Approaches To Floating Oral Drug Delivery System Biology Essay

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INTRODUCTION

Floating Oral Drug Delivery System (FODDS) are retained in the stomach and are useful for drugs that are poorly soluble or unstable in intestinal fluids. The density of the system can be reduced by incorporating a number of low density fillers into the systems such as hydroxyl cellulose, lactates or microcrystalline cellulose. The drug usually keeps floating in the gastric fluid and slowly dissolves at a predetermined rate to release the drug from the dosage form and maintain constant drug levels in the blood. The concept of floating tablets is mainly based on the matrix type drug delivery system such that the drug remains embedded in the matrix which after coming in contact with the gastric fluid swells up and the slow erosion of the drug without disintegration of the tablet takes place. Sometimes for generating a floating system we even need to add some effervescent or gas generating agent which will also ultimately reduce the density of the system and serve the goal of achieving a floating system for onward drug delivery.

APPROACHES TO FLOATING ORAL DRUG DELIVERY SYSTEM

A number of approaches have been used to increase floating time of a dosage form in stomach which is as follows [1]

a) Hydrodynamically balanced systems: HBS

b) Gas-generating systems

c) Raft-forming systems

d) Low-density systems

Floating systems

These have a bulk density lower than the gastric content. They remain buoyant in the stomach for a prolonged period of time, with the potential for continuous release of drug. Eventually, the residual system is emptied from the stomach. Gastric emptying is much more rapid in the fasting state and floating systems rely heavily on the presence of food to retard emptying and provide sufficient liquid for effective buoyancy. [2-4] The three approaches used in designing intragastric floating systems will now be described.

Hydrodynamically balanced systems (HBS)

These are single-unit dosage forms, containing one or more gel-forming hydrophilic polymers. Hydroxypropylmethylcellulose, Hydroxypropyl methylcellulose (HPMC) is the most common used excipient, although hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), sodium carboxymethylcellulose (NaCMC), agar, carrageenans or alginic acid are also used. Polysacchacarides and matrix forming polymer such as polycarbophil, polyacrylates and polystyrene, incorporated either in tablets or in capsule. On coming in contact with gastric fluid, the hydrocolloid in the system hydrates and forms a colloidal gel barrier around the gel surface. The air trapped by the swollen polymer maintains a density less than unity and confers buoyancy to this dosage forms (Figure 1).[5]

Figure 1: Hydrodynamically balanced system (HBS). The gelatinous polymer barrier formation results from hydrophilic polymer swelling. Drug is released by diffusion and erosion of the gel barrier.

Gas-generating systems

Floatability can also be achieved by generation of gas bubbles.CO2 can be generated in situ by incorporation of carbonates or bicarbonates, which react with acid-either the natural gastric acid or co-formulated as citric or tartaric acid.The optimal stoichiometric

ratio of citric acid and sodium bicarbonate for gas generation is reported to be 0.76:1.An alternative is to incorporate a matrix with entrapped of liquid, which forms a gas at body temperature (Figure 2).

Figure 2: Gas-generating systems

Raft-forming systems

Here, a gel-forming solution (e.g. sodium alginate solution containing carbonates or bicarbonates) swells and forms a viscous cohesive gel containing entrapped CO2 bubbles on contact with gastric fluid. Formulations also typically contain antiacids such as aluminium hydroxide or calcium carbonate to reduce gastric acidity. Because raft-forming systems produce a layer on the top of gastric fluids, they are often used for gastroesophageal reflux treatment as with Liquid Gaviscon (GlaxoSmithkline) (Figure 3).[6]

Figure 3: Barrier formed by a raft-forming system

Low-density systems

Gas-generating systems inevitably have a lag time before floating on the stomach contents, during which the dosage form may undergo premature evacuation through the pyloric sphincter. Low-density systems (<1 g/cm3) with immediate buoyancy have therefore been developed. They are made of low-density materials, entrapping oil or air. Most are multiple unit systems, and are also called ''microballoons'' because of the low-density core. Generally, techniques used to prepare hollow microspheres involve simple solvent evaporation or solvent diffusion evaporation methods. Polycarbonate, Eudragit S, cellulose acetate, calcium alginate, agar and low methoxylated pectin are commonly used

as polymers. Buoyancy and drug release are dependent on quantity of polymer, the plasticizer-polymer ratio and the solvent used (Figure 4).[7-11]

Figure 4: The structure of the low-density, floating matrix tablets.

FACTORS AFFECTING THE FLOATING AND FLOATING TIME

1. Density: - Floating is a function of dosage form buoyancy that is dependent on the density.

2. Shape of dosage form: - Tetrahedron and ring shaped devices with a flexural modulus of 48 and 22.5 kilo pounds per square inch (KSI) are reported to have better floating, 90% to 100% retention at 24 hours compared with other shapes.

