Patel S.R et al. / Journal of Pharmacy Research 2012,5(4), Available online through

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1 Review Article ISSN: Patel S.R et al. / Journal of Pharmacy Research 2012,5(4), Available online through Floating pulsatile drug delivery system for chronotherapy *Patel S.R., Patel A.K., Modasiya M.K., Patel V.M. APMC College of Pharmaceutical Education and Research, Himatnagar ,Gujarat-India. Received on: ; Revised on: ; Accepted on: ABSTRACT In the recent years, scientific and technological advancements have been made in the research and development of novel drug delivery systems by overcoming physiological troubles such as short gastric residence times and unpredictable gastric emptying times. Several approaches are currently utilized in the prolongation of the gastric residence times, including floating drug delivery systems, swelling and expanding systems, polymeric bioadhesive systems, modified shape systems, high-density systems and other delayed gastric emptying devices. Recent trends indicate that drug delivery systems are especially suitable for achieving controlled or delayed release oral formulations with low risk of dose dumping, flexibility of blending to attain desirable release patterns with less inter- and intra-subject variability. A blend of floating and pulsatile principles of drug delivery system seems to present the advantage that a drug can be released in the upper GI tract after a definite time period of no drug release. Floating pulsatile drug delivery system (FPDDS) concept was applied to increase the gastric residence of the dosage form having lag phase followed by a burst release. Diseases wherein FPDDS are promising include asthma, peptic ulcer, cardiovascular diseases, arthritis, and attention deficit syndrome in children. To overcome limitations of various approaches for imparting, buoyancy and lag controlling were prepared by floating pulsatile delivery systems, for which time controlling system like swelling and rupturable membranes, soluble or erodible coating, capsule shaped system, and multiparticulate system are primarily involved in the control of release. Key words: Gastric residence time, Floating drug delivery system, Chronotherapeutic. INTRODUCTION FLOATING PULSATILE DRUG DELIVERY SYSTEM The oral route is the most preferred route of administration of drugs because of low cost of therapy, ease of administration, patient compliance and flexibility in formulation, etc. During the past few decades, numerous oral drug delivery systems have been developed to act as drug reservoirs from which the active substance can be released over a specific period of time at a predetermined and controlled rate 1. It is evident from the recent scientific and patent literatures that an increased interest in novel oral controlled release dosage forms that designed to be retained in the gastrointestinal tract (GIT) for a prolonged and predictable period of time exists today 2. Several approaches are currently utilized in the prolongation of the gastric residence times (GRT), including floating drug delivery systems (FDDS) 3, low- density systems 4, raft systems incorporating alginate gels 5, bioadhesive or mucoadhesive systems 6, high-density systems 7, superporous hydrogels 8 and magnetic systems 9. The current review addresses briefly about the FDDS that is one of the most leading methodologies in gastroretentive drug formulations. 1. Floating drug Delivery System Floating drug delivery systems (FDDS) or hydrodynamically controlled systems are low-density systems that have sufficient buoyancy to float over the gastric contents and remain buoyant in the stomach without affecting the 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. However, besides a minimal gas- *Corresponding author. Patel S.R APMC College of Pharmaceutical Education and Research, Himatnagar , Gujarat-India. tric 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. Many buoyant systems have been developed based on granules, powders, capsules, tablets, laminated films and hollow microspheres. Table 1 enlists examples of various drugs formulated as different forms of FDDS. 1.1 Drug Candidates Suitable for FDDS Drugs that have narrow absorption window in GIT (e.g. L-DOPA, paminobenzoic acid, furosemide, riboflavin) 2 Drugs those are locally active in the stomach (e.g. misroprostol, antacids) 10 Drugs those are unstable in the intestinal or colonic environment (e.g. captopril, ranitidine HCl, metronidazole) 11 Drugs that disturb normal colonic microbes (e.g. antibiotics used for the eradication of Helicobacter pylori, such as tetracycline, clarithromycin, amoxicillin) 12 Drugs that exhibit low solubility at high ph values (e.g. diazepam, chlordiazepoxide, verapamil) Advantages of FDDS 14, 1. The Floating systems are advantageous for drugs meant for local action in the stomach. E.g. antacids. 2. Acidic substances like aspirin cause irritation on the stomach wall when come in contact with it. Hence FDDS may be useful for the administration of aspirin and other similar drugs. 3. The Floating systems are advantageous for drugs absorbed through the stomach. E.g. Ferrous salts, antacids. 4. Administration of prolongs release floating dosage forms, tablet or capsules, will result in dissolution of the drug in the gastric fluid. They dissolve in the gastric fluid would be available for absorption in the small intestine after emptying of the stomach contents. 5. It is therefore expected that a drug will be fully absorbed from floating dosage forms if it remains in the solution form even at the alkaline ph of the intestine.

