ABOUT AUTHOR:
Swetha Kotla
Malla Reddy Institute Of Pharmaceutical Sciences
Hyderabad, AP, India
swetha.pharma12@gmail.com
ABSTRACT
The study was aimed at formulation and evaluation of Fast Disintegrating Tablets (FDTs). Using a taste masking polymer Eudragit E100, to mask the taste of a delivered drug i.e., Quetiapine Fumarate (QTF). Taste masking was done by solvent evaporation technique in absolute Ethanol as solvent system. Fast Disintegrating Tablets of QTF were prepared by using different techniques like Superdisintegrants addition method (Croscarmellose sodium (CCS), Sodium starch glycolate (SSG) and crospovidone (CP)), sublimation method (Camphor) and Effervescent formulation approach (sodiumbicarbonate+citrcacid). All the formulations were evaluated for flow properties, hardness, friability, content uniformity, wetting time, in vivo disintegration time (DT), release profiles. All the formulations showed satisfactory mechanical strength and other formulation parameters within the range. Dissolution parameters such as, Initial Dissolution Rate (IDR), Dissolution Efficiency (DE), Mean Dissolution Time (MDT) and Relative Dissolution Rate (RDR) were calculated. The optimized formula D5 prepared by using 10 % CP as a superdisintegrant and 12 % Camphor as subliming agent, which showed shortest DT (17 Sec) ( Q10= 88%, WT= 37Sec). The drug polymer complex was subjected to FTIR studies to understand the degree of interaction between drug and polymer. The dissolution parameters such as IDR, DE, RDR for the optimized formulation exhibited 1.8 fold increase when compared to marketed product. It can be concluded that the orally fast disintegrating tablets of QTF with better biopharmaceutical properties than conventional marketed tablet obtained using formula D5.
REFERENCE ID: PHARMATUTOR-ART-1743
DRUG PROFILE
Non Proprietary Name: Atazanavir Sulphate
Proprietatry name: Latazanavir, Reyataz, Zrivada
Chemical name: methyl N-[(1S)-1-{N'-[(2S,3S)-2-hydroxy-3-[(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanamido]-4-phenylbutyl]-N'-{[4-(pyridin-2-yl)phenyl]methyl}hydrazinecarbonyl}-2,2-dimethylpropyl]carbamate.
Empirical formula: C38H52N6O7
Molecular weight: 704.856 g/mol
Structure:
Physicochemical Profile:
Description: Atazanavir Sulphate White to pale yellow crystalline powder .
Solubility: Freely soluble in water and methanol.
Pharmaceutical Profile:
Dosage Forms and dose: 100mg, 150mg, 200mg, 300mg capsules.
Pharmacopoeial status: United States Pharmacopoeia
Analytical Profile
Spectrophotometry: Spectrophotometric determination of Atazanavir Sulphate in methanol with the λmax at 301nm has been reported.
Pharmacokinetic Profile:
Oral absorption: 60-68%.
Plasma half life: 5-7 hours.
Protein binding: 86 %
Pharmacological Profile:
Therapeutical category: ANTI HIV
Mechanism of action: Atazanavir selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells by binding to the active site of HIV-1 protease, thus preventing the formation of mature virions. Atazanavir is not active against HIV-2.
Therapeutic/clinical uses: Used in combination with other antiretroviral agents for the treatment of HIV-1 infection, as well as postexposure prophylaxis of HIV infection in individuals who have had occupational or nonoccupational exposure to potentially infectious body fluids of a person known to be infected with HIV when that exposure represents a substantial risk for HIV transmission.
Adverse effects: Bilirubin levels in the blood are normally asymptomatically raised with atazanavir. A single case of torsades de pointes attributable to atazanavir therapy has been described.
Contraindication : Atazanavir should not be used with proton pump inhibitors, such as omeprazole (Prilosec), esomeprazole (Nexium), or rabeprazole (Aciphex). According to the FDA, "A 76% reduction in atazanavir area under the concentration-time curve (AUC) and a 78% reduction in atazanavir trough plasma concentration (Cmin) were observed when REYATAZ/ritonavir [a protease inhibitor, the same class as Azatanavir] 300/100 mg was coadministered with omeprazole 40 mg." In other words, proton pump inhibitors reduce the effects of atazanavir.
