Chronpharmaceutics, pulsatile drug delivery system ...

Chronpharmaceutics/Asian Journal of Pharmaceutical Sciences 2010, 5 (5): 204-230

Chronpharmaceutics, pulsatile drug delivery system as current trend Hitesh Dalvadia, *, Jayvadan K Patelb a

C K Pithawalla Institute of Pharmaceutical Science and Research, Via Magdalla Port, Surat, India b Nootan Pharmacy College, Visnagar, Gujarat, India Received 24 May 2010; Revised 1 November 2010; Accepted 20 December 2010

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Abstract Current research in the field of drug delivery devices, pulsatile drug delivery system is the most interesting time and site-specific system. This system is designed for chronopharmacotherapy. Thus, to mimic the function of living systems and in view of emerging chronotherapeutic approaches, pulsatile delivery, which is meant to release a drug following programmed lag phase, has increasing interest in the recent years. Diseases wherein pulsatile drug delivery systems are promising include asthma, peptic ulcer, cardiovascular diseases, arthritis, attention deficit syndrome in children, and hypercholesterolemia. In pursuit of pulsatile release, various design strategies have been proposed, mainly including time controlling, stimuli induced, externally regulated and multiparticulate formulations. These systems are beneficial for the drugs having chronopharmacological behavior where night time dosing is required and for the drug having high first pass metabolism effect and having specific site of adsorption in gastrointestinal tract. This review will cover methods that have been developed to control drug delivery profile with different polymeric systems like time controlling, internal stimuli induced (temperature induced and chemical stimuli-induced), and external induced (magnetic fields, ultrasound, electric fields and light stimulation) and multiparticulate system. Special attention has been given to time controlled pulsatile drug delivery. Keywords: Time controlling; Stimuli induce; Multiparticulate; Floating pulsatile; Model drug use _____________________________________________________________________________________________________________

1. Introduction

pulsatile or staggered fashion. For this mode of delivery, it is assumed that constant plasma drug levels are not preferred and that an optimal therapeutic effect comes from a periodically fluctuating drug concentration. Two different methodologies have been broadly investigated as possible solutions to this challenge. One is the fabrication of a delivery system that releases its payload after a predetermined time delay or in pulses of predetermined sequences [7]. Pulsed or pulsatile drug release is defined as the rapid and transient release of a certain amount of drug molecules within a short time-period immediately after a predetermined off-release period [8]. Pulsatile release is commonly found in the body, for example during hormone release, in which a baseline release is combined with pulsed, one-shot type release within a short time range. The dependence of several diseases and body function on circadian rhythm is well known. A genetic control of a “master clock” located in the nucleus suprachiasmaticus has been recently proposed. Numerous studies conducted, suggest that pharmacokinetics, drug efficacy and side effects can be modified by following

With the advancement of the technologies in the pharmaceutical field, drug delivery systems have drawn an increasing interest over the last few decades. Nowadays, the emphasis of pharmaceutical galenic research is turned towards the development of more efficacious drug delivery systems with already existing molecule rather going for new drug discovery because of the inherent hurdles posed in drug discovery and development process [1]. This challenge has been met by a wide range of techniques, including osmotically driven pumps [2], matrices with controllable swelling [3], diffusion [4] or erosion rates [5], non-uniform drug loading profiles [6] and multi-layered matrices. A second major challenge has been the controlled delivery of compounds in a __________ *Corresponding author. Address: C K Pithawalla Institute of Pharmaceutical Science and Research, Via Magdalla Port, Nr. Malvan Mandir, Dumas Road, Gavior Gam, Surat 395007, India. Tel: +91-261-6587286; Fax: +91-261-272399 E-mail: [email protected]

