Gastric Floating Controlled Released Tablet of Diuresis Drug : Formulation and In-Vitro Evaluation

Oral sustained drug delivery system is complicated by limited gastric residence time. Rapid gastrointestinal transit can prevent complete drug release in the absorption zone and reduce the efficacy of administered dose, since the majority of drugs are absorbed in stomach or the upper part of small intestine Floating drug delivery offers several applications for drugs having poor bioavailability because of the narrow absorption window in the upper part of the gastrointestinal tract. It retains the dosage form at the site of absorption and thus enhances the bioavailability 1.

1.1 Need for Gastro Floating Controlled Release System (GFCRS) ²

1. Conventional oral delivery is widely used in pharmaceutical field to treat diseases. However, conventional delivery had many drawbacks and major draw-back is non site specificity.
2. Some drugs are absorbed at specific site only. They require release at specific site or a release such that maximum amount of drug reaches to the specific site.
3. Pharmaceutical field is now focusing towards such drugs which require site specificity.
4. Gastro-retentive delivery is one of the site-specific deliveries for the delivery of drugs either at stomach or at intestine. It is obtained by retaining dosage form into stomach and drug is being released at controlled manner to specific site either in stomach, duodenum and intestine.

1.2 Potential candidates for Gastro Floating Controlled Release System

1. Drugs that are primarily absorbed in the stomach e.g. Amoxicillin.
2. Drugs that are poorly soluble in alkaline pH e.g. Furosemide, Diazepam.
3. Drugs that have narrow absorption window e.g. Levodopa, Methotrexate.
4. Drugs that degrade in the colon e.g. Ranitidine, Metformin HCL.
5. Drugs that disturb normal colonic microbes e.g. Antibiotics against Helicobacter pylori.
6. Drugs rapidly absorbed from the GI tract e.g. Tetracycline.
7. Drugs acting locally in the stomach.³

Drug delivery systems are used for maximizing therapeutic index of the drug and also for reduction in the side effects. The most preferred route is the oral route especially for the administration of therapeutic drugs because low cost of therapy and ease of administration leads to higher level of patient compliance. More than 50% of the drug delivery systems available are to be administered through oral route. Reasons behind using oral route are that it is the most promising route of the drug delivery and effective oral drug delivery may depend upon many factors such as gastric emptying process, gastrointestinal transit time of the dosage form, drug release from the dosage form and site of absorption of drug. High level of patient compliance is the major advantage of using the oral route. To modify the GI transit time is one of the main challenges in the development of oral controlled drug delivery system. Gastric emptying of pharmaceuticals is highly variable and dependent on the dosage form and the fed/fasted state of the stomach. Normal gastric residence time usually ranges between 5 minutes to 2 hours. In the fasted state the electrical activity in the stomach – the inter digestive myoelectric cycle or migrating myoelectric complex (MMC) governs the activity and the transit of dosage forms. It is characterized by four Phases.⁴

1.3 Anatomy of the stomach

The gastro intestinal tract can be divided into three main regions

1. Stomach
2. small intestine- duodenum, jejunum, and ileum
3. large intestine

The GIT is a muscular tube of about 9m which extends from mouth to anus. Its function is to take nutrients and eliminate out waste product by physiological processes such as digestion, absorption, secretion, motility and excretion. The stomach has three muscle layer called oblique muscles and it is situated in the proximal part of the stomach, branching over the fundus and higher regions of the gastric body. The stomach is divided into fundus, body and pylorus.⁵ The stomach is a shaped organ located in the upper left-hand portion of the abdomen. The main function of the stomach is to store the food temporarily, grind it and releases slowly in to the duodenum.  

1.4 Physiology of stomach ⁷

The stomach is divided into four major regions: fundus, body, antrum and pylorus. Its functions are mainly:

• reservoir function: achieved through the flexible volume of the stomach
• emptying function: achieved through low sustained pressure produced by the stomach body
• Mixing and homogenizing function: achieved through stomach contraction that produces grinding.
• Size restriction function: the particle sizes of food emptied through the pylorus is less than 1 millimeter during the fed state.

The stomach is an organ with a capacity for storage and mixing. Its fundus and body region are capable of displaying a large expansion to accommodate food without much increase in the intragastric pressure.