3. Single or multiple unit formulation: - Multiple unit formulations show a more predictable release profile and insignificant impairing of performance due to 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.

4. Fed or unfed state: - Under fasting conditions, the GI motility is characterized by periods of strong motor activity or the migrating myoelectric complex (MMC) that occurs every 1.5 to 2 hours.[12]

5. Nature of meal: - Feeding of indigestible polymers or fatty acid salts can change the motility pattern of the stomach to a fed state, thus decreasing the gastric emptying rate and prolonging drug release.[13]

6. Caloric content: - Floating can be increased by four to 10 hours with a meal that is high in proteins and fats.

7. Frequency of feed: - The floating can increase by over 400 minutes when successive meals are given compared with a single meal due to the low frequency of MMC.

8. Age: - Elderly people, especially those over 70, have a significantly longer; floating.

9. Posture: - Floating can vary between supine and upright ambulatory states of the patient.

10. Concomitant drug administration: - Anticholinergics like atropine and propantheline, opiates like codeine and prokinetic agents like metoclopramide and cisapride; can affect floating time.

11. Biological factors: - Diabetes and Crohn's disease, etc.

DRUGS USED IN THE FORMULATION OF FLOATING DOSAGE

FORMS

1. Floating microsphere: Aspirin, Griseofulvin, p-Nitroaniline, Ibuprofen, Terfinadine and Tranilast

2. Floating granules: Diclofenac sodium, Indomethacin and Prednisolone.

3. Floating capsules: Chlordiazepoxide hydrogen chloride, Diazepam, Furosemide, Misoprostol, L-Dopa, Benserazide, Ursodeoxycholic acid and Pepstatin.

4. Floating tablets and Pills: Acetaminophen, Acetylsalicylic acid, Ampicillin, Amoxycillin Trihydrate, Atenolol, Diltiazem, Fluorouracil, Isosorbide mononitrate, para Aminobenzoic acid, Piretamide, Theophylline and Verapimil hydrochloride, etc

5. Floating In-Situ Gel: aluminum hydroxide or calcium carbonate

POLYMERS AND OTHER INGREDIENTS USED TO PREPARATIONS OF FLOATING DRUGS

i) Polymers: The following polymers used to prepara-tions of floating drugs: HPMC K4 M, Calcium alginate, Eudragit S100 Eudragit RL, Propylene foam, Eudragit RS, ethyl cellulose, poly methyl meth acrylate, Methocel K4M, Polyethylene oxide, β Cyclodextrin, HPMC 4000, HPMC 100, CMC, Polyethylene glycol, polycarbonate, PVA, Polycarbo-nate, Sodium alginate, HPC-L, CP 934P, HPC, Eudragit S, HPMC, Metolose S.M. 100, PVP, HPC-H, HPC-M, HPMC K15, Polyox, HPMC K4, Acrylic polymer, E4 M and Car-bopol (Yie W. Chein et al, 1992, Sanjay Garg et al, 2003, Vedha hari b.n.et al, 2010).

ii) Inert fatty materials (5%-75%): Edible, inert fatty materials having a specific gravity of less than one can be used to decrease the hydrophilic property of formu-lation and hence increase buoyancy. E.g. Beeswax, fat-ty acids, long chain fatty alcohols, Gelucires® 39/01 and 43/01.

iii) Effervescent agents: Sodium bicarbonate, citric acid, tartaric acid, Di-SGC (Di-Sodium Glycine Carbo-nate, CG (Citroglycine).

iv) Release rate accelerants (5%-60%): eg. lactose, mannitol.

v) Release rate retardants (5%-60%): eg. Dicalcium phosphate, talc, magnesium stearate.

vi) Buoyancy increasing agents (upto80%): eg. Ethyl cellulose.

vii) Low density material: Polypropylene foam powder (Accurel MP 1000®).

ADVANTAGES OF FLOATING ORAL DRUG DELIVERY SYSTEM [14]

1. The principle of HBS of FODDS can be used for any particular medicament or class of medicament.

2. The FODDS 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.

3. The FODDS 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.

4. The efficacy of the medicaments administered utilizing the sustained release principle of FODDS has been found to be independent of the site of absorption of the particular medicaments.

5. 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 advantageous to keep the drug in floating condition in stomach to get a relatively better response.

6. FODDS provides advantages such as the delivery of drugs with narrow absorption windows in the small intestinal region.

7. Certain types of drugs can benefit from using FODDS. These include:

a) Drugs acting locally in the stomach.

b) Drugs those are primarily absorbed in the stomach.

c) Drugs those are poorly soluble at an alkaline pH.

d) Drugs with a narrow window of absorption.

e) Drugs absorbed rapidly from the GI tract.

f) Drugs those degrade in the colon.