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therapy matching the biological rhythm. Specificity in delivering higher amount of drug in a burst at circadian timings correlated with specific pathological disorder is a key factor to achieve maximum drug effect [9-11]. Particular rhythms in the onset and extent of symptoms were observed in diseases such as, bronchial asthma, myocardial infarction, angina pectoris, rheumatic disease, ulcer, diabetes, attention deficit syndrome, hypercholesterolemia, and hypertension [12]. Advantages and drawbacks of pulsatile drug delivery systems are shown on Table 1. The focus of the present review is primarily on the pulsatile drug delivery methodologies and the up coming technologies, which are being exploited on a new technique development. Circadian rhythm regulates many body functions in humans, viz., metabolism, physiology, behavior, sleep patterns, hormone production, etc. It has been reported of that more shocks and heart attacks occur during morning hours [13]. The level of cortisol is higher in the morning hours, and its release is reported to decline gradually during the day. Blood pressure is also reported to be high in the morning till late afternoon, and then drops off during night [14]. Patients suffering from osteoarthritis are reported to have less pain in the morning than night, while patients suffering from rheumatoid arthritis feel more pain in the morning hours. Nocturnal asthma, the circadian rhythm of asthma has been increased airway responsiveness and worsening of lung function. Symptoms typically occur between midnight and 8 am, especially around 4.00 am [15]. Normal gastric acid secretion follows a circadian rhythm with a sudden surge of gastric acidity when gastric pH level goes far below 4 for at least 1 h in the midnight [16]. Cholesterol synthesis is generally higher during the night time than during day light. The maximal production occurs early in the morning, i.e., 12 h after last meal. Studies with 3-hydroxy-3methylglutaryl-coenzyme A (HMG CoA) reductase inhibitors have suggested that evening dosing was more effective than morning dosing [17]. For instance, insulin is an example of a hormone that experiences triggered release in the body. Basal release of insulin stimulates the synthesis of proteins and

glycogen in muscle and adipose tissues. In addition, triggered insulin release occurs during and after the intake of foods to regulate blood glucose levels [7]. Pulsatile release of gastrointestinal hormones, stimulated by food in the gastrointestinal tract (GIT), generally causes the release of digestive enzymes from the pancreas and the stomach. Many other hormones, including follicle stimulating hormone (FSH), leutinizing hormone (LH), leutinizing hormone releasing hormone (LHRH), estrogen and progesterone, are released upon certain responses and are regulated in the body in a pulsatile manner. A continuous dose of hormones generally induces down-regulation of hormone receptors on the target cellular membranes and leads to undesired side effects in the body. Consequently, to prevent downregulation of hormone receptors and to achieve efficient therapeutic effects, triggered-release technologies are highly desirable. These systems will have application in fields such as insulin delivery, contraception, controlled animal breeding and growth promotion [18-19]. Table 1 Advantages and drawbacks of pulsatile drug delivery systems [12]. Advantages Predictable, reproducible and short gastric residence time Less inter- and intra-subject variability Improve bioavailability Reduced adverse effects and improved tolerability Limited risk of local irritation No risk of dose dumping Flexibility in design Improve stability Improve patient comfort and compliance Achieve a unique release pattern Extend patent protection, globalize product, and overcome competition Drawbacks Lack of manufacturing reproducibility and efficacy Large number of process variables Multiple formulation steps Higher cost of production Need of advanced technology Trained/skilled personal needed for manufacturing

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2. Methods for pulsatile drug delivery