HYDROXYPROPYLMETHYLCELLULOSE (HPMC) (SS)
Nomenclature
Non-proprietary names
• JP : Hydroxypropylmethylcellulose
• BP : Hypromellose
• Ph Eur : Methylhydroxypropylcellulosum
• USP : Hypromellose
Chemical Name: Cellulose hydroxypropyl methyl ether
Synonyms: Benecel MHPC; E464; hydroxypropyl methylcellulose; HPMC; hypromellosum; Methocel; methylcellulose propylene glycol ether; methyl hydroxypropylcellulose; Metolose; MHPC; Pharmacoat; Tylopur; Tylose MO.
Structural Formula:
Where R is H, CH3, or CH3CH(OH)CH2
Physical and chemical properties
* Molecular weight : 10,000 - 15,00,000
* Color: White to creamy-white
* Nature : Fibrous or granular powder
* Odour : Odourless
* Taste: Tasteless
* Density: 0.3-1.3 g/ml
* Specific gravity: 1.26* Solubility: Soluble in cold water, practically insoluble in Chloroform, ethanol (95%) and ether but Soluble in mixture of ethanol and Dichloromethane.
Viscosity: HPMC K100LV: 80-120 mPas
HPMC-K4M: 2663–4970
HPMC K15M: 14 000-16 000
HPMC K100M: 72,750–135,800
Melting point: Browns at 190-200 ºC, chars at 225-230 ºC,
Glass transition temperature is 170-180ºC.
Functional Category
Coating agent, film-forming, rate-controlling polymer for sustained release, stabilizing agent, suspending agent, tablet binder, viscosity-increasing agent.
Application
• In oral product HPMC is primarily used as tablet binder, in film coating and as an extended release tablet matrix. Concentration between 2-5% w/w may be used as a binder in either wet or
• dry granulation process. High viscosity grade may be used to retard the release of water-soluble drug from a matrix.
• HPMC is widely used in oral and topical pharmaceutical formulation.
• Concentration of 0.45-1% w/w may be added as a thickening agent to vehicle for eye drop and artificial tear solution.
• HPMC is used as an adhesive in plastic bandage and as a wetting agent for hard contact lenses. It is widely used in cosmetics and food products.
• In addition, HPMC is used as an emulsifier, suspending agent and stabilizing agent in topical gels and ointments. As a protective colloid, it can prevent droplets and particle from coalescing or agglomerating thus, inhibiting the formation of sediments.
Stability and storage
It is stable although it is slightly hygroscopic. The bulk material should be stored in an airtight container in a cool and dry place. Increased in temperature reduces the viscosity of the solution.
Safety
It is generally regarded as a non-toxic and non-irritant material so it is widely used in many oral and topical pharmaceutical formulations. Excessive consumption of HPMC may have laxative effect.
SODIUM BICARBONATE
Nomenclature
Non-proprietary names
- JP: Sodium bicarbonate
- BP: Sodium bicarbonate
- Ph Eur : Natrii hydrogencarbonas
- USP: Sodium bicarbonate
Chemical Name: Carbonic acid monosodium salt
Structural Formula: NaHCO3
Physical and chemical properties
Molecular weight: 84.01
Colour: White
Nature: Crystalline powder
Odour: Odourless
Taste: Saline/slight alkaline
Density: 0.869-2.173 g/cm3
Moisture content: less than 1%w/w
Solubility: Soluble in water, practically insoluble in ethanol (95%) and ether.
Osmolarity: 1.39% w/v aqueous solution is isoosmotic with serum.
Melting point: 270 ºC (with decomposition)
Functional category
Alkalizing agent, therapeutic agent
Applications
- Used in pharmaceutical formulation as a source of carbon dioxide in effervescent tablets and granules.
- Used to produce or maintain an alkaline pH in a preparation, like solution of Erythromycin, Lidocaine, and Niacin etc.
- Used to produce a sodium salt of the active ingredient that has enhanced solubility.
- Used as a freeze-drying stabilizer and in toothpaste.
- Used as a gas forming agent in alginate raft system and in floating drug delivery system.
Stability and Storage
Sodium bicarbonate is stable in dry air but slowly decomposed in moist air and should therefore be store in well-closed container in a cool dry place.