Whereas, the antrum is the main site for mixing motions and act as a pump for gastric emptying by propelling actions. Under fasting conditions, the stomach is a collapsed bag with a residual volume of 50 ml and contains a small amount of gastric fluid (pH 1-3) and air. Under physiological condition, the gastric absorption of most drugs is insignificant as a result of its limited surface area (0.1-0.2 m2) covered by thick layer of mucous coating, the lack of villi on the mucosal surface, and the short residence time of most drug in the stomach. Rapid gastric emptying, also called dumping syndrome, occurs when undigested food empties too quickly into the small intestine. Stomach emptying is a coordinated function by intense peristaltic contractions in the antrum.  At the same time, the emptying is opposed by varying degrees of resistance to passage of chyme at the pylorus. Rate depends on pressure generated by antrum against pylorus resistance. Chyme = food in stomach which has been thoroughly mixed with stomach secretions. Gastric emptying occurs during fasting as well as fed states. The pattern of motility is however distinct in the 2 states. During the fasting state an inter-digestive series of electrical events take place, which cycle both through stomach and intestine every 2-3 hours. This is called the inter-digestive myoelectric cycle or migrating myoelectric cycle (MMC).

1.5 FACTORS AFFECTING GASTRIC RESIDENCE TIME OF GFCRS ⁸

a) Formulation factors 

i) Size of tablets 

Retention of floating dosage forms in stomach depends on the size of tablets. Small tablets are emptied from the stomach during the digestive phase, but large ones are expelled during the house keeping waves. Floating and non-floating capsules of 3 different sizes having a diameter of 4.8 mm (small units), 7.5 mm (medium units), and  9.9  mm  (large units), were formulated and analyzed for their different properties. It was found that floating dosage units remained buoyant regardless of their sizes on the gastric contents throughout their residence in the gastrointestinal tract, while the non-floating dosage units sank and remained in the lower part of the stomach. Floating units away from the gastro?duodenal junction were protected from the peristaltic waves during digestive phase while the non-floating forms stayed close to the pylorus and were subjected to propelling and retro Pelling waves of the digestive phase.

ii) Density of tablets

Density is the main factor affecting the gastric residence time of dosage form. A buoyant dosage form having a density less than that of the gastric fluid’s floats, since it is away from the pyloric sphincter, the dosage unit is retained in the stomach for a prolonged period. A density of less than 1.0g/ml i.e. less than that of gastric contents has been reported. However, the floating force kinetics of such dosage form has shown that the bulk density of a dosage form is not the most appropriate parameter for describing its buoyancy capabilities.

iii) Shape of tablets

The shape of dosage form is one of the factors that affect its gastric residence time. Six shapes (ring tetrahedron, cloverleaf, string, pellet, and disk) were screened in vivo for their gastric retention potential. The tetrahedron (each leg 2cm long) rings (3.6 cm in diameter) exhibited nearly 100% retention at 24 hr.

iv) Viscosity grade of polymer

Drug release and floating properties of FDDS are greatly affected by viscosity of polymers and their interaction. Low viscosity polymers (e.g., HPMC K100 LV) were found to be more beneficial than high viscosity polymers (e.g., HPMC K4M) in improving floating properties. In addition, a decrease in the release rate was observed with an increase in polymer viscosity.

b) Idiosyncratic factor 

i) Gender  

Women have slower gastric emptying time than do men. Mean ambulatory GRT in meals (3.4±0.4 hours) is less compared with their age and race?matched female counterparts (4.6±1.2 hours), regardless of the weight, height and body surface.

ii) Age

Low gastric emptying time is observed in elderly than do in younger subjects. Intra subject and inter subject variations also are observed in gastric and intestinal transit time. Elderly people, especially those over 70 years have a significantly longer GRT.

c) Posture

i) Upright position

An upright position protects floating forms against postprandial emptying because the floating form remains above the gastric contents irrespective of its size. Floating dosage forms show prolonged and more reproducible GRTs while the conventional dosage form sink to the lower part of the distal stomach from where they are expelled through the pylorus by antral peristaltic movements.

ii) Supine position

This position offers no reliable protection against early and erratic emptying. In supine subjects’ large dosage forms (both conventional and floating) experience prolonged retention. The gastric retention of floating forms appears to remain buoyant anywhere between the lesser and greater curvature of the stomach. On moving distally, these units may be sweptaway by the peristaltic movements that propel the  gastric  contents towards the pylorus, leading to significant reduction in GRT  compared with upright subjects.

d) Concomitant intake of drugs

Drugs such as prokinetic agents (e.g., metoclopramide and cisapride), anti-Cholinergic (e.g., atropine or propantheline), opiates (e.g., codeine) may affect the performance of FDDS. The co-administration of GI?motility decreasing drugs can increase gastric emptying time. 

e) Feeding regimen

Gastric residence time increases in the presence of food, leading to increased drug dissolution of the dosage form at the most favourable site of absorption. A GRT of 4?10 h has been reported after a meal of fats and proteins.