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 [21]. The buoyant layer, prepared with Methocel K4M, Carbopol 934P and sodium bicarbonate, provides buoyancy to increase the retention of the oral dosage form in the stomach. The effect of the hydrophilic erodible polymer characteristics on the lag time and drug release was investigated. Developed formulations were evaluated for their buoyancy, dissolution and pharmacokinetic, as well gamma-scintigraphically. A certain lag time before the drug released generally due to the erosion of the dry coated layer. Floating time was controlled by the quantity and composition of the buoyant layer. Both pharmacokinetic and gamma-scintigraphic data point out the capability of the system of prolonged residence of the tablets in the stomach and releasing drugs after a programmed lag time. A dry coated drug delivery system with an impermeable cup, swellable top layer and pulsatile release. Develop a core-in-cup dry coated tablet, where the core tablet surrounded on the bottom and circumference wall with inactive material is proposed. The system consists of three different parts, a core tablet, containing the active ingredient, an impermeable outer shell and a top cover layer-barrier of a soluble polymer [22]. The core contained either diclofenac sodium or ketoprofen as model drugs. The impermeable coating cup consisted of cellulose acetate propionate and the top cover layer of hydrophilic swellable materials, such as polyethylene oxide, sodium alginate or sodium carboxymethyl cellulose. The effect of the core, the polymer characteristics and quantity at the top cover layer, on the lag time and drug release was investigated. That the system release of the drug after a certain lag time generally due to the erosion of the top cover layer. The quantity of the material, its characteristics (viscosity, swelling, gel layer thickness) and the drug solubility was found to modify lag time and drug release. The lag time increased when the quantity of top layer increased, whereas drug release

Methodologies for the pulsatile drug delivery system can be broadly classified into four classes. 2.1. Time controlled pulsatile release system Time-dependent dosage forms are formulated to release their drug load after a predetermined lag time. The action of a certain drug should coincide with the proper site and time for optimal effect. Therefore, the development of a time-controlled release system is desired for the treatment of patients. These systems are designed to release drug in pulses governed by the device fabrication and ideally, independent of the environment. 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 drug free layers, osmotically controlled erosion coating layer. 2.1.1. Delivery system provided with erodible coating layers In such systems the drug release is controlled by the dissolution or erosion of the outer coat which is applied on the core containing drug. Time dependent release of the active ingredient can be obtained by optimizing the thickness of the outer coat is shown in Fig. 1. Erodible coating layer

Core tablet Lag-time for drug release

Core tablet Start of drug release

Fig. 1. Schematic diagram of drug delivery with erodible coating layer.

Preparation of a dry coated drug delivery system with hydrophilic polymer. Hao Zou, et al. pulsatile concept was applied to increase the gastric residence of the dosage form having lag phase followed by a burst release [20]. We generated the system which 1 206 1


decreased. The use of sodium carboxymethyl cellulose resulted in the greatest swelling, gel thickness and lag time, but the lowest drug release from the system. Polyethylene oxide showed an intermediate behaviour while, the sodium alginate exhibited the smallest swelling, gel thickness and the shortest lag time, but the fastest release. These findings suggest that drug delivery can be controlled by manipulation of these formulations. L. ZEMA, et al when used as release-controlling coating agents for tableted core-based pulsatile delivery systems, three different hydroxypropyl methylcellulose (HPMC) grades, Methocel ® E5, E50, and K4M, provided lag phases of varying duration (Methocel ® K4M > E50 > E5) and a prompt and quantitative model drug release [23-24]. Dissolution/mechanical erosion, permeability increase and disruption of the hydrated polymeric layer were assumed to participate in the definition of the overall release pattern. Based on these premises, we investigated what process(es) might prevail in the release-controlling mechanism for each HPMC grade. The polymers were evaluated for dissolution and swelling, while the finished systems were concomitantly evaluated for drug release and polymer dissolution. The obtained results indicated likely similarities between Methocel® E5 and E50 performances, which we hypothesized to be mainly dissolution/erosion-controlled, and a clearly different behavior for Methocel® K4M. This polymer indeed proved to yield higher viscosity and slower dissolving gel layer, which was able to withstand extensive dissolution/erosion for periods that exceeded the observed lag phases. The particular characteristics of swollen Methocel® K4M were shown to be associated with possible drug diffusion phenomena, which might impair the prompt and quantitative release phase that is typical of pulsatile delivery. C. Guse, et al the study was to develop programmable implants with a reproducible delayed onset of release followed by several weeks of controlled release. For this purpose, a drug-loaded core was embedded into a drug-free bulk-eroding [25] poly (D,L-lactic-coglycolic acid) or poly(D,L-lactic acid) mantle [26]. The manufacturing procedure was established and optimized