Safety
Orally ingested sodium bicarbonate neutralizes gastric acid with the evolution of carbon dioxide and may cause stomach cramps and flatulence (Rowe et al., 2003)
LACTOSE ANHYDROUS:
Nonproprietary Names:
- BP: Anhydrous Lactose
- JP: Anhydrous Lactose
- PhEur: Lactose, Anhydrous
- USP-NF: Anhydrous Lactose
Synonyms: Anhydrous 60M; Anhydrous Direct Tableting (DT); Anhydrous DT High Velocity; Anhydrous Impalpable; Lactopress Anhydrous; Lactopress Anhydrous 250; lactosum anhydricum; lattosio; milk sugar; SuperTab 21AN; SuperTab 22AN; saccharum lactis.
Chemical Name : O-b-D-Galactopyranosyl-(1!4)-b-D-glucopyranose
Structural Formula:
Functional Category: Directly compressible tablet excipient; dry powder inhaler carrier; lyophilization aid; tablet and capsule diluent; tablet and capsule filler.
Applications in Pharmaceutical Formulation or Technology:
Anhydrous lactose is widely used in direct compression tableting applications, and as a tablet and capsule filler and binder. Anhydrous lactose can be used with moisture-sensitive drugs due to its low moisture content. It may also be used in intravenous injections.
Description:
Anhydrous lactose occurs as white to off-white crystalline particles or powder. Several different brands of anhydrous lactose are commercially available which contain anhydrous b-lactose and anhydrous a-lactose. Anhydrous lactose typically contains 70–80% anhydrous b-lactose and 20–30% anhydrous a-lactose.
Stability and Storage Conditions:
Mold growth may occur under humid conditions (80% RH and above). Lactose may develop a brown coloration on storage, the reaction being accelerated by warm, damp conditions. Lactose anhydrous should be stored in a well-closed container in a cool, dry place.
Safety:
Adverse reactions to lactose are largely due to lactose intolerance, which occurs in individuals with a deficiency of the intestinal enzyme lactase, and is associated with oral ingestion of amounts well over those found in solid dosage forms.
MAGNESIUM STEARATE
Magnesium Stearate is a very fine, light white, precipitated or milled, impalpable powder of low bulk density, having a faint odor of stearic acid and a characteristic taste. The powder is greasy to the touch and readily adheres to the skin. It is widely used in cosmetics, foods, and pharmaceutical formulations. It is primarily used as a lubricant in capsule and tablet manufacture at concentrations between 0.25% and 5.0% w/w. It is also used in barrier creams. It is practically insoluble in ethanol, ethanol (95%), ether and water; slightly soluble in warm benzene and warm ethanol (95%). Magnesium Stearate is officially available in IP, BP, and USP.
TALC
It is very fine, white to grayish-white, odorless, impalpable and unctuous crystalline powder. Powder is soft to touch and readily adhere to the skin and free from grittiness. It is used as anti caking agent, tablet and capsule diluents and tablet and capsule lubricant. It is insoluble in dilute acids, alkalis, organic solvents and water. It is stable and should be stored in a well-closed container, in a cool and dry place. Talc is officially available in IP, BP, and USP.
INTRODUCTION
The oral route is the predominant and most preferable route for drug delivery, but drug absorption is unsatisfactory and highly variable in the individuals despite excellent in vitro release patterns. The major problem is in the physiological variability such as gastrointestinal transit as well as GRT; the later plays a dominating role in overall transit of the dosage forms. GRT of the oral controlled release system is always less than 12 h. (Pawar et al., 2011.)
There are numerous drugs that demonstrate poor efficacy and bioavailability when administered via the oral route. Such drugs include those that a) act locally within the stomach (e.g. amoxicillin), b) are absorbed within the stomach or specific regions of the upper intestine (e.g. furosemide), c) are unstable in intestinal fluids (e.g. captopril) and d) are poorly soluble within the alkaline environment of the intestine (e.g. diazepam). A significant factors leading to the poor bioavailability of numerous drugs is due to their narrow absorption window (NAW), most commonly located in the upper region of the small intestine i.e. the duodenum and jejunum. These segments of the small intestine posses extensive drug absorptive properties and absorption of NAW drugs is limited due to the rapid transport of drug past these regions. Therefore this has led to researchers exploring the possibilities of extending the gastric residence time (GRT) of the drug and therefore indirectly prolonging the time drug is in contact with its absorption window for maximal site-specific absorption. (Murphy et al., 2009).