1.6 Suitable Drugs for Gastro Floating Controlled Release System ⁸

Delivery of the Drugs in continuous and controlled manner have a lower level of side effects and provide their effects without the need for repeated dosing or with a low dosage frequency. Sustained release in the stomach is also useful for therapeutic agents that the stomach does not readily absorb, since sustained release prolongs the contact time of the agent in the stomach or in the upper part of the small intestine, from where absorption occurs and contact time is limited. Appropriate candidates for controlled release gastro retentive dosage forms are molecules that have poor colonic absorption but are characterized by better absorption properties at the upper parts of the GIT.

1. Narrow absorption window in GI tract, e.g., riboflavin and Levodopa
2. Basically, absorbed from stomach and upper part of GIT, e.g., chlordiazepoxide and cinnarizine.
3. Drugs that disturb normal colonic bacteria, e.g., amoxicillin trihydrate.
4. Locally active in the stomach, e.g., antacids and misoprostol.
5. Drugs that degrade in the colon, e.g., ranitidine HCl and Metronidazole.

1.7 Mechanism of Gastric floating systems ⁹

Various attempts have been made to retain the dosage form in the stomach as a way of increasing the retention time. These attempts include introducing floating dosage forms  Gas generating systems Swelling or expanding Mucoadhesive systems High-density systems Low density system Floating drug delivery systems (FDDS) have a bulk density less than gastric fluids and so remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. The drug is released slowly at the desired rate from the system. After release of drug, the residual system is emptied from the stomach. This results in an increased GRT and a better control of the fluctuations in plasma drug   concentration. However, besides a minimal gastric content needed to allow the proper achievement of the buoyancy retention principle, a minimal level of floating force (F) is also required to keep the dosage form reliably buoyant on the surface of the meal. To measure the floating force kinetics, a novel apparatus for determination of resultant weight has been reported in the literature. The apparatus operates by measuring continuously the force equivalent to F (as a function of time) that is required to maintain the submerged object. The object floats better if F is on the higher positive side. This apparatus helps in optimizing FDDS with respect to stability and durability of floating forces produced in order to prevent the drawbacks of unforeseeable intra gastric buoyancy capability variations.

1.7.1 Based on the mechanism of buoyancy GFCRS can be Classified into ⁹

0. 1. 1. 1. Single Unit Floating Dosage Systems
1. Effervescent Systems (Gas-generating Systems)
2. Non-effervescent Systems
   1. 1. 2. Multiple Unit Floating Dosage Systems

1. Non-effervescent Systems
2. Effervescent Systems (Gas-generating Systems)
3. Hollow Microspheres
   1. 1. 3. Raft Forming Systems.

1.8 TYPES OF GASTRIC FLOATING DRUG DELIVERY

SYSTEMS 10

Various approaches have been pursued to increase the retention of an oral dosage form in the stomach. These systems include:

1. Floating systems 
2. Bioadhesive systems
3. Swelling and expanding systems
4. High density systems and
5. Modified systems

A. Gastric Floating Drug Delivery Systems:

Floating drug delivery system is also called the hydrodynamically balanced system (HBS). Floating drug delivery systems (FDDS) have a bulk density less than gastric fluids and so remain buoyant in the stomach without affecting gastric emptying rate for a prolonged period of time. While the system is floating on the gastric contents, the drug is released slowly at the desired rate from the system. After release of drug, the residual system is emptied from the stomach. This results in an increased GRT and a better control of the fluctuations in plasma drug concentration. This delivery system is further divided into in to non-effervescent and effervescent (Gas-generating system).

i) Non-Effervescent Systems

The Non-effervescent FDDS is based on mechanism of swelling of polymer or bio adhesion to mucosal layer in GI tract. The most commonly used excipients in non- effervescent FDDS are gel forming or highly swellable cellulose type hydrocolloids, hydrophilic gums, polysaccharides and matrix forming materials such as polycarbonate, polyacrylate, polymethacrylate, polystyrene as well as bio adhesive polymers such as Chitosan and carbopol.