for three mantle materials, which showed delay times ranging from 7 to 83 d. Triglycerides with fatty acid chain lengths from C12 to C18 were investigated as core materials, producing release periods from 2 to 16 weeks. Concomitantly, applying a convolution/deconvolution model showed the possibility of theoretical prediction of the resulting release profiles. Manish Ghimire, et al the current study was to investigate the in-vitro and in-vivo performance of a press-coated tablet (PCT) intended for time delayed drug release, consisting of a rapidly disintegrating theophylline core tablet, press-coated with barrier granules containing glyceryl behenate (GB) and lowsubstituted hydroxypropylcellulose (L-HPC) [27]. The Tablet showed pulsatile release with a lag time dependent upon the GB and L-HPC composition of the barrier layer. In-vivo γ-scintigraphic studies were carried out for Tablets containing GB: L-HPC in different concentration in the barrier layer in four beagle dogs, in either the fed or fasted state. The invivo lag time in both the fed and fasted states did not differ significantly (P > 0.05) from the in-vitro lag time. Additionally, no significant difference (P < 0.05) between in vivo fed and fasted disintegration times was observed, demonstrating that in-vivo performance of the tablet was not influenced by the presence or absence of food in the GIT. A distinct lag time was obtained prior to the appearance of drug in plasma and correlated (R2 = 0.98) with disintegration time observed from scintigraphic images. However, following disintegration, no difference in pharmacokinetic parameters (AUC0–6 dis, Ke, Cmax) was observed. The current study highlighted the potential use of these formulations for chronopharmaceutical drug delivery. 2.1.2. Delivery system provided with reputable coating layer Most pulsatile delivery systems are reservoir devices coated with a rupturable polymeric layer. Upon medium ingress, drug is released from the core after rupturing of the surrounding polymer layer, due to pressure buildup within the system. The pressure necessary to rupture the coating can be achieved with swelling agents, gas1 207 1


solution and the in vivo release rate was better reflected by that performed in pH 6.8 buffer. Hoda A. El-Maradny, et al developed pulsatile tablets consisting of core coated with two layers of swelling and rupturable coatings [29]. Cores containing the drug were prepared by direct compression using microcrystalline cellulose and Ludipress as hydrophilic excipients with the different ratio. Cores were then coated sequentially with an inner swelling layer of different swellable materials; either Explotab, croscarmellose sodium, or starch RX 1500, and an outer rupturable layer of different levels of ethyl cellulose. The effect of the nature of the swelling layer and the level of the rupturable coating on the lag time and the water uptake were investigated. Lag time and water uptake prior to tablet rupture on the nature of the swelling layer and the coating levels. Increasing the level of ethylcellulose coating retarded the diffusion [30] of the release medium to the swelling layer and the rupture of the coat, thus prolonging the lag time. Ying Zhu, et al developed theophylline pulsatile release tablets consisting of a fast swelling core with water-insoluble ethyl cellulose [31]. Effects of coating material, the amount of the plasticizer, subcoating, the type of the disintegrant, and coating level on the release profiles were investigated. Rupture time increased with increasing the amount of the plasticizer. Tablets with Methocel® E50 as subcoating was most optimal in order to achieve a long lag time and followed by a rapid release. The lag time of tablets containing different disintegrants increased in the following order: croscarmellose (Ac-Di-Sol®) low-substituted hydroxypropyl cellulose (L-HPC) > sodium starch glycolate (Explotab®) > crospovidone (Kollidonw CL) > hydroxypropyl methylcellulose (Methocel® K100M). A linear correlation existed between the swelling energy and the water uptake. The swelling behavior of Ac-Di-Solw depended on the ionic strength and the pH of the medium due to a competition for free water and the acidic nature of this polymer. The swelling behavior and the rupture of the outer polymeric coating of a pulsatile drug delivery system were demonstrated in simulation tests. Formulation variables affecting the performance of a rupturable capsule-based drug delivery system with pulsatile drug release. A. Dashevsky et al the system consisted of a drug-containing hard gelatin capsule, a swelling layer of croscarmellose (Ac-Di-Sol1) and a binder, and an outer ethylcellulose coating [36,37]. The capsule-to-capsule uniformity in the amount of swelling layer and outer ethylcellulose coating, which significantly affected the lag time prior to rupture of the capsule, decreasing the batch size, and by increasing the rotational pan speed and the distance between the spray nozzle and the product bed. The type of baffles used in the coating pan also affected the layering uniformity. Fully-filled hard gelatin capsules had a shorter lag time with a higher reproducibility compared to only half-filled capsules, because the swelling pressure was directed primarily to the outer ethylcellulose coating and not to the inner capsule core. 2.1.3. Capsule shaped system provided with release controlling plug Several pulsatile dosage forms with a capsular design have been developed. Most consist of an insoluble capsular body (shown Fig. 2), which contains the drug, and a plug, which is removed after a predetermined lag time because of swelling, erosion or dissolution. The leg time controlled by plug, which gets pushed away by swelling or erosion, and the drug is release from the insoluble capsule body. 1 209 1