2 Patel S.R et al. / Journal of Pharmacy Research 2012,5(4), 1.3 Disadvantages of FDDS 1. Floating system is not feasible for those drugs that have solubility or stability problem in G.I. tract. 2. These systems require a high level of fluid in the stomach for drug delivery to float and work efficiently coat, water. 3. The drugs that are significantly absorbed through out gastrointestinal tract, which undergo significant first pass metabolism, are only desirable candidate. 1.4 Types Of Floating Drug Delivery Systems Based on the mechanism of buoyancy, two distinctly different technologies have been utilized in the development of FDDS. 15, 16 i) Non-Effervescent FDDS The Non-effervescent FDDS is based on mechanism of swelling of polymer or bioadhesion to mucosal layer in GI tract. The most commonly used excipients in noneffervescent 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 bioadhesive polymers such as Chitosan and carbopol. The various types of this system are as: a. 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 maintains bulk density of less than unity. They are formulated by intimate mixing of drug with low-density enteric materials such as HPMC. b. Bi-layer Floating Tablets: A bi-layer tablet contain two layer one immediate release layer which releases 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 b. Gas-generating Systems: These buoyant delivery systems utilize effervescent reactions between carbonate/bicarbonate salts and citric/tartaric acid to liberate CO2, which gets entrapped in the gellified hydrocolloid layer of the systems thus decreasing its specific gravity and making it to float over 17, 18 chyme. 2. Pulsatile Drug Delivery System Oral controlled drug delivery systems represent the most popular form of controlled drug delivery systems for the obvious advantages of oral route of drug administration. Such systems release the drug with constant or variable release rates. These dosage forms offer many advantages, such as nearly constant drug level at the site of action, prevention of peak-valley fluctuations, reduction in dose of drug, reduced dosage frequency, avoidance of side effects, and improved patient compliance 19, 20. However, there are certain conditions for which such a release pattern is not suitable. These conditions demand release of drug after a lag time. In other words, it is required that the drug should not be released at all during the initial phase of dosage form administration. Such a release pattern is known as pulsatile release. A pulsatile drug delivery system is characterized by a lag time that is an interval of no 19, 20 drug release followed by rapid drug release. c. Alginate Beads: Multi-unit floating dosage forms were developed from freeze dried alcium alginate. Spherical beads of approximately 2.5 mm diameter 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. d. Hollow Microspheres: Hollow microspheres (microballoons), loaded with drug in their outer polymer shells are prepared by a novel emulsion-solvent diffusion method. The ethanol: A: Ideal Sigmoidal Release B & C: Delayed Release After Initial Lag Time 19, 20 Figure 1 Drug release profile of pulsatile drug delivery system dichloromethane solution of the drug and an enteric acrylic polymer is poured into an agitated aqueous solution of PVA that is thermally controlled at 40 C. The gas phase generated in dispersed polymer droplet by evaporation of dichloromethane forms an internal cavity in microsphere of polymer with drug. ii) Effervescent FDDS a.volatile liquid containing system: The GRT of a drug delivery system can be sustained by incorporating an inflatable chamber, which contains a liquid e.g. ether, cyclopentane, that gasifies at body temperature to cause the inflatation of the chamber in the stomach. The device may also consist of a bioerodible plug made up of Poly vinyl alcohol, Polyethylene, etc. that gradually dissolves causing the inflatable chamber to release gas and collapse after a predetermined time to permit the spontaneous ejection of the inflatable systems from the stomach. 17 In this context, the aim of the research was to achieve a so-called sigmoidal release pattern (pattern A in Figure).The characteristic feature of the formulation was a defined lag time followed by a drug pulse with the enclosed active quantity being released at once. Thus, the major challenge in the development of pulsatile drug delivery system is to achieve a rapid drug release after the lag time. Often, the drug is released over an extended period of time (patterns B & C in Figure). In chronopharmacotherapy (timed drug therapy) drug administration is synchronized with biological rhythms to produce maximal therapeutic effect and minimum harm for the patient. By basing drug delivery on circadian patterns of diseases drug effect can be optimized and side effects can be reduced. If symptoms occur at day time a conventional dosage form can be administered just prior the symptoms are worsening. If symptoms of a disease became worse during the night or in the early morning the timing of drug administration and nature of the drug delivery system need careful 21, 22 consideration.