One of the most feasible approaches for this in the gastrointestinal tract (GIT) is to control GRT using GRDF that will provide us with new and important therapeutic options. GRDF are designed on the basis of one of the several approaches like formulating low density dosage form that remain buoyant above the gastric fluid (FDDS) or high density dosage form that is retained at the bottom of the stomach, imparting bio-adhesion to the stomach mucosa, reducing motility of the GIT by concomitant administration of drugs or pharmaceutical exicipients, expanding the dosage form by swelling or unfolding to a large size which limits the emptying of the dosage form through the polymeric sphincter, utilizing ion–exchange resin which adheres to mucosa, or using a modified shape system ( Pawar et al. 2011)
GASTROINTESTINAL TRACT PHYSIOLOGY
The intrinsic properties of the drug molecule and the target environment for delivery are the major determining factors in bioavailability of the drug. Factors such as pH, enzymes, nature and volume of secretions, residence time, and effective absorbing surface area of the site of delivery play an important role in drug liberation and absorption.
The stomach is situated in the left upper part of the abdominal cavity immediately under the diaphragm. Its size varies according to the amount of distension: up to 1500 ml following a meal; after food has emptied, a collapsed state is obtained with resting volume of 25–50 ml.
The stomach is anatomically divided into three parts: fundus, body, and antrum (or pylorus). The proximal stomach, made up of fundus and body regions, serves as a reservoir for the ingested materials, while the distal region (antrum) is the major site of mixing motions, acting as a pump to accomplish gastric emptying( Pawar et al. 2011). In stomach there are several types of cells that secrete up to 2–3 liters of gastric juice daily. For example, goblet cells secrete mucus, parietal cells secrete hydrochlororic acid, and chief cells secrete pepsinogen. The contraction forces of the stomach churn the chyme and mix it thoroughly with the gastric juice. The average length of the stomach is about 0.2 meter, and the apparent absorbing surface area is about 0.1 m2.( Talukder and Fassihi et al., 2004).
Figure 1. Anatomy of stomach
Gastric pH
The gastric pH is not constant rather it is influenced by various factors like diet, disease, presence of gases, fatty acids, and other fermentation products ( Rubinstein).In addition, the gastric pH exhibits intra-as well as inter-subject variation. This variation in pH may significantly influence the performance of orally administered drugs. Radiotelemetry, a noninvasive device, has successfully been used to measure the gastrointestinal pH in human. It has been reported that the mean value of gastric pH in fasted healthy subjects is 1.1±0.15.(lui et al). On the contrary, the mean gastric pH in fed state in healthy males has been reported to be 3.6±0.4, [14] and the pH returns to basal level in about 2 to 4 hours. However, in fasted state, basal gastric secretion in women is slightly lower than that of in Men (charman et al., 1997).
Gastric pH may be influenced by age, pathological conditions and drugs. About 20% of the elderly people exhibit either diminished (hypochlorohydria) or no gastric acid secretion (achlorohydia) leading to basal pH value over 5.0.(varis et al.,1979) Pathological conditions such as pernicious anemia and AIDS may significantly reduce gastric acid secretion leading to elevated gastric pH. In addition, drugs like H2 receptor antagonists and proton pump inhibitors significantly reduce gastric acid secretion.
The pH in the proximal duodenum may rise as high as 4 pH units from the stomach.(benn et al., 1971) This increase in pH is caused by the bicarbonate secreted by the pancreas and the duodenal mucosa that neutralize the acidic chyme peristalsed from the stomach. The mean pH value in fasted duodenum has been reported to be 5.8±0.3 in healthy subjects (Mojaverian et al., 1989) while the fasted small intestine has been observed to have a mean pH of 6.0±0.14. Passing from jejunum through the mid small intestine and ileum, pH rises from about 6.6 to_7.5.
Table 1. Salient features of upper gastrointestinal tract.
|
section |
Length (m) |
Transit time (h) |
pH |
Microbil count(a) |
absorbing |
Absorption |
|
stomach |
0.2 |
Variable |
1–4 |
<103 |
0.1 |
P,C,A |
|
small intestine |
6–10 |
3±1 |
5–7.5 |
103–1010 |
120–200 |
P,C,A,F.I,E,CM |
a ) Number of microorganisms per gram of gastrointestinal contents.
b) P, Passive diffusion; C, Convective or aqueous channel transport; A, Active transport; F, Facilitated transport; I, ion-pair transport; E, entero-or pinocytocis; CM, Caveolin mediated transport.