correlated well with the erosion properties of plugs and the composition of the plug could be controlled by the weight of the plug. The buoyancy of the whole system depended on the bulk density of the dosage form. Gamma-scintigraphic evaluation in humans was used to establish methodology capable of showing the subsequent in vivo performance of the floating and pulsatile release capsule. Programmed drug delivery of a novel system, which contains a water-soluble cap, impermeable capsule body [40], and two multi-layered tablets [41]. Sodium alginate and hydroxy-propyl methyl cellulose (HPMC E5) as the candidate modulating barrier material. Through adjusting ratio of sodium alginate and lactose, lag time was controllable between the first two pulsatile release. Through adjusting the ratio of HPMC E5/ lactose, lag time between the second and the third pulse can be successfully modulated. Drug release rate of the second pulsatile dose can be improved by adding a separating layer between the third and the modulating barrier layer in the three-layered tablet. To contribution of bulking agent to drug release rate, lactose, sodium chloride, and effervescent blend were investigated. Programmed drug delivery to achieve pulsatile drug release for three times daily can be obtained from these tablets in capsule system by systemic formulation approach. J. T. Mc Conville, et al investigated an erodible tablet (ET), sealing the mouth of an insoluble capsule, controlled the lag-time prior to drug release [5,42]. The time-delayed capsule (TDC) lag-time may be altered by manipulation of the excipients used in the preparation of the ET. Erosion rates and drug release profiles from TDCs were prepared with four different excipient admixtures with lactose: calcium sulphate dihydrate (CSD), dicalcium phosphate (DCP), hydroxypropylmethyl cellulose (HPMC; Methocel K100LV grade) and silicified microcrystalline cellulose (SMCC; Prosolv1 90 grade). Capsule integrity was confirmed to be most suitable for oral delivery when the insoluble ethyl cellulose coat was applied to a hard gelatin capsule using an organic spray coating process. The novel time delayed capsule device may be assembled to include an erodible tablet with a known concentration

Fig. 2. Schematic diagram of drug delivery with release controlling plug.

Nayak, et al developed pulsatile capsule dosage form of valsartan for controlled delivery. In the majority of individuals blood pressure rises in the early morning hours, which lead to serious cardiovascular complications [38]. The prepared system contained swellable polymer (L-hydroxypropyl cellulose (L-HPC), xanthan gum, polyethylene oxide or sodium alginate) together with drug tablet and erodible tablet (L-HPC or guar gum) in a pre-coated capsule. The type, amount of polymers and erodible tablet influenced the drug release. The formulation containing sodium alginate and erodible tablet containing 50% guar gum and 46% lactose showed 5–6 h lag time and drug release in initial 6 h following rapid release of drug was observed. The continuous dissolution–absorption study conducted using everted rat intestinal segment indicated delay in absorption of drug. Thus this approach can provide a useful means for timed release of valsartan and may be helpful for patients with morning surge. Development of 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 GIT after a definite time period of no drug release. Pulsatile capsule was prepared by sealing the drug tablet and the buoyant material filler inside the impermeable capsule body with erodible plug [39]. 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 1 210 1


