar YSR, Gohar EY, Abdallah OY, Nanoemulsion liquid preconcentrates for raloxifene hydrochloride: optimization and in vivo appraisal, Int J Nanomedicine,7, pp-3787–3802,2012.
29. A. Patel, S. Ray and R. S. Thakur. In vitro evaluation and optimization of controlled release floating drug delivery System of metformin hydrochloride. DARU. 14(2), pp-57-64, 2006.
30. Raida S. Al-Kassas, Omaimah M.N. Al-Gohary, Monirah M. Al-Faadhel, Controlling of systemic absorption of gliclazide through incorporation into alginate beads, International Journal of Pharmaceutics 341,pp- 230–237,2007.
31. S. Durgapal, A. Das, S. Das, A. Ghosh, J. Deb, G. Tyagi, M. Upadhyay and S. Saha. Formulation, Evaluation and Optimization of Floating Microparticulate System of Ofloxacin for Oral Controlled Delivery System. Int J Pharm Sci Bio. 1(2), pp 86-92, 2010.
32. R. Garg and G. D. Gupta. Gastro-retentive Floating Microspheres of Silymarin: Preparation and In vitro Evaluation. Trop J Pharm Res. 9(1), pp 59-66, 2010.
33. A. K. Jain, P. Jain, Y. S. Tanwar and P. S. Naruka. Formulation, characterization and In vitro evaluation of floating microspheres of famotidine as gastro retentive dosage form. Asian J Pharm. 3(3), pp 222-26, 2009.
34. A. Martin, J. Swarbrick and A. Cammarata. Physical Pharmacy. Varghese Company, Bombay. 3rd edition, pp 513-21, 1991
35. M. Abazinge. Comparison of Invitro and Invivo Release Characteristics of Sustained Release Ofloxacin Microspheres. Drug delivery, 7: pp- 77-81,2000.
36. T.S. Keerthi, S. K. Senthil Kumar, Formulation and Evaluation of Microspheres of Losartan Pottasium Using Biodegradable Natural Polymer, International Bulletin of Drug Research, 1(2),pp-120-131,2010
37. Aliasgar J. Kundawala., Vishnu A. Patel, Harsha V. Patel and Dhaglaram Choudhary, Isoniazid loaded chitosan microspheres for pulmonary delivery: Preparation and characterization, Pelagia Research Library, 2 (5),pp-88-97,2011.
38. P. Phutane, S. Shidhaye, V. Lotlikar, A. Ghule, S. Sutar and V. Kadam. In-Vitro Evaluation of Novel Sustained Release Microspheres of Glipizide Prepared By the Emulsion Solvent Diffusion-Evaporation Method. J Young Pharm, 2(1),pp 35-41,2010.
39. Santhosh Kumar Mankala, Appanna Chowdary Korla, Sammaiah Gade, Development and evaluation of drug loaded controlled release Muco-adhesive microcapsules using various polymers and techniques in management of type-2 diabetis, International Journal of Pharmacy and Industrial Research, pp- 83-94,2008.
40. S. Fartyal, S. K. Jha, M. S. Karchuli, R. Gupta and A. Vajpayee. Formulation and Evaluation of Floating Microspheres of Boswellic acid. International Journal of Pharm Tech Research. 3(1), pp 76-81, 2011.
41. S. Ganguly, K. V. Ramana Rao and V. K. Mohan. Structure of hollow polystyrene microspheres: an SEM study. J. Microencapsulation. 6(2), pp 193-98, 1989.
42. M. S. Khan, D.V. Gowda and A. Bathool. Formulation and characterization of Piroxicam floating microspheres for prolonged gastric retention. Der Pharmacia Lettre. 2(6), pp 217-22, 2010.
43. P. Costa and J. M. S. Lobo. Modeling and comparison of dissolution profiles. Eur J Pharm Sci. 13, pp 123-33, 2001.
44. S. Dash, P. Narasimha Murthy, L. Nath and P. Chowdhury. Kinetic Modeling on Drug Release from Controlled Drug Delivery Systems, Drug Research. 67(3), pp 217-223, 2010.
45. L. Lachman, H. A. Lieberman and J. L. Kanig. Kinetic principles and stability. Theory and practice of industrial pharmacy. Varghese publishing house. 3rd ed. Philadelphia. pp 760-803, 1986.
46. ICH Q1A (R2), Stability testing guidelines: Stability testing of new drug substances and products. The European agency for the evaluation of medicinal products. CPMP/ICH/2736/99, pp 4-20, 2003.
Received on 12.01.2016 Modified on 24.01.2016
Accepted on 14.02.2016 © RJPT All right reserved
Research J. Pharm. and Tech. 9(3): Mar., 2016; Page 313-321
DOI: 10.5958/0974-360X.2016.00057.3