Introduction Approaches to gastro retention. Mechanism of FDDS Types of FDDS Advantages & Disadvantages Polymers and other ingredients Drugs explored in FDDS

Introduction:Floating systems are low-density systems that have sufficient buoyancy to float over the gastric contents and remain in the stomach for a prolonged period. While the system floats over the gastric contents, the drug is released slowly at the desired rate, which results in increased gastro-retention time and reduces fluctuation in plasma drug concentration. FDDS helps in the local drug delivery to the stomach & proximal small intestine. FDDS enhances gastric residence time.

1) Highdensity systems 2) Swelling and expanding systems 3) Incorporating delaying excipients 4) Modified systems 5) Mucoadhesive & bioadhesive systems 6) Floating systems.

Mechanism of FDDS:The object floats better if F is on the higher positive sideF = F(b) - F(g) F = (df ds ) gv = ( df - w/v ) gv Where, F = resultant weight of the object df, ds = fluid density and solid object density g = acceleration due to gravity w, v = weight and volume of the test objects

Types of Floating Drug Delivery Systems (FDDS):Based on the mechanism of buoyancy, two distinctly different technologies have been utilized in development of FDDS that are: Effervescent System Non- Effervescent System Effervescent systems further classified into two types Gas Generating systems Volatile Liquid/Vacuum Containing Systems

I.

Gas Generating Systems:

1. Intra Gastric Single Layer Floating Tablets or Hydrodynamically Balanced System (HBS): These are formulated by intimately mixing the CO2 generating agents and the drug with in the matrix tablet

2. Intra Gastric Bilayer Floating Tablets:These are also compressed tablet and containing two layers Immediate release layer Sustained release layer

3. Multiple Unit type floating pills: These systems consist 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.

II. Volatile Liquid/Vacuum Containing Systems: 1. Intragastric Floating Gastrointestinal Drug Delivery System: This system 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 microporous compartment .

2. 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, then encapsulated in a gelatin capsule.

3. 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 intragastirc osmotically controlled drug delivery device .

B. Non Effervescent Systems: The Non-effervescent FDDS based on mechanism of swelling of polymer or bioadhesion to mucosal layer in GI tract. The most commonly used excipients in non-effervescent FDDS are gel forming or highly swellable cellulose type hydrocolloids, polysaccharides and matrix forming material such as polycarbonate, polyacrylate, polymethacrylate, polystyrene as well as bioadhesive polymer such as chitosan and carbopol. 1. 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 maintain bulk density of less than unity. The air trapped by the swollen polymer confers buoyancy to these dosage forms.

2. 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.

3. 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

4. Hollow Microspheres:

Hollow microspheres (microballoons), loaded with drug in their outer polymer shells were prepared by a novel emulsion-solvent diffusion method.

Factors affect floating time:Density Size Shape of dosage form Fed or unfed state. Nature of meal. Caloric content Frequency of feed Gender Age Posture Biological factors

1. Floating dosage forms such as tablets or capsules will remains 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 diarrhea 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 due to drugs, by drug releasing slowly at controlled rate. 7. Treatment of gastrointestinal disorders 8. Ease of administration and better patient compliance. 9. Site-specific drug delivery.

ADVANTAGES OF FLOATING DRUG DELIVERY SYSTEMS:

DISADVANTAGES OF FDDS: 1. Floating systems are not feasible for those drugs that have solubility or stability problems in gastric fluids. 2. Drugs such as Nifedipine, which is 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 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

Ideal drug candidates for floating drug delivery:Drugs those are locally active in the stomach. Eg.Misoprostol, antacids etc. Drugs which have narrow absorption window in the GIT. Eg. Furosemide, L-dopa, Para-amino benzoic acid, riboflavin.etc. Drugs that exhibit low solubility at high pH values. Eg.Diazepam, Chlordiazepoxide, Verapamil hydrochloride. Drugs that are unstable in the intestinal or colonic environment. E.g. captopril, ranitidine HCl,metronidazole. Drugs that disturb normal colonic microbes. E.g.antibiotics against Helicobacter pylori. Drugs having a specific site of absorption in the upper part of small intestine. Drugs having a bulk density of less than 1 to remain in the stomach for a prolonged period of time.

