buoyant sustained release drug delivery systems

Rao G U et al. / Pharmacie Globale (IJCP) 2012, 2 (01)

Available online at www.pharmacie-globale.info

ISSN 0976-8157

Review Article

PHARMACIE GLOBALE INTERNATIONAL JOURNAL OF COMPREHENSIVE PHARMACY

BUOYANT SUSTAINED RELEASE DRUG DELIVERY SYSTEMS CURRENT POTENTIALS ADVANCEMENTS AND ROLE OF POLYMERS: A REVIEW G Umamaheswara Rao* and Murari pavan Department of Pharmaceutics, R R College of pharmacy, Banglore, Karnataka, India. Received: 19 December 2011; Revised: 12 January 2012; Accepted: 28 January 2012; Available online: 5 February 2012

ABSTRACT

Controlled and sustained released formulations are widely used in modern era for the delivery of various ingredients. Drugs with narrow absorption window in the gastrointestinal tract have poor absorption therefore gastroretentive drug delivery systems (GRDDs) have been developed which prolong the gastric emptying time. Of this many techniques like floating, high density mucoadhesive microspheres in situ gelling systems etc, are utilized to deliver the drug to the better site where it is absorbed. All pharmaceutical dosage forms contain many additives besides the active ingredients to assist manufacturing and to obtain the desired effect polymers have been successfully employed in the formulations to sustain the release of drug. Both the natural and synthetic polymers are employed in this process. This review discuss about the basic physiology of GIT, techniques polymers (natural and synthetic) and recent advancements in GRDDs. Keywords: GRDDs; In-situ; polymers.

INTRODUCTION

Oral drug administration still remains the route of choice for the majority of clinical applications some drugs have ideal characteristics for good absorption to occur throughout the gastrointestinal tract.1 Gastric retention is an approach for the drug delivery in which desirable for optimizing the therapeutic benefit of a drug. Drugs get absorbed in the initial part of GIT drugs that were less soluble or get degraded in the alkaline pH may be benefited from prolonged gastric retention. A prolonged gastric retention increases bioavailability, decreases wastage of drugs, increases solubility of drugs. Drugs that have narrow absorption window in the gastro intestinal tract will have poor absorption for these drugs gastroretentive drug delivery system offer the advantages in prolonging the gastric emptying time. To formulate a successful stomach specific or gastroretentive drug delivery system several techniques are employed like low density, high density, raft systems incorporating alginate gels, bioadhesive or mucoadhesive systems, super porous hydrogels magnetic systems and in-situ floating gels.

undigested material, capable of displaying a large expansion to accommodate food without much increase in intragastric pressure. Whereas the antrum is the main site for mixing motions and act as a pump for gastric emptying by propelling actions. The opening nearer to esophagus is called as cardiac end characterized by pyloric sphincter. Under fasting conditions the stomach is collapsed bag with residual volume of 50 ml and contains a small amount of gastric fluid and air. Basic structure of gastrointestinal tract and stomach are shown in (figure 1 & 2) Mucosal lining is covered throughout the stomach under this layer specialized cells are present that secret gastric juice into stomach. Figure 1. Gastrointestinal tract

The present study attempts to provide valuable information and highlights advances with reference to the various types of gastroretentive drug delivery systems (GRDDS) as well as provides the overview of the recent advances and changes that have taken place in this arena. Basic anatomy of Stomach and its physiology The stomach is an organ for storage and mixing. Anatomically the stomach is divided into 3 regions: fundus, body, and antrum (pylorus). The proximal part made of fundus and body acts as a reservoir for *Corresponding Author: G Umamaheswara Rao Department of Pharmaceutics, R R College of pharmacy, Banglore, Karnataka, India. Contact no: +91-8088092239; Email: [email protected]

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About 2 to 3 liters of gastric juice secreted daily by specialized cells in the mucosa. (~60 ml with approximately 4 moles of hydrogen ions per hour. It consists of:  Water  Gastric enzymes (pepsin, gastric lipase, gastrin, renin and other enzymes)  Mucus- glycoprotein  Intrinsic factor Pharmacie Globale© (IJCP), Vol. 03, Issue 2


Hydrochloric acid, sodium, calcium, potassium, chloride, bicarbonate, phosphate and sulfate. Figure 2. Structure of stomach 

concentrations as in phase II of fasted state. These contractions result in reducing the size of food particles (> 1 mm), which are propelled towards the pylorus in suspension form. During the fed state onset of MMC is delayed resulting in slow down of gastric emptying rate.2,3