Gastrointestinal motility
Two distinct patterns of gastrointestinal motility and secretion exist corresponding to the fasted and fed states. As a result the bioavailability of orally administered drugs will vary depending on the state of feeding. In the fasted state, it is characterized by an inter-digestive series of electrical event and cycle, both through the stomach and small intestine every 2–3 h. This activity is called the interdigestive myoelectric cycle or Migrating motor complex (MMC). MMC is often divided into four consecutive phases: basal (Phase I), pre-burst (Phase II), burst (Phase III), and Phase IV intervals.
• Phase I (basal phase) lasts from 40–60 min with rare contractions.
• Phase II (pre-burst phase) lasts for 40–60 min with intermittent action potential and contractions. As the phase progresses the intensity and frequency also increases gradually.
• Phase III (burst phase) lasts for 4–6 min. It includes intense and regular contractions for short periods. Due to this contraction all the undigested material is swept out of the stomach down to the small intestine. This is also known as the housekeeper wave.
Figure 2.Schematic representation of interdigestive motility pattern.
• Phase IV lasts for 0–5 min and occurs between phases III and I for two consecutive cycles.
The motor activity in the fed state is induced 5–10 min after the ingestion of a meal and persists as long as food remains in the stomach. The larger the amount of food ingested, the longer the period of fed activity, with usual time spans of 2–6 h, and more typically 3–4 h, with phasic contractions similar to Phase II of MMC.
Emptying of dosage form from the stomach
To achieve gastric retention, the dosage form must resist premature gastric emptying. For this, the dosage form must be able to withstand in the stomach against the force caused by peristaltic waves. Furthermore, once its purpose has been served the dosage form should be removed from the body with ease. Table 2 explains the GIT transit time of various dosage forms ( Pawar et al., 2011).
Table 2. Transit times of various dosage forms across the GIT.
Transit time in (h)
| Dosage form | stomach | intestine | total |
| Tablets | 2.7±1.5 | 3.1±0.4 | 5.8 |
| Pellets | 1.2±1.3 | 3.4±14. | 6 |
| Capsules | 0.8±1.2 | 3.2±0.8 | 4 |
| Solution | 0.3±0.07 | 4.1±0.5 | 4.4 |
Factors Affecting Gastric Retention:
a) Density: GRT is a function of dosage form buoyancy that is dependent on the density.
b) Size: Dosage form units with a diameter of more than 7.5 mm are reported to have an increased GRT compared to those with a diameter of 9.9 mm.
c) Shape of dosage form: Tetrahedron and ring shaped unfolding expandable GRDF with a flexural modulus of 48 and 22.5 kilo pounds per square inch (KSI), respectively, are reported to have better GRT ≈ 90–100% retention at 24 h compared with other shapes like continuous stick, planar disc, planar multilobe, and string.
Table 3.polymers used in FDDS
d) Single or multiple unit formulation: Multiple unit formulations show a more predictable release profile and insignificant impairing of the performance due to the failure of units, allow co-administration of units with different release profiles or containing incompatible substances, and permit a larger margin of safety against dosage form failure compared with single unit dosage forms.
e) Fed state: Under fasting conditions, the gastrointestinal motility is characterized by the periods of strong motor activity or the MMC that occur every 2–3 h. The MMC sweeps undigested material from the stomach and, if the timing of administration of formulation coincides with that of the MMC, then GRT of the unit may be expected to be very short. However, in the fed state, MMC is delayed and GRT is considerably longer.
f) Nature of meal: Feeding of indigestible polymers or fatty acid salts like cellulose, starch, polydextrose, and reffinose can change the motility pattern of the stomach by delaying the MMC, thus decreasing the gastric emptying rate and prolonging drug release.
g) Caloric content: GRT can be increased by 4–10 h with a meal that is high in proteins and fats.
h) Frequency of feed: The GRT can increase by over 400 min when successive meals are given compared with a single meal due to the low frequency of MMC.
i) Gender: It was observed that mean GRT in males (3.4 ± 0.6 h) is less than the female subjects (4.6 ± 1.2 h) of same age and race. Females emptied their stomach slowly in comparison to male candidates, regardless of their weight, height, and body surface area.