DISADVANTAGES OF FODDS

1. There are certain situations where gastric retention is not desirable. Aspirin and non-steroidal anti-inflammatory drugs are known to cause gastric lesions, and slow release of such drugs in the stomach is unwanted.

2. Thus, drugs that may irritate the stomach lining or are unstable in its acidic environment should not be formulated in gastroretentive systems.

3. Furthermore, other drugs, such as isosorbide dinitrate, that are absorbed equally well throughout the GI tract will not benefit from incorporation into a gastric retention system.

LIMITATIONS

1. The major disadvantage of floating system is requirement of a sufficient high level of fluids in the stomach for the drug delivery to float. However this limitation can be overcome by coating the dosage form with the help of bioadhesive polymers that easily adhere to the mucosal lining of the stomach

2. Floating system is not feasible for those drugs that have solubility or stability problem in gastric fluids.

3. The dosage form should be administered with a minimum of glass full of water (200-250 ml).

4. The drugs, which are absorbed throughout gastro-intestinal tract, which under go first-pass metabolism (nifedipine, propranolol etc.), are not desirable candidate.

5. Some drugs present in the floating system causes irritation to gastric mucosa.

MARKETED PRODUCTS

Table 1.Marketed Products of FODDS

Brand name

Delivery system

Drug (dose)

Company name

Valrelease®

Floating capsule

Diazepam (15mg)

Hoffmann-LaRoche, USA

Madopar® HBS

(Prolopa® HBS)

Floating, CR capsule

Benserazide (25mg)

& L-Dopa (100mg)

Roche Products, USA

Liquid Gaviscon®

Effervesent floating liquid alginate preparations

Al hydroxide (95mg),

Mg Carbonate (358mg)

GlaxoSmithkline, India

Topalkan®

floating liquid alginate preparations

Al - Mg antacid

Pierre Fabre Drug, France

Almagate Flot coat®

Floating dosage form

Al - Mg antacid

------

Conviron®

Colloidal gel forming FDDS

Ferrous sulphate

Ranbaxy, India

APPLICATIONS OF FLOATING DRUG DELIVERY SYS-TEMS

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 con-comitantly to influence the magnitude of drug absorp-tion.

2. SUSTAINED DRUG DELIVERY Oral CR formulations are encountered with problems such as gastric residence time in the GIT. These prob-lems can be overcome with the HBS 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 suffi-cient 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 ab-sorption.

5. MINIMIZED ADVERSE ACTIVITY AT THE COLON

Retention of the drug in the HBS systems at the sto-mach minimizes the amount of drug that reaches the colon. Thus, undesirable activities of the drug in colon may be prevented. This Pharmacodynamic aspect pro-vides the rationale for GRDF formulation for betalac-tam 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 CONCENTRA-TION

Continuous input of the drug following CRGRDF admin-istration 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 ef-fects that are associated with peak concentrations can be prevented. This feature is of special importance for drugs with a narrow therapeutic index (Yie W. Chein et al, 1992, Sanjay Garg et al, 2003, Vedha hari b.n.et al, 2010).

FUTURE POTENTIAL

FODDS is novel drug delivery system which is so far limited to the experimental works, but system is having lot of potential. in present era patient compliance is a major issue in front of formulation and development pharmacist. In such situation FODDS will play an important role in following aspects. The reduced fluctuations in the plasma level of drug results from delayed gastric emptying. Drugs that have poor bioavailability because of their limited absorption to the upper gastrointestinal tract can be delivered efficiently thereby maximizing their absorption and improving their absolute bioavailability. FODDS considered as a beneficial strategy for the treatment of gastric and duodenal cancers. FODDS concept can also be utilized in the development of various anti-reflux formulations.

APPLICATIONS OF FLOATING DRUG DELIVERY SYS-TEMS

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 con-comitantly to influence the magnitude of drug absorp-tion.

2. SUSTAINED DRUG DELIVERY Oral CR formulations are encountered with problems such as gastric residence time in the GIT. These prob-lems can be overcome with the HBS 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 suffi-cient 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 ab-sorption.

5. MINIMIZED ADVERSE ACTIVITY AT THE COLON

Retention of the drug in the HBS systems at the sto-mach minimizes the amount of drug that reaches the colon. Thus, undesirable activities of the drug in colon may be prevented. This Pharmacodynamic aspect pro-vides the rationale for GRDF formulation for betalac-tam 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 CONCENTRA-TION

Continuous input of the drug following CRGRDF admin-istration 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 ef-fects that are associated with peak concentrations can be prevented. This feature is of special importance for drugs with a narrow therapeutic index (Yie W. Chein et al, 1992, Sanjay Garg et al, 2003, Vedha hari b.n.et al, 2010).

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