APPROACHES FORMULATION

Gastric pH is as follows Fasted healthy subject 1.1 ± 0.15. , Fed healthy subject 3.6 ± 0.4. Arterial blood is supplied to the stomach by branches of coeliae artery and venous drainage into the portal vein. Gastric emptying and motility Gastric emptying occurs during fasting as well as fed states. The passage of drug from stomach to the small intestine is called gastric emptying. It is the rate limiting step for drug absorption because the major site for absorption in intestine. Generally rapid gastric emptying increase bioavailability of the drug. Faster onset requires for drugs that degrade in gastric environment. Delayed gastric emptying promotes dissolution of the drugs, which are poorly soluble drugs and for the drugs that is majorly absorbed from stomach or proximal part of the intestine. The pattern of motility is however distinct in the 2 states. During the fasting state an interdigestive series of electrical events take place, which cycle both through stomach and intestine every 2 to 3 hours. This is called the interdigestive myloelectric cycle or migrating myloelectric cycle (MMC), which is further divided into following 4 phases are:  Phase I (basal phase) lasts from 40 to 60 minutes with rare contractions.  Phase II (preburst phase) lasts for 40 to 60 minutes with intermittent action potential and contractions. As the phase progresses the intensity and frequency also increases gradually.  Phase III (burst phase) lasts for 4 to 6 minutes. It includes intense and regular contractions for short period. It is due to this wave that all the undigested material is swept out of the stomach down to the small intestine. It is also known as the housekeeper wave.  Phase IV Period of transition from phase III and phase I last for 0 to 5 minutes.  Schematic representation of Gastrointestinal Motility Figure 3. Figure 3. Gastrointestinal Motility

After the ingestion of food, the pattern of contractions changes from fasted to that of fed state. This is known as digestive motility pattern and comprises continuous

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GASTRORETENTIVE

Floatation Floating drug delivery system (FDDS) was first described by Davis in 1968 FDDS is an effective technology to prolong the gastric residence time in order to improve the bioavailability of the drug. FDDS are low-density systems that have sufficient buoyancy to float over the gastric contents and remain in the stomach for a prolonged period. The single-unit floating dosage forms are associated with problems such as sticking together or being obstructed in the GIT, which may produce gastric irritation. However, multiple-unit floating systems may be an attractive alternative since they have been shown to reduce inter and intra- subject availabilities in drug absorption as well as to lower the possibility of dose dumping Floating systems can be classified as effervescent and non effervescent systems. Effervescent floating systems This delivery system is desirable for drugs with an absorption window in the stomach or in the upper small intestine. FDDS have a bulk density less then gastric fluids and so remain buoyant in the stomach without affecting gastric emptying rate for a prolonged period of time and the drug is released slowly as a desired rate from the system. After oral administration in the GIT, CO2 is liberated from these drug delivery systems, which reduces the density of the system and making it float on the gastric fluid.4 Properties should possess by FDDS  It should release contents slowly to serve as a reservoir.  It must maintain specific gravity lower than gastric contents (1.004 – 1.01 gm/cm3).  It must form a cohesive gel barrier. Effervescence Agents: Sodium bicarbonate, Citric acid, Tartaric acid, Calcium carbonate, Di-SGC (Di-Sodium Glycine Carbo-nate, CG (Citroglycine). (Figure 4) Figure 4. Mechanism of floating (Multiple unit floating systems)

Non Effervescent systems Non effervescent systems incorporate a high level (20– 75% w/w) of one or more gel-forming, highly swellable, cellulosic hydrocolloids (e.g., hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose Pharmacie Globale© (IJCP), Vol. 03, Issue 2


[HPMC], and sodium carboxymethylcellulose), polysaccharides, or matrix-forming polymers (e.g., polycarbophil, polyacrylates, and polystyrene) into tablets or capsules. Upon coming into contact with gastric fluid, these gel formers, polysaccharides, and polymers hydrate and form a colloidal gel barrier that controls the rate of fluid penetration into the device and consequent drug release. As the exterior surface of the dosage form dissolves, the gel layer is maintained by the hydration of the adjacent hydrocolloid layer. The air trapped by the swollen polymer lowers the density of and confers buoyancy to the dosage form.5 Single Layer Floating Tablets They are formulated by intimate mixing of drug with a gelforming hydrocolloid, which swells in contact with gastric fluid and maintain bulk density of less than unity. The air trapped by the swollen polymer confers buoyancy to these dosage forms. Bilayer Floating Tablets A bilayer tablet contain two layer one immediate release layer which release 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. 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 a 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 hour. Hollow Microspheres Hollow microspheres (micro balloons), loaded with drug in their outer polymer shells were prepared by a novel emulsion-solvent diffusion method. The ethanol: dichloromethane solution of the drug and an enteric acrylic polymer was poured into an agitated aqueous solution of PVA that was thermally controlled at 400C. The gas phase generated in dispersed polymer droplet by evaporation of dichloromethane formed an internal cavity in microsphere of polymer with drug the micro balloons floated continuously over the surface of acidic dissolution media containing surfactant for more than 12 hrs in-vitro. High-density Systems Sedimentation has been employed as a retention mechanism for pellets that are small enough to be retained in the rugae or folds of the stomach body near the pyloric region, which is the part of the organ with the lowest position in an upright posture. Dense pellets (approximately 3g/cm3) trapped in rugae also tend to withstand the peristaltic movements of the stomach wall. With pellets, the GI transit time can be extended from an average of 5.8–25 hours, depending more on density than on diameter of the pellets, although many conflicting reports stating otherwise also abound in literature. Commonly used Excipients are barium sulphate, zinc oxide, titanium dioxide and iron powder, etc. These materials increase density by up to 1.5–2.4 g/cm3. However, no successful high density system has made it to the market.