The various types of this system are as:

I. Colloidal gel barrier systems / Single Layer Floating Tablets:

Hydrodynamically balanced system (HBS), which contains drugs with gel forming hydrocolloids was first designed by Sheth and Tossounian. These systems incorporate a high level (20-75%w/w) of one or more gel forming, highly swellable, cellulose type hydrocolloids, polysaccharides and matrix forming polymers. On coming in contact with gastric fluid, the hydrocolloids in the system hydrate and form a colloidal gel barrier around its surface.  This  gel barrier controls the rate of  fluid  penetration into the device and consequent release of the drug.

II. Bi-layer floating tablets:

A bi-layer tablet contains two-layer one immediate release layer which releases initial dose from system while  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.

III. Micro porous compartment systems

This technology is based on the encapsulation of a drug reservoir inside a micro porous compartment with apertures along its top and bottom walls. The peripheral walls of the drug reservoir compartment are completely sealed to prevent any direct contact of the gastric mucosal surface with the undissolved drug.

IV. Multi particulate system: Floating Beads / Alginate Beads

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 0.05-2.00mm. multi-unit floating dosage forms were developed from freeze- dried calcium alginate. Spherical beads 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. Thusmulti 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 sub units are filled into a sachet. Multiple unit type of floating pills and it’s floating behaviour. 

V. Micro balloons / Hollow Microspheres:

There are various approaches in delivering substances to the target site in a controlled release fashion. One such approach is using polymeric microballoons as carrier for drugs. Hollow microspheres are known as the micro balloons. Micro balloons were floatable in vitro for 12 Hrs, when immersed in aqueous media. Radio graphical studies proved that icro balloons orally administered to human were dispersed in the upper part of stomach and retained there for three hr against peristaltic movements.

1.9 Advantages of Gastric Floating Drug Delivery Systems ¹⁰

Floating dosage systems form important technological drug delivery systems with gastric retentive behavior and offer several advantages in drug delivery. These advantages include:

1. 1. Floating dosage forms such as tablets or capsules will remain in the solution for prolonged time even at the alkaline pH of the intestine.
   2. FDDS are advantageous for drugs meant for local action in the stomach eg:  Antacids
   3. FDDS dosage forms are advantageous in case of vigorous intestinal movement and in diarrhoea to keep the drug in floating condition in stomach to get a relatively better response.
   4. Acidic substance like aspirin causes irritation on the stomach wall when come in contact with it hence; HBS/FDDS formulations may be useful for the administration of aspirin and other similar drugs.
   5. The FDDS are advantageous for drugs absorbed through the stomach eg: Ferrous salts, Antacids. Improved drug absorption, because of increased GRT and more time spent by the dosage form at its absorption site.
   6. Controlled delivery of drugs. Minimizing the mucosal irritation dueto drugs, by drug releasing slowly at controlled rate.
   7. Treatment of gastrointestinal disorders such as gastroesophageal reflux.
   8. Ease of administration and better patient compliance.
   9. Site-specific drug delivery.

1.10 Disadvantages of Gastric Floating Drug Delivery systems ¹⁰

1. 1. Floating systems are not feasible for those drugs that have solubility or stability problems in gastric fluids.
   2. Drugs which are well absorbed along the entire GI tract and which undergo significant first pass metabolism, may not be suitable candidates for FDDS since the slow gastric emptying may lead to reduced systemic bioavailability. Also, there are limitations to the applicability of FDDS for drugs that are irritant to gastric mucosa.
   3. One of the disadvantages of floating systems is that they require a sufficiently high level of fluids in the stomach, so that the drug dosages form float therein and work efficiently.
   4. These systems also require the presence of food to delay their gastric emptying.
   5. Gastric retention is influenced by many factors such as gastric motility, pH and presence of food. These factors are never constant and hence the buoyancy cannot be predicted.
   6. Drugs that cause irritation and lesion to gastric mucosa are not suitable to be formulated as floating drug delivery system. 
   7. Gastric emptying of floating forms in supine subjects may occur at random and becomes highly dependent on the diameter and size. Therefore, patients should not be dosed with floating forms just before going to bed.

1.11 Application of Gastric floating drug delivery system¹⁰

1. Enhanced Bioavailability:

The bioavailability of riboflavin CR-GRDF is significantly enhanced in comparison to the administration of non-GRDF CR polymeric formulations. There are several different processes, related to absorption and transit of the drug in the gastrointestinal tract, that act concomitantly to influence the magnitude of drug absorption.

2. Sustained drug delivery:

Oral CR formulations are encountered with problems such as gastric residence time in the GIT. These problems can be systems which can remain in the stomach for long periods and have a bulk density <1 as a result of which they can float on the gastric contents. These systems are relatively larger in size and passing from the pyloric opening is prohibited. 

