FLOATING DRUG DELIVERY
SYSTEMS
BY

VENKATESH THOTA
M.PHARMACY
SRI KAKATIYA INSTITUTE OF PHARMACEUTICALSCIENCES
HANAMKONDA-...
CONTENTS
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INTRODUCTION
FACTORS AFFECTING FDDS
MECHANISMS OF FLOATING
NON EFFERVESCENT FDDS
EFFERVESCEN...
INTRODUCTION
•
•

•
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Drug delivery systems are used for maximizing therapeutic index of the drug and
also for reduction ...
GASTROINTESTINAL PHYSIOLOGICAL CONSIDERATIONS
•

•
•
•
•






Drugs having a short half-life are eliminated quickly from the blood circulation.
Various oral contr...
FACTORS AFFECTING FDDS
•
•
•
•
•
•
•
•
•
•
•
•
•

Density
Size : 7.5 mm
Shape : Tetrahedron and ring-shaped devices
Single...
MECHANISMS OF FLOATING

F = Fbuoyancy – Fgravity = (Df – Ds) g v
NON EFFERVESCENT FDDS
 HYDRODYNAMICALLY BALANCED SYSTEMS

 Excipients
 Gel forming hydrocolloid
 Shape and bulk densit...
•

A recent patent issued to G.D. Searle and Co. described a bilayer buoyant dosage
form consisting of a capsule, which in...
Intragastric floating tablet

Intragastric floating device

Intragastric bilayer floating tablet
HALLOW MICROSPHERES
•

•
•
•

Hollow microspheres are considered as one of the most promising buoyant
systems as they poss...
•
•

•
•

•

•

Drug-loaded polycarbonate microspheres using a solvent evaporation technique.
Polymers such as polycarbona...
Preparation and Mechanism of Microballoon formation
•

•

•
•

•

•

A multiple-unit floating dosage form from freeze-dried calcium alginate beads
Spherical beads of approxim...
Floating alginate beads

Freeze dried floating alginate bead
EFFERVESCENT FDDS
•

•
•
•

•

These buoyant delivery systems utilize matrices prepared with swellable polymers
such as Me...
(a) A multiple unit dosage form. (b) Stages of floating mechanism: (A)
penetration of water; (B) generation of CO2 and flo...
Preparation of Core Mini Capsules
•

•

•
•

•

Floating bioadhesive system : The carbonates, in addition to imparting buoyancy to
these formulations, provi...
Pictorial presentation of floating effervescent ionic resin bead
Intragastric Osmotic controlled Drug
Delivery System

Gastro- Inflatable Drug Delivery Device
RAFT FORMING SYSTEMS
 Raft forming systems have received much attention for the
delivery of antacids and drug delivery fo...
EVALUATION OF FLOATING DRUG DELIVERY
SYSTEMS
 Measurement of buoyancy capabilities of the FDDS
•

•

•

•

It was given b...
•

Surface morphology was observed by SEM, which serves to confirm qualitatively a
physical observation relating to surfac...
 Floating time and dissolution
•
•
•

Done in stimulated gastric fluid or 0.1 mol/l HCl maintained at 37˚C.
Floating lag-...
 X-ray/gamma scintigraphy
•
•

It helps to locate the dosage form in the GIT and it can be used to predict and
correlate ...
Drug and polymers

Floating media/Dissolution medium and method

Pentoxyfylline (HPMC K4M)

500ml simulated gastric fluid ...
List of drugs explored for various floating dosage forms

Microspheres

Aspirin, griseofulvin,
p-nitroaniline , Ibuprofen,...
MARKETED PREPARATIONS OF FDDS
Schematic of the OROS Push-Pull system.
APPLICATIONS
•

•
•

•
•
•

•
•

The administration of diltiazem floating tablet twice a day might be more effective
compa...
RECENT ADVANCES
•

•

•

•

Ninan Ma et al developed a type of multi-unit floating alginate (Alg) microspheres
by the iono...
CONCLUSION
•

The currently available polymer-mediated noneffervescent and effervescent FDDS,
designed on the basis of del...
REFERENCES
1.