LIST OF DRUGS FORMULATED AS SINGLE AND MULTIPLE UNIT FORMS OF FLOATING DRUG DELIVERY SYSTEMS.Tablets:Chlorpheniramine maleate, Theophylline ,Furosemide, Ciprofolxacin, Pentoxyfillin captopril, Acetylsalicylic, Nimodipine, Propranlol, Terfenadine, Amoxycillin trihydrate, Verapamil HCl, Isosorbide di nitrate, Sotalol, Atenolol, Isosorbide mono nitrate, Acetaminophen, Ampicillin, Cinnarazine, Diltiazem, Florouracil,Piretanide, Prednisolone, losartan, dexchlorpheniramine, lamivudine, acyclovir, tizanidine hcl, liquorice,metronidazole, metroprolol succinate, nimedipine,labetalol, feneverine, metforminhcl, norflaxcin, ranitidinehcl.

Capsules :Nicardipine, L-Dopa and benserazide, chlordizepoxide HCI, Furosemide, Misoprostal, Diazepam,Propranlol, Urodeoxycholic acid. Microspheres :Verapamil, Aspirin, Griseofulvin, and p-nitroanilline, Ketoprofen, Tranilast, Iboprufen, Terfenadine, valcyclovir,ranitidine hcl, azithromycin, tramadol, rifampicin, rosiglitazone, itopride hcl , levodopa, nifidipine, fluouracil, famotidine, riboflavin, diclofenac, acyclovir, thophylline, jasamycin, celecoxib, orlistat, repaglimide, acetohydroxamic acid, cholestyramine, chlorpheniramine maleate, acetohydroxamic acid, verampil, piroxicam, furosemide. Granules :Indomethacin, Diclofenac sodium, Prednisolone. Films :Drug delivery device. Cinnarizine

POLYMERS AND OTHER INGREDIENTS USED IN PREPARATIONS OF FLOATING DRUGS: Polymers: The following polymers used in preparations of floating drugs HPMC K4 M, Calcium alginate, Eudragit S100, Eudragit RL,Propylene foam, Eudragit RS, ethyl cellulose, poly methylmethacrylate, Methocel K4M, Polyethylene oxide, Cyclodextrin,HPMC 4000, HPMC 100, CMC, Polyethylene glycol,polycarbonate, PVA, Polycarbo-nate, Sodium alginate, HPC-L, CP934P, HPC, Eudragit S, HPMC, Metolose S.M. 100, PVP, HPC-H, HPC-M, HPMC K15, Polyox, HPMC K4, Acrylic polymer, E4M and Carbopol. 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 formulation and hence increase buoyancy. E.g. Beeswax, fatty acids, long chain fatty alcohols, Gelucires 39/01 and 43/01.

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

Release rate accelerants (5%-60%): eg. lactose, mannitol.Release rate retardants (5%-60%): eg. Dicalcium phosphate,talc, magnesium stearate. Buoyancy increasing agents (upto80%): eg. Ethyl cellulose. Low density material: Polypropylene foam powder (Accurel MP 1000).

Preparation of buoyant beads:Sodium alginate Sunflower oil Calcium chloride dihydrate Hydrochloric acid

Formulation design of drug containing polymeric beads:In the formulation design of various batches of drug containing alginate beads, the ratio of drug to polymer and oil to water were kept as variable parameters. Each variable parameter was investigated at two levels; (high and low) in order to determine the effect of these formulation variables on bead size, drug entrapment, floating time and the in vitro release profile.

Preparation of alginate beads:Alginate gel beads were prepared by the ionotropic gelation method.

The solution of sodium alginate was prepared by adding sodium alginate in double distilled water .Drug was added to it with continuous stirring. Sunflower oil was added drop wise to the dispersion by stirring at 6000 rpm continuously for 40 minutes to get a stable o/w emulsion. The emulsion was poured drop wise into 50 ml 5% w/v calcium chloride dihydrate (CCD) solution through an 18-gauge stainless steel needle. The beads were left in contact with CCD solution for 10 minutes. They were separated from the solution using stainless steel grid and air dried for 24 hours.

Evaluation parameters:Determination of bead size, weight, swelling & morphology Determination of drug entrapment efficiency In vitro buoyancy study In-vitro drug release study