j) Age: Elderly people, especially those over 70, have a significantly longer GRT.
k) Posture: GRT can vary between supine and upright ambulatory states of the patient. For the floating systems it was reported that when subjects were kept in the upright ambulatory position the dosage form stayed continuously on gastric content in comparison to the supine state of the patients. Thus, in the upright position of the patients floating dosage forms protected against post-prandial emptying.
l) Concomitant drug administration: Clonidine, lithium, nicotine, progesterone, anti-cholinergics like atropine and propantheline, and opiates like codeine prolong GRT. On the other hand, erythromycin and octreotide enhance the gastric emptying. (pawar et al.,2011)
MECHANISTIC ATTEMPTS AT GASTRORETENTION
Various polymeric drug delivery systems have been developed that attempt to exploit the anatomy and physiology of the GIT environment. These include buoyant systems, bioadhesive systems, high density systems, modified shape systems, gastric-emptying delaying devices and coadministration of gastric-emptying delaying drugs (Figure 3). Among these, buoyant drug delivery systems have been used most often.
HIGH DENSITY SYSTEMS
The density of gastric fluid is approximately 1.004g/cm3. Pellets with a density of between 2.4-2.8g/cm3 have shown to sink to the bottom of the stomach when a patient is in an upright position. The pellets become entrapped within the folds of the mucosa thereby withstanding the effects caused by peristalsis (Rouge et al., 1998). conducted a comparative study with an immediate release system, a high density system and a low
Figure 3.Schematic depicting the classification of gastric retentive systems.
density system. The results showed gastric residence times of 0.5, 1 and 2 hours respectively, indicating that the high density system did not demonstrate any significant extension of the gastric residence time. Excipients which are commonly used in order to increase the density of drug delivery systems include: barium sulphate, zinc oxide, iron powder and titanium dioxide . Although high density drug delivery systems have not shown remarkable significance for the delivery of drugs in a human model, success has been illustrated with the administration of pellets with a density of 2.0g/cm3 in the bovine model.
Figure 4: Schematic localization of high density system in the stomach.
FLOATING SYSTEMS :
The concept of FDDS was described in literature as early as 1968 (D.W. Davis et al), when Davis disclosed a method for overcoming the difficulty experienced by some persons of gagging or choking while swallowing medicinal pills. The author suggested that such difficulty could be overcome by providing pills having a density of less than 1.0 g/ml so that pill will float on water surface. Since then development of FDDS. Several approaches have been used to develop an in ideal floating delivery system.
Based on the mechanism of buoyancy, two distinctly different technologies, i.e., noneffervescent and effervescent systems have been utilized in the development of FDDS. The various approaches used in and their mechanisms of buoyancy are discussed in the following subsections.
NONEFFERVESCENT FDDS
The most commonly used excipients in noneffer-vescent FDDS are gel-forming or highly swellable cellulose type hydrocolloids, polysaccharides, and matrix forming polymers such as polycarbonate, polyacrylate, polymethacrylate and polystyrene. One of the approaches to the formulation of such floating dosage forms involves intimate mixing of drug with a gel-forming hydrocolloid, which swells in contact with gastric fluid after oral administration and maintains a relative integrity of shape and a bulk density of less than unity within the outer gelatinous barrier (Hilton et al., 1992). The air trapped by the swollen polymer confers buoyancy to these dosage forms. In addition, the gel structure acts as a reservoir for sustained drug release since the drug is slowly released by a controlled diffusion through the gelatinous barrier.
Sheth and Tossounian (Sheth and Tossounian et al., 1978 ) postulated that when such dosage forms come in contact with an aqueous medium, the hydrocolloid starts to hydrate by first forming a gel at the surface of the dosage form. The resultant gel structure then controls the rate of diffusion of solvent-in and drug-out of the dosage form. As the exterior surface of the dosage form goes into solution, the gel layer is maintained by the immediate adjacent hydrocolloid layer becoming hydrated. As a result, the drug dissolves in and diffuses out with the diffusing solvent, creating a ‘receding boundary.
The various types of this system are as:
A. Single Layer Floating Tablets
They are formulated by intimate mixing of drug with a gel-forming hydrocolloid, which swells in contact with gastric fluid and maintains bulk density of less than unity. They are formulated by intimate mixing of drug with low-density enteric materials such as CAP, HPMC.