Brahma N. Singh, Kwon H. Kim. A review of floating drug delivery systems: an
approach to oral controlled dr...
5. Bulgarelli E, Forni F, Bernabei MT. Effect of matrix composition and process
conditions on casein gelatin beads floatin...
THANK YOU
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  1. 1. FLOATING DRUG DELIVERY SYSTEMS BY VENKATESH THOTA M.PHARMACY SRI KAKATIYA INSTITUTE OF PHARMACEUTICALSCIENCES HANAMKONDA-A.P(506001)
  2. 2. CONTENTS • • • • • • • • • • INTRODUCTION FACTORS AFFECTING FDDS MECHANISMS OF FLOATING NON EFFERVESCENT FDDS EFFERVESCENT FDDS RAFT FLOATING SYSTEMS EVALUATION OF FDDS MARKETED PREPARATIONS OF FDDS APPLICATIONS ANDRECENT ADVANCES CONCLUSION • REFERENCES
  3. 3. INTRODUCTION • • • • Drug delivery systems are used for maximizing therapeutic index of the drug and also for reduction in the side effects. The oral route is considered as 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. To modify the GI transit time is one of the main challenge 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. 4. GASTROINTESTINAL PHYSIOLOGICAL CONSIDERATIONS
  5. 5. • • • • •      Drugs having a short half-life are eliminated quickly from the blood circulation. Various oral controlled delivery systems have been designed which can overcome the problems of unpredictable gastric emptying due to physiological problems and presence of food and also release the drug to maintain its plasma concentration for a longer period of time. This has led to the development of oral gastroretentive floating dosage forms. This dosage form improves bioavailability, therapeutic efficacy and may allow a reduction in the dose because of steady therapeutic levels of drug. Drug absorption from the GIT is a complex procedure and is subject to many variables. Controlled release drug delivery systems that retain in the stomach for a long time have many advantages over sustained release formulations. GRDDS are advantageous for drugs like Antacids Poorly soluble in intestine absorbed in stomach Narrow absorption window and site specific delivery From the formulation and technological point of view, floating drug delivery system (FDDS) is considerably easy and logical approach in development of GRDFs.
  6. 6. FACTORS AFFECTING FDDS • • • • • • • • • • • • • Density Size : 7.5 mm Shape : Tetrahedron and ring-shaped devices Single or multiple unit formulations Fed or fasted state Nature of the meal Caloric content Frequency of feeding Gender Age Posture Biological factors Concomitant drug administration
  7. 7. MECHANISMS OF FLOATING F = Fbuoyancy – Fgravity = (Df – Ds) g v
  8. 8. NON EFFERVESCENT FDDS  HYDRODYNAMICALLY BALANCED SYSTEMS  Excipients  Gel forming hydrocolloid  Shape and bulk density  Buoyancy  Sustained drug release  Receding boundary Working principle of the hydrodynamically balanced systems (HBS)
  9. 9. • A recent patent issued to G.D. Searle and Co. described a bilayer buoyant dosage form consisting of a capsule, which included a non-compressed bilayer formulation. • Each layer included a hydrocolloid gelling agent such as hydroxy propylmethylcellulose (HPMC), gums, polysaccharides and gelatin, which upon contact with gastric fluid formed a gelatinous mass, sufficient for cohesively binding the drug release layer and floating layer. • CR floating tablets of theophylline using agar and light mineral oil :  Preparation : Tablets were made by dispersing a drug/ mineral oil mixture in a warm agar gel solution and pouring the resultant mixture into tablet molds, which on cooling and air drying formed floatable CR tablets. • A multilayered, flexible, sheet-like medicament device that was buoyant in the gastric juice of the stomach and had SR characteristics. • The device consisted of at least one dry, self supporting carrier film a barrier film overlaying the carrier film. • SR floating tablets that were hydrodynamically balanced in the stomach for an extended period of time until all the drug-loading dose was released.
  10. 10. Intragastric floating tablet Intragastric floating device Intragastric bilayer floating tablet
  11. 11. HALLOW MICROSPHERES • • • • Hollow microspheres are considered as one of the most promising buoyant systems as they possess the unique advantages of multiple unit systems as well as better floating properties, because of the central hollow space inside the microsphere. The general techniques involved in their preparation include simple solvent evaporation, and solvent diffusion and evaporation. The drug release and better floating properties mainly depend on the type of polymer, plasticizer and the solvents employed for the preparation. Polymers used are Cellulose acetate, Chitosan, Eudragit, Acrycoat, Methocil, Polyacrylates, Polyvinyl acetate, Agar, Polyethylene oxide, Polycarbonates, Acrylic resins and Polyethylene oxide.