3 Patel S.R et al. / Journal of Pharmacy Research 2012,5(4), 21, 22 Figure2: A 24-hr clock diagram of the peak time of selected human circadian Rhythm with reference to the day-night cycle Control release systems for 12 or 24 hr drug release are not suitable for diseases, which follow circadian variation. In that condition there is requirement for time or pulsatile drug delivery system. 2.1 Necessities Of Pulsatile Dds: 1. First pass metabolism: Some drugs, such as beta blockers,and salicylamide, undergo extensive first pass metabolism and require fast drug input to saturate metabolizing enzymes in order to minimize pre-systemic metabolism. 2. Biological tolerance: Drug plasma profiles are oftenaccompanied by a decline in thepharmacotherapeutic effect of the drug, e.g.,biological tolerance of transdermal nitroglycerin, salbutamol sulphate. 3. Special chronopharmacological needs: Circadian rhythms in certain physiological functions are well established. It has been recognized that many symptoms and onset of disease occur during specific time periods ofthe 24 hour day, e.g., asthma and angina pectoris attacks are most frequently in the morning hours. Figure 3: Possible causes of morning increase in the incidence of coronaryevent 22

4 Patel S.R et al. / Journal of Pharmacy Research 2012,5(4), 4. Local therapeutic need: For the treatment of local disorders such as inflammatory bowel disease, the delivery of compounds to the site of inflammation with no loss due to absorption in the small intestine is highly desirable to achieve the therapeutic effect and to minimizeside effects. 5. Gastric irritation or drug instability in gastric fluid: Protection from gastric environment is essential for the drugs that undergo degradation in gastric acidic medium (eg,peptide drugs), irritate the gastric mucosa (NSAIDS) or induce nausea and vomiting. 2.2 Advantages: 1. Many body functions that follow circadian rhythm. A number of hormones like rennin, aldosterone, and cortisol show daily fluctuations in their blood levels. Circadian effects are also observed in case of ph and acid secretion in stomach, gastric emptying, and 19, 20 gastro-intestinal blood transfusion. 2. Diseases like bronchial asthma, myocardial infarction, angina pectoris, rheumatic disease, ulcer, and hypertension display time dependence. Sharp increase in asthmatic attacks during early morning hoursa drug delivery system administered at bedtime, but releasing drug well after the time of administration (during morning hours), would be ideal in this case. It is true for preventing heart attacks in the middle of the night and the morning stiffness typical 19, 20 of people suffering from arthritis. 3. The lag time is essential for the drugs that undergo degradation in gastric acidic medium (e.g., peptide drugs) irritate the gastric mucosa or induce nausea and vomiting. These conditions can be satisfactorily handled by enteric coating, and in this sense, enteric coating can be considered as a pulsatile drug delivery system. 4. The drugs that undergo extensive first-pass metabolism (?-blockers) and those that are characterized by idiosyncratic pharmacokinetics or pharmacodynamics resulting in reduced bioavailability, altered drug/metabolite ratios, altered steady state levels of drug and metabolite, and potential food-drug interactions require delayed 19, 20. release of the drug to the extent possible. 2.3 Disdvantages: Low drug loading Proportionally higher need for excipient Lack of manufacturing reproducibility and efficacy Large number of process variables Multiple formulation steps Higher cost of production Need of advanced technology Trained or skilled personal needed for manufacturing 3. Floating Pulsatile Drug Delivery System Site- and time-specific oral drug deliveries have recently been of great interest in pharmaceutical field to achieve improved therapeutic efficacy. Drug delivery system is an approach to prolong gastric residence time, thereby targeting site-specific or time-specific drug release in upper gastrointestinal tract 23, 24. Over the last three decades, various approaches have been pursued to increase the retention of an oral dosage form in the stomach, including floating systems 25,26 which decrease in density upon contact with gastric fluids based on swelling of polymer or carbon dioxide (CO 2 ) generation, mucoadhesive systems which adhere to mucosal surfaces, 27, 28 modified-shape systems, 29, 30,31 expandable (size-increasing), 32, 33 high-density systems, 34 and other delayed gastric emptying devices 35. The dosage forms possessing gastric retention capabilities have a bulk density lower than gastric fluids and thus remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. Floating approach has been used for gastric retention of pulsatile dosage form. Floating-pulsatile concept was applied to increase the gastric residence of the dosage