Raimar Löbenberga, et al. were to investigate differences in the pharmacokinetic patterns among a pulsatile drug delivery system using a pulsatile capsule, an immediate release tablet and a controlled release tablet [47]. The dosage forms were administered to four dogs and the plasma levels were measured using LC-MS/MS. Pharmacokinetic parameters were determined for each dosage form. The pulsatile drug delivery capsule caused two defined Cmax values for each dose between 1–1.75 and 2.5–3.5 h. Implications for the use of a pulsatile drug delivery device for chronopharmacotherapy are discussed. Pulsatile drug delivery offers a promising way for chronopharmacotherapy if the time of administration and pulse time are adjusted to the circadian pattern.

of HPMC. A variety of suitable drugs for targeted chronopharmaceutical therapy can be incorporated into such a device, ultimately improving drug efficacy and patient compliance, and reducing harmful side effects. M. C. Gohel, et al obtained programmed drug delivery from hard gelatin capsules containing a hydrophilic plug (HPMC or guar gum). A chronpharmaceutical capsule with erodible plug drug delivery system capable of releaseing drug after predetermined time delays. The drug formulation is sealed inside the insoluble body by erodible tablet (erodible plug). The significance of factors such as type of plug (powder or tablet), plug thickness and the formulation of fill material on the release pattern of diltiazem HCl [43-44]. The body portion of the hard gelatin capsules was crosslinked by the combined effect of formaldehyde and heat treatment. The plugs of HPMC in tablet form, with or without a 3 water soluble adjuvant (NaCl or lactose) were used for obtaining immediate drug release after the lag time. The capsules containing HPMC K15M tablet plug and effervescent blend in body portion of the capsule met the selection criteria of less than 10% drug release in 4 h and immediate drug release thereafter. Programmable pulsatile release has been achieved from capsule device over a 2–12 h period, consistent with the demands of chronpharmaceutic drug delivery. The time of drug release can be controlled by manipulation of plug formulation. Howard N.E. Stevens et al, Pulsincap™ formulations designed to deliver a dose of drug following a 5-h delay were prepared to evaluate the capability of the formulation to deliver dofetilide to the lower GIT [45,46]. Plasma analysis permitted drug absorption to be determined as a function of GIT site of release. Dofetilide is a well-absorbed drug, but showed a reduction in observed bioavailability when delivered from the Pulsincap™ formulations, particularly at more distal GIT sites. Dispersion of the drug from the soluble excipient used in this prototype formulation relies on a passive diffusion mechanism and the relevance of this factor to the reduced extent and consistency of absorption from the colon is discussed. The scintigraphic analysis demonstrated good in vitro–in vivo correlation for time of release from Pulsincap™ preparations.

2.2. Internal stimuli induced pulsatile release system Responsive drug release from those systems results from the stimuli-induced changes in the gels or in the micelles, which may deswell, swell, or erode in response to the respective stimuli. There has been much interest in the development of stimuli- sensitive delivery system that releases therapeutic agents in presence of specific enzyme or protein. In these systems there is release of the drug after stimulation by any biological factor like temperature or any other chemical stimuli. K. S. Soppimath, et al had done research activity in the development of stimulus-responsive polymeric hydrogels. These hydrogels are responsive to external or internal stimuli and the response can be observed through abrupt changes in the physical nature of the network. The stimuli can be temperature, pH, ionic strength, etc. [48]. A majority of the literature related to the development of stimulus-responsive drug delivery systems deals with temperature sensitive poly(N-isopropyl acrylamide) (pNIPAAm) and its various derivatives. However, acrylic-based pH-sensitive systems with weakly acidic/basic functional groups have also been widely studied. Quite recently, glucose-sensitive hydrogels that are responsive to glucose concentration have been developed to monitor the release of insulin. Recent developments in the area of stimulus-responsive hydrogels, particularly those that respond to temperature and pH, and their applications in drug delivery. 1 211 1