  12. 12. • • • • • • Drug-loaded polycarbonate microspheres using a solvent evaporation technique. Polymers such as polycarbonate has been used to develop hollow microspheres that were capable of floating on the gastric fluid and released their drug contents for prolonged period of time. Hollow microspheres (microballoons) with drug in their outer polymer shells, prepared by a novel emulsion solvent diffusion method. Invitro testing, the microballoons floated continuously over the surface of an aqueous or an acidic dissolution medium containing surfactant for more than 12 hr A patent assigned to Eisai Co. Ltd. of Japan described a floatable coated shell which consisted essentially of a hollow globular shell made from polystyrene. The external surface of the shell was coated with an under-coating and a final coating. While the former was a layer of a cellulose acetate phthalate, the latter consisted of a layer of ethyl cellulose and HPMC in combination with an effective amount of a pharmaceutically active ingredient selected from the group consisting of a gastric acid secretion inhibitor, a gastric acid neutralizer and an anti-pepsin inhibitor.
  13. 13. Preparation and Mechanism of Microballoon formation
  14. 14. • • • • • • A multiple-unit floating dosage form from freeze-dried calcium alginate beads Spherical beads of approximately 2.5 mm in diameter were produced by dropping a sodium alginate solution into aqueous calcium chloride. After the internal gelation was complete, beads were separated from the solution and snap-frozen in liquid nitrogen before being freeze-dried at -40°C for 24h. The results of resultant-weight measurements suggested that these beads maintained a positive floating force for over 12 h. A multiple-unit system that contained an air compartament was prepared . The units forming the system were composed of a calcium alginate core separated by an air compartment from a membrane of calcium alginate or calcium alginate /PVA. The porous structure generated by leaching of the PVA, which was employed as a water-soluble additive in the coating composition, was found to increase the membrane permeability, preventing the collapse of the air compartment. The in vitro results suggested that the floating ability increased with an increase in PVA concentration and molecular weight.
  15. 15. Floating alginate beads Freeze dried floating alginate bead
  16. 16. EFFERVESCENT FDDS • • • • • These buoyant delivery systems utilize matrices prepared with swellable polymers such as Methocel or polysaccharides, e.g., chitosan, and effervescent components, e.g., sodium bicarbonate and citric or tartaric acid or matrices containing chambers of liquid that gasify at body temperature. Single unit type : Includes single layered or bilayered tablet for sustained release. Also formulated as capsule. Multiple-unit type : The system was found to float completely within 10 min and approximately 80% remained floating over a period of 5 h irrespective of pH and viscosity of the test medium. While the system was floating, a drug (p-amino- benzoic acid) was released. A variant of this approach utilizing citric acid (anhydrous) and sodium bicarbonate as effervescing agents and HPC-H grade as a release controlling agent has also been reported In vitro results indicated a linear decrease in the FT of the tablets with an increase in the amount of effervescing agents in the range of 10–20%.
  17. 17. (a) A multiple unit dosage form. (b) Stages of floating mechanism: (A) penetration of water; (B) generation of CO2 and floating; (C) dissolution of drug. Key: (a) conventional 2 SR pills; (b) effervescent layer; (c) swellable layer; (d) expanded swellable membrane layer; (e) surface of water in the beaker 37°C).
  18. 18. Preparation of Core Mini Capsules
  19. 19. • • • • • Floating bioadhesive system : The carbonates, in addition to imparting buoyancy to these formulations, provide the initial alkaline microenvironment for polymers to gel . Moreover, the release of CO2 helps to accelerate the hydration of the floating tablets, which is essential for the formation of a bioadhesive hydrogel. Floating ion exchange resin beads : componets : Resin beads, bicarbonate, negatively charged drug, semipermeable membrane. Floating dosage forms with an in situ gas generating mechanism are expected to have greater buoyancy and improved drug release characteristics. However, the optimization of the drug release may alter the buoyancy and, therefore, it is sometimes necessary to separate the control of buoyancy from that of drug release kinetics during formulation. It is noteworthy here that release kinetics for effervescent floating systems significantly deviate from the classical Higuchi model and approach zero-order kinetics systems
  20. 20. Pictorial presentation of floating effervescent ionic resin bead
  21. 21. Intragastric Osmotic controlled Drug Delivery System Gastro- Inflatable Drug Delivery Device