Figure 5.Working principle of the hydrodynamically balanced system (HBS).
B. Bi-layer Floating Tablets
A bi-layer tablet contain two layer one immediate release layer which releases initial dose from system while the another sustained release layer absorbs gastric fluid, forming an impermeable colloidal gel barrier on its surface, and maintain a bulk density of less than unity and thereby it remains buoyant in the stomach (Oth et al., 1992).
Figure 6. Intragastric floating bilayer tablet
C. Alginate Beads
Multi-unit floating dosage forms were developed from freeze-dried calcium alginate. Spherical beads of approximately 2.5 mm diameter can be prepared by dropping sodium alginate solution into aqueous solution of calcium chloride, causing precipitation of calcium alginate leading to formation of porous system, which can maintain a floating force for over 12 hours. When compared with solid beads, which gave a short residence time of 1 hour, and these floating beads gave a prolonged residence time of more than 5.5 hours (katayama et al., 1999).
D. Hollow Microspheres
Hollow microspheres (microballoons), loaded with drug in their outer polymer shells are prepared by a novel emulsion-solvent diffusion method. The ethanol: dichloromethane solution of the drug and an enteric acrylic polymer is poured into an agitated aqueous solution of PVA that is thermally controlled at 400C. The gas phase generated in dispersed polymer droplet by evaporation of dichloromethane forms an internal cavity in microsphere of polymer with drug. The microballoons float continuously over the surface of acidic dissolution media containing surfactant for more than 12 hours in vitro (Kawashima, 1992).
2) Effervescent System
Effervescent systems include use of gas generating agents, carbonates (ex. Sodium bicarbonate) and other organic acid (e.g. citric acid and tartaric acid) present in the formulation to produce carbon dioxide (CO2) gas, thus reducing the density of the system and making it float on the gastric fluid. An alternative is the incorporation of matrix containing portion of liquid, which produce gas that evaporates at body temperature.
These effervescent systems further classified into two types.
1. Gas generating systems
2. Volatile Liquid/Vacuum Containing Systems.
1. Gas Generating Systems
A. Tablets
Floating bilayer tablets with controlled release for furosemide were developed by Ozdemir et al., 2000. The low solubility of the drug could be enhanced by using the kneading method, preparing a solid dispersion with β cyclodextrin mixed in a 1:1 ratio (Singh and Brahma, 2000). One layer contained the polymers HPMC K4M, HPMC K100M and CMC (for the control of the drug delivery) and the drug. The second layer contained the effervescent mixture of sodium bicarbonate and citric acid. The in vitro floating studies revealed that the lesser the compression force the shorter is the time of onset of floating, i.e., when the tablets were compressed at 15 MPa, these could begin to float at 20 minutes whereas at a force of 32 MPa the time was prolonged to 45 minutes. Radiographic studies on 6 healthy male volunteers revealed that floating tablets were retained in stomach for 6 hours and further blood analysis studies showed that bioavailability of these tablets was 1.8 times that of the conventional tablets. On measuring the volume of urine the peak diuretic effect seen in the conventional tablets was decreased and prolonged in the case of floating dosage form.
Yang et al., 1999. Developed a swellable asymmetric triple-layer tablet with floating ability to prolong the gastric residence time of triple drug regimen (tetracycline, metronidazole, and clarithromycin) in Helicobacter pylori–associated peptic ulcers using hydroxypropylmethyl cellulose (HPMC) and polyethylene oxide (PEO) as the rate-controlling polymeric membrane excipients. The design of the delivery system was based on the swellable asymmetric triple-layer tablet approach. Hydroxypropylmethylcellulose and polyethylene oxide were the major rate- controlling polymeric excipients. Tetracycline and metronidazole were incorporated into the core layer of the triple-layer matrix for controlled delivery, while bismuth salt was included in one of the outer layers for instant release.
The floatation was accomplished by incorporating a gas-generating layer consisting of sodium bicarbonate: calcium carbonate (1:2 ratios) along with the polymers. The in vitro results revealed that the sustained delivery of tetracycline and metronidazole over 6 to 8 hours could be achieved while the tablet remained afloat. The floating feature aided in prolonging the gastric residence time of this system to maintain high localized concentration of tetracycline and metronidazole.