2.2.1. Temperature–induced pulsatile release

importance in the control of hydrogel swelling and drug release from thermosensitive hydrogels. G. Lewis, et al prepared poly (N-isopropylacrylamide) hydrogel spheres, which exhibited an LCST of 32˚C. The core-shell polyamide microcapsules were prepared from ethylenediamine and terephthaloyl dichloride by interfacial polymerization. First, the organic phase containing terephthaloyl dichloride was added to the water phase containing sodium dodecyl sulfate (SDS) as an emulsifier. Different types of mixed organic solvents were used. Then, the mixture was mechanically agitated for 10 min with a stirring speed of 800 r/min to yield an oil-in-water emulsion [54]. The stirring speed was then reduced to 200 r/min, and both the buffer and ethylene diamine were added to the emulsion, and the mixture further stirred. During emulsification and interfacial polymerization, the temperature was kept at a constant 10˚C using a thermostatic unit. The microcapsules were separated by centrifugation, and washed three times using deionized water in order to remove any emulsifier and remnants of the monomer. Liangyin Chu, et al developed a thermo-responsive core-shell microcapsule with a porous membrane and poly(N-isopropylacrylamide) (PNIPAM) gates was prepared using interfacial polymerization to prepare polyamide core-shell microcapsules, and plasma-graft pore-filling polymerization to graft PNIPAMinto the pores in the microcapsule wall. The proposed thermoresponsive microcapsule could be a positive thermoresponse controlled-release one or a negative thermoresponse one by changing the PNIPAM graft yield [55]. When the graft yield is low, the release rate from the microcapsules is higher at temperatures above the lower critical solution temperature (LCST) than that below the LCST, due to the opened/closed pores in the microcapsule membranes controlled by the PNIPAM gates. In contrast, when the graft yield is high, the release rate is lower at temperatures above the LCST than that below the LCST, due to the hydrophilic/ hydrophobic phase transition of the PNIPAM gates. Temperature-sensitive poly (N-isopropylacrylamide)g-poly (L-lactide-co-ε-caprolactone) nanofibers was developed By Sung In Jeong. PLCL was synthesized as previously described. Equal molar amounts of L-lactide

Temperature is the most widely utilized triggering signal for a variety of triggered or pulsatile drug delivery systems. The use of temperature as a signal has been justified by the fact that the body temperature often deviates from the physiological temperature (37 ˚C) in the presence of pathogens or pyrogens. This deviation sometimes can be a useful stimulus that activates the release of therapeutic agents from various temperature-responsive drug delivery systems for disease accompanying fever. Thermal stimuli-regulated pulsed drug release is established through the design of drug delivery device such as hydrogels and micelles. 2.2.1.1. Thermoresponsive hydrogel systems The drug delivery systems that are responsive to temperature utilize various polymer properties, including the thermally reversible coil/globule transition of polymer molecules [49], swelling change of networks [50], glass transition and crystalline melting [51]. The dried hydrogel discs were loaded by sorption of an aqueous or ethanolic drug solution, followed by solvent removal in a dessicator at room temperature to entrap the drug molecules. Loading of diltiazem HCl was % w/w based on dried hydrogel disc (of drug). Loading content was controlled by complete sorption of a known volume of drug solution for 48 h in a suitable glass vial before drying out [52,53]. Hydrogels were loaded with drug and thermally triggered swelling/ deswelling and release were performed. The hydrogel swelling rate was slowed by the presence of the hydrophobic drugs and this decreased rate was solubility dependant for the benzoates. In all cases, the magnitude and rate of hydrogel contraction were proportional to the extent of swelling prior to temperature switch. Drug release was by diffusion below the lower critical solution temperature (LCST), while a solubilitydependent drug pulse release on temperature switch was observed for the hydrophobic series. The hydrophilic series produced a molecular size-dependent drug pulse on temperature switch above the LCST. Drug solubility, size and chemical nature were shown to be of particular 1 212 1