  22. 22. RAFT FORMING SYSTEMS  Raft forming systems have received much attention for the delivery of antacids and drug delivery for gastrointestinal infections and other disorders.  Mechanism of raft formation  Ingredients – gel forming agents and alkaline bicarbonates.  Antacid raft forming floating system – alginic acid , sodium bicarbonate, and an acid neutralizer .  A patent assigned to Reckitt and Colman Products Ltd., describes a raft forming formulation for the treatment of Helicobacter pylori (H. Pylori) infections in the GIT.
  23. 23. EVALUATION OF FLOATING DRUG DELIVERY SYSTEMS  Measurement of buoyancy capabilities of the FDDS • • • • It was given by the vectorial sum of buoyancy F(b) and gravitational forces F(g) acting on the test object. F = Fb - Fg F = ( df – ds ) gV = (df – W/V) gV Dissolution tests generally performed using USP dissolution apparatus. USP 28 states the dosage unit is allowed to sink to the bottom of the vessel before rotation of the blade is started. A helical wire sinker was applied to the swellable floating system of theophylline, which is sparingly soluble in water and concluded that the swelling of the system was inhibited by the wire helix and the drug release also slowed down. To overcome this limitation a method was developed in which the floating drug delivery system was fully submerged under a ring or mesh assembly and an increase in drug release was observed.
  24. 24. • Surface morphology was observed by SEM, which serves to confirm qualitatively a physical observation relating to surface area. • Hollow structure of microspheres made of acrylic resins was estimated by by measuring particle density (Pp) by a photographic counting method and a liquid displacement method. • An image analyzer was used to determine the volume (v) of particles (n) of weight (w): P = w/v where porosity Ε = ( 1 – Pp – Pt) × 100 • Bulgarelli et al., developed casein gelatin beads and determined their porosity by mercury intrusion technique. • The principle of this technique is that pressure (P) required to drive mercury through a pore decreases as described by the Washburn equation: P = (– 4 σ cos θ) d
  25. 25.  Floating time and dissolution • • • Done in stimulated gastric fluid or 0.1 mol/l HCl maintained at 37˚C. Floating lag-time and floation time It is determined using USP dissolution apparatus containing 900 ml 0.1 mol/l HCl as the dissolution medium at 37˚C.  Drug release  Content uniformity, hardness, friability (tablets)  Drug loading, drug entrapment efficiency, particle size analysis, surface characterization (for floating microspheres and beads) • • • The percentage drug loading is calculated by dividing the amount of drug in the sample by the weight of total beads or microspheres. The particle size and the size distribution of the beads or microspheres are determined in the dry state by optical microscopy. The external and cross-sectional morphology (surface characterization) is carried out by scanning electron microscopy (SEM).
  26. 26.  X-ray/gamma scintigraphy • • It helps to locate the dosage form in the GIT and it can be used to predict and correlate the gastric emptying time and the passage of the dosage form in the GIT. The inclusion of a λ-emitting radio-nuclide in a formulation allows indirect external observation using a λ-camera or scintiscanner.  Pharmacokinetic studies • • • Sawicki studied the pharmacokinetics of verapamil, from floating pellets containing the drug, filled into a capsule, and compared with conventional verapamil tablets with a similar dose (40 mg). The tmax and AUC values for floating pellets were comparatively higher than those obtained for the conventional verapamil tablets . Very little difference was found between the Cmax values of both formulations, suggesting the improved bioavailability of the floating pellets compared with the conventional tablets.  Specific gravity
  27. 27. Drug and polymers Floating media/Dissolution medium and method Pentoxyfylline (HPMC K4M) 500ml simulated gastric fluid pH 1.2 (with out enyzme), USP XXIII dissolution apparatus Amoxicillin (Calcium alginate) 900ml of deaerated 0.1 M HCl pH 1.2, USP XXII apparatus Ketoprofen S100) (Eudragit RL & 20 ml simulated gastric fluid pH 1.2 (with out enyzme), 50 mg microparticles in 50 ml beaker % of floating is calculated. 900ml of 0.1N HCl or pH 6.8 Phosphate buffer, USP apparatus 1 Verapamil (Propylene foam, 30ml of 0.1N HCl pH 1.2, floatation was studied by placing 60 Eudragit RS, ethyl cellulose) particles in 30 ml flask Captopril (HPMC K4M) 900ml 0.1 N HCl pH 1.2 (with out enyzme), USP XXIII dissolution apparatus II Theophylline (HPMC K4M, 0.1 N HCl pH 1.2, USP XXIII dissolution apparatus II PEO) Furosemide (HPMC 4000 & 100, Gastric fluid pH 1.2, flow through cell flow rate 9ml/min CMC, PEG) Piroxicam (Polycarbonate) Ampicillin (Sodium alginate) 900ml dissolution medium in USP apparatus II 500ml distilled water, JP XII disintegration test medium pH 1.2 and pH 6.8 in JP XII dissolution apparatus with paddle