Figure 7. (a) A multiple-unit oral floating dosage system.(b) stages of floating mechanism: (A) penetration of water; (B) generation of CO and floating; (C) dissolution of drug. Key: (a) conventional SR pills; (b) effervescent layer; (c) swellable layer; (d) expanded swellable membrane layer; (e) surface of water in the beaker (370C).
B. Floating capsules
Floating capsules are prepared by filling with a mixture of sodium alginate and sodium bicarbonate. The systems were shown to float during in vitro tests as a result of the generation of CO2 that was trapped in the hydrating gel network on exposure to an acidic environment.
C. Multiple unit type floating pills
The system consists of sustained release pills as ‘seeds’ surrounded by double layers. The inner layer consists of effervescent agents while the outer layer is of swellable membrane layer. When the system is immersed in dissolution medium at body temp, it sinks at once and then forms swollen pills like balloons, which float as they have lower density. This lower density is due to generation and entrapment of CO2 within the system.
D. Floating system with Ion-Exchange resins
A floating system using ion exchange resin that was loaded with bicarbonate by mixing the beads with 1M sodium bicarbonate solution (Shweta Arora et al., 2005). The loaded beads were then surrounded by a semipermeable membrane to avoid sudden loss of CO2. Upon coming in contact with gastric contents an exchange of chloride and bicarbonate ions took place that resulted in CO2 generation thereby carrying beads toward the top of gastric contents and producing a floating layer of resin beads. The in vivo behavior of the coated and uncoated beads was monitored using a single channel analyzing study in 12 healthy human volunteers by gamma radio scintigraphy. Studies showed that the gastric residence time was prolonged considerably (24 hours) compared with uncoated beads (1 to 3 hours).
Figure 8.Pictorial presentation of working of effervescent floating drug delivery system based on ion exchange resin.
Highly Porous Systems
The inclusion of low density polymeric carriers in a formulation may result in a matrix with a density of less than 1g/cm3, thereby becoming buoyant. There are numerous low density polymeric carriers available, including porous silicon dioxide, polypropylene foam, magnesium aluminometa silicate, porous calcium silicate [Jain, S.K et al] and polypropylene foam powder [Sher a et al]. These porous carriers possess certain characteristics which add to their attractiveness for use in drug delivery systems design, including a high surface area, tunable pore sizes with narrow distributions, stable uniform porous structures and well-defined surface properties thus allowing for the absorption of drugs and drug release in a reproducible and predictable manner [Sher et al., 2007].
Hot-Melt Extrusion
Hot melt extrusion is a method of continuous mixing and design of moldable materials. It is possible to produce tablets, microspheres, granules, transdermal and transmucosal delivery systems through this approach [Mididoddi et al., 2007]. Polymethacrylate polymers are the most commonly used polymers for this approach due to their thermoplastic properties. When selecting a polymer, it is important to consider the glass transition temperature, melt viscosity and stability under high temperature. Hot-melt extrusion is associated with numerous advantages. These advantages include fewer processing steps are involved, the absence of solvents, no need for compressionand the thorough mixing of formulation components [Mididoddi et al., 2007].
2. Volatile Liquid / Vacuum Containing Systems
A. Intra-gastric floating gastrointestinal drug delivery system
These systems can be made to float in the stomach because of floatation chamber, which may be a vacuum or filled with air or a harmless gas, while drug reservoir is encapsulated inside a micro-porous compartment.
Figure 9.Intra gastric floating gastrointestinal drug delivery device.
B. Inflatable gastrointestinal delivery systems
In these systems an inflatable chamber is incorporated, which contains liquid ether that gasifies at body temperature to cause the chamber to inflate in the stomach. These systems are fabricated by loading the inflatable chamber with a drug reservoir, which can be a drug impregnated polymeric matrix, encapsulated in a gelatin capsule. After oral administration, the capsule dissolves to release the drug reservoir together with the inflatable chamber. The inflatable chamber automatically inflates and retains the drug reservoir compartment in the stomach. The drug continuously released from the reservoir into the gastric fluid.
Figure 10.Inflatable gastrointestinal delivery system.
C. Intragastric osmotically controlled drug delivery system
It is comprised of an osmotic pressure controlled drug delivery device and an inflatable floating support in a biodegradable capsule. In the stomach, the capsule quickly disintegrates to release the intra-gast
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