form having lag phase followed by a burst release. Chronopharmacotherapy, the drug regime based on circadian rhythm, regulates many body functions in human beings, viz., metabolism, physiology, behavior, sleep patterns, hormone production, etc Various diseases like asthma has been reported to have increased airway responsiveness and worsening of lung function measured over a 24-hour cycle will show a characteristic circadian rhythm with the peak during the afternoon and the trough in the early hours of the morning 36, 37, 38. Heart rate and blood pressure both exhibit a strong circadian pattern with values for blood pressure, double product typically peaking in the early morning period compare with till late afternoon, and then drops off during night (hypertension), 39, 40, 41 gastric acidity was observed toward an increase in intragastric acidity during the time period from the middle of the night to the early dawn, and toward a decrease in intragastric acidity during the early morning, 42,43,44 rheumatoid arthritis feel more pain in the morning hours show circadian variation that demand timedependant drug release for effective drug action, for example, more pain with morning body stiffness, asthma, and heart attack in early hours of the day 44. Circadian rhythm disturbances are observed in children with attentiondeficit/hyperactivity disorder and sleep onset insomnia 45. Nowadays, chronotherapeutic formulations are developed, specifically to time-controlled release dosage forms, in order to achieve the maximum drug concentration in the plasma at the peak time of the symptomatology. To follow this principle, dosage form ought to be taken at the convenient time before sleep, providing maximum drug release in the morning. The major disadvantage of these systems reclines in achieving long residence time which is desired for diseases needing morning medication. With conventional pulsatile release dosage forms, the highly variable nature of gastric emptying process can result in vivo variability and bioavailability problems.to overcome this novel approach term as floating pulsatile drug delivery system was developed. A combination of floating and pulsatile principles of drug delivery system would have the advantage that a drug can be released in upper GI tract after a defined time period of no drug release. 47 A pulsatile drug delivery that can be administered at bed time but releases drug in early morning would be a promising chronotherapeutic system. The potential benefits of floating pulsatile drug delivery system: Advantages: Retention of drug delivery system in stomach prolongs overall. Acidic substance like aspirin cause irritation on the stomach wall when come into contact with it hence floating pulsatile formulation may be useful for administration of aspirin and other similar drugs. It has application also local drug delivery to the stomach and proximal small intestine e.g., ranitidine for nocturnal acid breakthrough. No risk of dose dumping 41. The formulation is to be taken after meal, where immediate release dose will provide from acid secretion in response to the meal; while time controlled floating pulsatile tablet with delay burst release will attenuate midnight acidity. This will provide an ideal therapeutic regimen with enhanced patient compliance. Floating pulsatile drug delivery system for obtaining no drug re-

5 lease during floating and rapid drug release in distal small intestine to achieve chronotherapeutic release e.g. indomethacin. Floating with no drug release in acidic medium by pulse drug release in basic medium. When there is vigorous intestine movement and 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 relative better response. Floating pulsatile drug delivery increase drug bioavaibility; predictable, reproducible, and improved generally short gastric residence time; no risk of dose dumping; local drug action; and the flexibility to blend dosage form with different composition and release pattern. Disadvantage: Drug which are irritant to gastric mucosa is also not desirable or suitable 47. The dosage form should be administered with full glass of water( ml) 48 Manufacturing this type of dosage form requires multiple formulation steps, higher cost of production, need of advance technology, and trained or skilled personnel needed form manufacturing. 3.1 Design of Floating Pulsatile Drug Delivery System The purpose of designing by which the drug is released from dosage form depends on the type of coating; insoluble coating under all physiological conditions, ph-dependent coating whose solubility changes dramatically at some point in GI tract, and slowly erodible coating. The method of application and processing conditions may influence the porosity of the coating and consequently the release mechanism. Patel S.R et al. / Journal of Pharmacy Research 2012,5(4), residence time and in (2) a pulsatile dosage form, in which the drug is released rapidly in a time-controlled manner after rupturing of the coating. Floating-pulsatile concept was applied to increase the gastric residence of the dosage form having lag phase followed by a burst release. 