  28. 28. List of drugs explored for various floating dosage forms Microspheres Aspirin, griseofulvin, p-nitroaniline , Ibuprofen, Terfenadine , Tranilast Granules Diclofenac sodium Indomethacin, Prednisolone Films Cinnarizine, Drug delivery device Capsules Chlordiazepoxide HCl , Diazepam , Furosemide , L-Dopa and benserazide , Misoprostol Tablets /Pills Acetaminophen, Ampicillin , Atenolol ,Chlorpheniramine maleate, Fluorouracil . Powders Several basic drugs.
  29. 29. MARKETED PREPARATIONS OF FDDS
  30. 30. Schematic of the OROS Push-Pull system.
  31. 31. APPLICATIONS • • • • • • • • The administration of diltiazem floating tablet twice a day might be more effective compared to normal tablets in controlling the blood pressure of hypertensive patient. Madopar HBS- containing L-dopa and benserazide - here drug was released and absorbed over a period of 6-8 hour and maintain substantial plasma concentration for parkinson’s patients. Cytotech — containing misoprostol, a synthetic prostaglandin- E1 analog, for prevention of gastric ulcers caused by non-steroidal anti-inflammatory drugs (NSAIDS). As it provides high concentration of drug within gastric mucosa, it is used to eradicate pylori (A causative organism for chronic gastritis and peptic ulcers). 5-Fluorouracil has been successfully evaluated in patients with stomach neoplasm. Developing HBS dosage form for tacrine provides a better delivery system and reduces its GI side effects in alzheimer’s patients. Treatment of gastric and duodenal cancers. Alza corporation has developed a gastroretentive platform for the OROS system, which showed prolong residence time
  32. 32. RECENT ADVANCES • • • • Ninan Ma et al developed a type of multi-unit floating alginate (Alg) microspheres by the ionotropic gelation method with calcium carbonate (CaCO3) being used as gas forming agent. Rajnikanth and Mishra have developed a floating in situ gelling system for clarithromycin (FIGC) using gellan as the gelling polymer and calcium carbonate as the floating agent for the treatment of gastric ulcers, associated with Helicobacter pylori. Sher et al have proposed a specific technology, based on combining floating and pulsatile principles, to develop a drug delivery system, intended for chronotherapy of arthritis. Jang et al prepared a gastro-retentive drug delivery system of DA-6034, a new synthetic flavonoid derivative, for the treatment of gastritis using an effervescent floating matrix system (EFMS).
  33. 33. CONCLUSION • The currently available polymer-mediated noneffervescent and effervescent FDDS, designed on the basis of delayed gastric emptying and buoyancy principles, appear to be an effective and rational approach to the modulation of controlled oral drug delivery. • The FDDS become an additional advantage for drugs that are absorbed primarily in the upper segments of GI tract, i.e., the stomach, duodenum, and jejunum. • Some of the unresolved, critical issues related to the rational development of FDDS include  the quantitative efficiency of floating delivery systems in the fasted and fed states;  the role of buoyancy in enhancing GRT of FDDS; and  the correlation between prolonged GRT and SR/PK characteristics. • Finally, with an increasing understanding of polymer behavior and the role of the biological factors mentioned above, it is suggested that future research work in the floating drug delivery systems should be aimed at discovering means to accurately control the drug input rate into the GI tract for the optimization of the pharmacokinetic and toxicological profiles of medicinal agents.
  34. 34. REFERENCES 1. Brahma N. Singh, Kwon H. Kim. A review of floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention . Journal of Controlled Release .2000; 63 , 235-259. 2. Shweta Arora, Javed Ali, Alka Ahuja, Roop K. Khar, and Sanjula Baboota. Floating Drug Delivery Systems: A Review. AAPS PharmSciTech 2005; 6 (3) : Article 47 (http://www.aapspharmscitech.org). S. H. Shahaa, J. K. Patel, K. Pundarikakshudu, N. V. Patel. An overview of a gastroretentive floating drug delivery system. Asian Journal of Pharmaceutical Sciences 2009; 4 (1): 65-80 3. 4. Pooja Mathur, Kamal Saroha, Navneet Syan , Surender Verma and Vipin Kumar Floating drug delivery system: An innovative acceptable approach in gastroretentive drug delivery. Archives of Applied Science Research, 2010; 2 (2):257-270. (http://scholarsresearchlibrary.com/archive.html)
  35. 35. 5. Bulgarelli E, Forni F, Bernabei MT. Effect of matrix composition and process conditions on casein gelatin beads floating properties. Int J Pharm. 2000;198:157Y165. 6. Ninan M; Lu X; Wanga Q; Zhanga X. Int J Pharm, 2008, 358, 82-90. 7. Sawicki W. Eur J Pharm Biopharm, 2002, 53, 29-35. 8. Janga S; Lee J; Park S. Int J Pharm, 2008, 356, 88-94. 9. Rajinikanth P; Mishra B. J Cont Rel, 2008, 25, 33-41.
  36. 36. THANK YOU

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