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Here, a gel forming solution (example Sodium alginate solution containing carbonates or bicarbonates) swells and forms a viscous cohesive gel containing entrapped CO2 bubbles in contact with gastric fluid. Formulations also typically contain antacids such as aluminum hydroxide or calcium carbonate to reduce gastric acidity. Because raftforming systems produce a layer on the top of gastric fluids, they are often used for gastroesophageal reflux treatment as with liquid Gaviscon (GlaxoSmithKline). Bio/Muco-adhesive Systems Bio/muco-adhesive systems are those which bind to the gastric epithelial cell surface or mucin and serve as a potential means of extending the GRT of drug delivery system (DDS) in the stomach, by increasing the intimacy and duration of contact of drug with the biological membrane The surface epithelial adhesive properties of mucin have been well recognized and applied to the development of GRDDS based on bio/muco-adhesive polymers. The ability to provide adhesion of a drug (or a delivery system) to the GI wall provides a longer residence time in a particular organ site, thereby producing an improved effect in terms of local action or systemic effect.6-8 In-situ oral floating gels In situ gel forming drug delivery systems are a revolution in oral drug delivery. These hydrogels are liquids at room temperature but undergo gelation when in contact with body fluids or change in pH. These have a characteristic property of temperature dependant and cation-induced gelation. This gelation involves formation of the double helical junction zones followed by aggregation of the double helical segments to form a three dimensional network by complexation with cations and hydrogen bonding.9

FLOATING DDS ADVANTAGES 

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The principle of floating drug delivery system can be used for any particular medicament or class of medicament. The Floating drug delivery system are advantageous for drugs absorbed through the stomach e.g. ferrous salts and for drugs meant for local action in the stomach and treatment of peptic ulcer disease e.g. antacids. Floating DDS provides advantages such as the delivery of drugs with narrow absorption windows in the small intestinal region. The Floating drug delivery formulations are not restricted to medicaments, which are principally absorbed from the stomach. Since it has been found that these are equally efficacious with medicaments which are absorbed from the intestine. e.g. Chlorpheniramine maleate.

Certain types of drugs can benefit from using FDDS. These include:  Drugs acting locally in the stomach.  Drugs those are primarily absorbed in the stomach.  Drugs those are poorly soluble at an alkaline pH.  Drugs with a narrow window of absorption.  Drugs absorbed rapidly from the GI tract.  Drugs those degrade in the colon. The efficacy of the medicaments can be increased utilizing the sustained release. When there is vigorous intestinal movement and a short transit time as might occur in certain type of diarrhea, poor absorption is expected under such circumstances it may be advantage drug in floating condition in stomach to get a relatively better. Pharmacie Globale© (IJCP), Vol. 03, Issue 2


FLOATING DDS DISADVANTAGES

There are certain situations where gastric retention is not desirable. Aspirin and non steroidal antiinflammatory drugs are known to cause gastric lesions, and slow release of such drugs in the stomach is unwanted. Thus, drugs that may irritate the stomach lining or are unstable in its acidic environment should not be formulated in gastroretentive systems. Furthermore, other drugs, such as isosorbide dinitrate, that are absorbed equally well throughout the GI tract, drugs undergoing first pass metabolism will not benefit from incorporation into a gastric retention system. It requires sufficient high level of fluids in the stomach for the drug delivery to float. The dosage form should be administered with a full glass of water (200-250 ml)

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SUSTAINED DRUG DELIVERY

HBS systems can remain in the stomach for long periods and hence can release the drug over a prolonged period of time. The problem of short gastric residence time encountered with an oral CR formulation hence can be overcome with these systems. These systems have a bulk density of