51 We generated the system which consisted of three different parts, a core tablet, containing the active ingredient; an erodible outer shell; and a top cover buoyant layer. The dry coated tablet consists in a drug-containing core, coated by a hydrophilic erodible polymer which is responsible for a lag phase in the onset of pulsatile release. The buoyant layer, prepared with HPMC K4M, Carbopol ; 934P, and sodium bicarbonate, provides buoyancy to increase the retention of the oral dosage form in the stomach. 3.4 Reservoir System With Rupturable Coating Reservoir-type delivery systems based on the expansion of the core have been evaluated for both floating delivery systems having a lower density than GI fluids, and for pulsatile systems in which the core expansion causes rupturing of the coating to allow rapid drug release.the major challenge was to develop a tablet which can float and also provide a burst release once the outer time-lagged coating ruptures 44. Krogel and Bodmeier developed floating and pulsatile drug delivery systems based on a reservoir system consisting of a drug-containing effervescent core and a polymeric coating. 53 Studies identified important core and coating properties for the two systems. The system consists of a drug-containing core tablet coated with a protective layer (HPMC), a gas-forming layer (sodium bicarbonate), and a gas-entrapped membrane, respectively 54. The mechanical properties of acrylic polymers (Eudragit ; RL 30D, RS 30D, NE 30D) and EC were characterized. Eudragit ; RL 30D was chosen as a gasentrapped membrane due to its high flexibility and high water permeability. 3.2 Time Controlling Floating Pulsatile Drug Delivery Time-dependent dosage forms are formulated to release their drug load after a predetermined lag time. The release mechanisms employed include bulk erosion of the polymer, in which drug by diffusion is restricted, surface erosion of layered devices composed of altering drug-containing and drugfree layers, and osmotically controlled erosion coating layer. 3.3 Reservoir System with Eroding Polymer or Soluble Barrier Coating A pulsatile-floating drug delivery system consists of three different parts, a core tablet, containing the active ingredient; an erodible outer shell; and a top cover buoyant layer, as 3.5 Capsule Shape System Provided With Release Controlling Plug The novel system consists of a drug tablet placed within an impermeable polymeric cylinder closed with an erodible drug-free plug and floating material filled at the bottom [figure 2]. When in contact with the aqueous fluids, the erodible drug-free plug is responsible for a lag phase preceding the onset of release and the floating material filled at the bottom is responsible for buoyancy properties of the formulation. Figure 4. Design of floating pulsatile release tablet shown in figure 4. One layer is for buoyancy and the other for drug pulsatile release. The pulsatile release system with various lag times was prepared by compression with different erodible polymeric layers. Combined usage of hydroxypropyl methylcellulose (HPMC) and carbomer in a gastric floating or mucoadhesive drug delivery system has been reported 49, 50 to improve the floating properties or mucoadhesiveness of the combined system. The novel system could result in (1) a floating dosage form with a prolonged gastric Figure 5: Schematic diagram of the floating pulsatile release delivery system with

6 Patel S.R et al. / Journal of Pharmacy Research 2012,5(4), release controlling plug A blend of floating and pulsatile principles of drug delivery system seems to present the advantage that a drug can be released in the upper GI tract after a definite time period of no drug release 55.System was to develop and evaluate a floating and pulsatile drug delivery system based on an impermeable cylinder. Pulsatile capsule was prepared by sealing the drug tablet and the buoyant material filler inside the impermeable capsule body with erodible plug.the drug delivery system showed typical floating and pulsatile release profile, with a lag time followed by a rapid release phase. The lag time prior to the pulsatile drug release correlated well with the erosion properties of plugs and the composition of the plug could be controlled by the weight of the plug. A multifunctional drug delivery system based on HPMC-matrices (tablets) placed within an impermeable polymeric cylinder 56 was developed. The release behavior of the different devices was investigated as a function of its viscosity grade, HPMC content, type of drug (chlorpheniramine maleate or ibuprofen), matrix weight, position of the matrix within the polymeric cylinder, addition of various fillers (lactose, dibasic calcium phosphate, or microcrystalline cellulose), and agitation rate of the release medium. 