3. Site specific drug delivery systems:

These systems are particularly advantageous for drugs that are specifically absorbed from the stomach or the proximal part of the small intestine. The controlled, slow delivery of drug to the stomach provides sufficient local therapeutic levels and limits the systemic exposure to the drug. This reduces side effects that are caused by the drug in the blood circulation. In addition, the prolonged gastric availability from a site directed delivery system may also reduce the dosing frequency. Eg: Furosemide and Riboflavin.

4. Absorption enhancement:

Drugs which are having poor bioavailability because of site specific absorption from the upper part of the GIT are potential candidates to be formulated as floating drug delivery systems, there by maximizing their absorption.

5. Minimized adverse activity at the colon:

Retention of the drug in the HBS systems at the stomach minimizes the amount of drug that reaches the colon. Thus, undesirable activities of the drug in colon may be prevented. This Pharmacodynamic aspect provides the rationale for GRDF formulation for beta lactam antibiotics that are absorbed only from the small intestine, and whose presence in the colon leads to the development of microorganism’s resistance.

6. Reduced fluctuations of drug concentration:

Continuous input of the drug following CRGRDF administration produces blood drug concentrations within a narrower range compared to the immediate release dosage forms. Thus, fluctuations in drug effects are minimized and concentration dependent adverse effects that are associated with peak concentrations can be prevented. This feature is of special importance for drugs with a narrow therapeutic index.

Materials

• Amiloride HCl – Anant Pharmaceuticals
• Okra gum – Goldking Biogene Pvt. Ltd.
• HPMC K4M – Mahalakshmi Chemicals
• Sodium bicarbonate, citric acid – Analytical grade
• Avicel PH 102 – Diluent
• Magnesium stearate – Lubricant
• Talc – Glidant
• Other: 0.1 N HCl (dissolution), KBr (FTIR)

Preparation Method

1. Weighing & Sieving – All ingredients were accurately weighed and passed through a #60 mesh sieve, except magnesium stearate and talc, which were passed through #80 mesh.
2. Blending – Drug, polymers, sodium bicarbonate, citric acid, and Avicel PH 102 were mixed uniformly in a mortar-pestle.
3. Lubrication – Magnesium stearate and talc were added to the blend and mixed gently to avoid de-mixing.
4. Compression – The final blend was compressed into tablets (average weight: 120 mg) using 8 mm biconcave punches in a multi-station rotary press.
   Tablet hardness was maintained between 5–7 kg/cm².

7. RESULTS

7.1. Identification test for Amiloride

7.1.1 Organoleptic Properties:

The test was performed as per procedure given in material and method. The result is illustrated in following table

Table 17: Tests and Observations

7.1.2 Determination of wavelength maxima (λmax) of Amiloride

The solution of 10µg/ml in 0.1N HCl was prepared and scanned in the range of 200-400 nm and wavelength maxima was determined by usingShimandzu U.V. Spectrophotometer shown in Figure 6 and was found tobe 285 nm.

Fig. 6 Scanning of Amiloride in 0.1N HCl

Table 18: Standard Calibration curve of Amiloride in 0.1 N HCl

7.1.4 Solubility study of Amiloride in different solvents:

Solubility study of Amiloride was done in aqueous and non-aqueous media.

Table 19: Solubility study of Amiloride in different solvents

7.2 Evaluation of powder parameters (Pre-Formulation):

Table 21: Pre formulation studies of various batches

(n=3)

7.3 Evaluation of Tablet (Post-Formulation):

Table 22: Physical evaluation of formulated tablet batches

(n=3)\

Table 23: Tablet Densities, Buoyancy Lag Time and Total Floating Time

(n=3)

Table 24: Swelling index of Batches F1-F9

Figure 14: Relationship between Swelling Index & Time of batchesF1- F9

Table 25: In-vitro drug release profile of Amiloride gastric floating tablet (F1-F9)

Figure 15: Comparative study of % cumulative Amiloride release from F1 – F9

7.7 Kinetic treatment of data of dissolution studies

Table 26: Kinetic treatment of data of dissolution profile of optimized F8 batch

Figure 16: Kinetic treatment of F8 in various dissolution models

7.9 Stability studies

Table 27: Evaluation of formulation F8 kept for stability at 40⁰C /75% RH

Table 28: In-vitro drug release study of formulation F8 kept for stability at 40 0C/75% RH

Figure 17: In-vitro release profiles of formulation F8 kept for stabilityat 400 ± 20C and 75 ± 5% RH for 3 months