3.6 Multiparticulate Drug Delivery System Functional membranes (referred to as lag-time coating) are formed of a typical pellet or bead in a multiparticulate system with bi-modal pulse. It comprises of an external water-insoluble polymer (e.g., EC) or enteric polymer (e.g., hypromellose phthalate) over an immediate release drug layer, followed by a release control polymer over the timed pulsatile release drug layer applied on core granules. Figure 6: Schematic diagram of the floating multiparticulate pulsatile drug delivery system with multiple coating Multiparticulate systems are made by using this type of methods as systems based upon change in membrane permeability, systems with soluble or eroding polymer coatings, and systems based upon rupturable coating figure 6. Multiparticulate pulsatile release dosage forms like Reservoir systems with rupturable polymeric coatings, soluble or eroding polymer coatings and changed membrane permeability are having longer residence time in the GI tract and due to highly variable nature of gastric emptying process, may result in poor and bioavailability problems in vitro/in vivo relationship. In contrary, floating multiparticulate pulsatile dosage forms reside in stomach only and are not affected by variability of ph, local environment, or gastric emptying rate. Shaji and Patole developed a multiple-unit, floating-pulsatile drug delivery system (FPDDS) for obtaining no drug release during floating and in the proximal small intestine followed by pulsed, rapid drug release to achieve chronotherapeutic release of indomethacin 57. Badve et al. developed hollow calcium pectinate beads for floating-pulsatile release of diclofenac sodium or aceclofenac intended for chronopharmacotherapy 58. To overcome limitations of various approaches for imparting buoyancy, hollow/porous beads 59 were prepared by simple process of acid-base reaction during ionotropic crosslinking. In vivo studies by gamma scintigraphy determined on rabbits showed gastroretention of beads up to 5 hours. The floating beads provided expected two-phase release pattern with initial lag time during floating in acidic medium followed by rapid pulse release in phosphate buffer. Sharma and Pawar reported that a blend of floating and pulsatile principles of drug delivery system would have the advantage that a drug can be released in the upper GI tract after a definite time period of no drug release. A multiparticulate FPDDS was developed using porous calcium silicate (Florite RE ; [FLR]) and sodium alginate, for time- and site-specific drug release of meloxicam for chronopharmacotherapy of rheumatoid arthritis 38. Meloxicam was adsorbed on the FLR by fast evaporation of solvent from drug solution containing dispersed FLR. Drug adsorbed FLR powder was used to prepare calcium alginate beads by ionotropic gelation method. Floating time was controlled by density of beads and hydrophobic character of drug. Sher et. al. was to design a novel/conceptual delivery system using ibuprofen, anticipated for chronotherapy in arthritis with porous 60 material to overcome the formulation limits (multiple steps, polymers, excipients) and drug loading for a desired release profile suitable for in vitro investigations. This delivery system lies in the availability of maximum drug amount for absorption in the wee hours as recommended 61. Drug loading on porous carrier, synthesized by high internal phase emulsion technique using styrene and divinylbenzene, was done through solvent evaporation using methanol (M) and dichloromethane (DCM). This uniqueness helped in achieving the least drug release an ideal one, without using any release modifiers, making it distinct from other approaches/technologies for time-controlled release and for chronotherapy. Present work conceptualizes a specific technology has been conceptualized, based on combining floating and pulsatile principles to develop drug delivery system, 62 intended for chronotherapy in arthritis. This approach was achieved by using low-density microporous polypropylene, Accurel MP 1000 ;, as a multiparticulate carrier along with drug of choice ibuprofen. 3.7 Current and Future Development The development of floating pulsatile-release products is most challenging as to get the right drug to the right place at the right time. The novel FPDDS pays more attention on site- and time-specific drug delivery. In these systems, there is release of the drug after eroding or rupturing the polymer coating of dosage form. During the last two decades, technologies to ensure time-controlled floating pulsatile release of bioactive compounds or drug have been developed. 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