and ε-caprolactone were co-polymerized, using stannous octoate (1 mmol) as a catalyst, at 150˚C for 24 h in a 50 ml glass ampoule under anhydrous conditions. After the reaction, the product was dissolved in chloroform and micro-filtered, and the purified solution was reprecipitated with an excess amount of methanol [56]. The molar ratio of lactide to caprolactone in the final product was determined by nuclear magnetic resonance spectroscopy. Gel permeation chromatography confirmed that the number average (Mn) and weight average (Mw) molecular weights were 271,000 and 348,000, respectively. Specifically, the PLCL solution was loaded in a 20 ml glass syringe equipped with a blunt 23 gauge needle. The glass syringe was then placed in a syringe pump and the needle was connected to the positive output of a high voltage power supply [57]. The polymer solution was then electrospun directly to the aluminum foil wrapping around the ground collector (9 cm in diameter), located at a fixed distance of 20 cm from the needle, at room temperature (RT). The flow rate of the solution, applied voltage, and spinning time were set to 2 ml/h, 18–20 kV, and 24 h, respectively. And N-isopropylacrylamide (NIPAAm) was then grafted onto their surfaces under aqueous conditions using 60Co-γ irradiation. The graft yield increased with increasing irradiation dose from 5 to 10 kGy. Unique temperature-responsive swelling behavior of PNIPAAm-g-PLCL nanofibers, showing the ability to absorb a large amount of water at < 32˚C, and abrupt collapse when the temperature was increased to 40˚C. R . Yo s h i d a s t u d i e d t h e p o l y m e r p o l y (N-isopropylacrylamide) gel has negative temperature dependency of swelling behavior in aqueous solution. In this study, IPAAm copolymer gel was utilized to design positive thermosensitive pulsatile drug release system to induce drug release with increasing temperature and stop the release with decreasing temperature [58,59]. Skin structure of the shrunken gel at higher temperature was controlled by introduction of hydrophilic acrylamide to allow drug release. Using an impermeable capsule equipped with a release orifice, positive thermosensitive pulsatile release was achieved by diffusion area-regulating mechanism, which was

different from surface-regulating mechanism to achieve conventional negative thermosensitive pulsatile release. A new concept to convert negative thermosensitivity of IPAAm gels to positive thermosensitive pulsatile release has been demonstrated. 2.2.1.2. Thermoresponisve polymeric micelle system Jianxiang Zhang, et al synthesized thermally responsive amphiphilic poly(N-isopropylacrylamide) (PNIPAm)-grafted-polyphosphazene (PNIPAm-gPPP) by stepwise cosubstitution of chlorine atoms on polymer backbones with amino-terminated NIPAm oligomers and ethyl glycinate (GlyEt) [60]. Poly (dichlorophosphazene) was synthesized by thermal ring-opening polymerization and polymer was purified by dissolving in toluene and precipitating into dry petroleum ether. Oligo-PNIPAm in dry THF containing dry triethylamine was added drop wise into poly (dichlorophosphazene) in THF (20 ml), and reaction solution was stirred magnetically at room temperature. After 24 h, excess amount of GlyEt in THF (20 ml) together with freshly distilled triethylamine was added slowly into the reaction mixture, which was stirred for 48 h. The solution was filtered, and after the filtrate was concentrated, it was poured into diethyl ether to obtain a precipitate. The lower critical solution temperature (LCST) of PNIPAm-g-PPP was observed to be 30˚C in water. Diflunisal (DIF)-loaded micelles were prepared by dialysis method. In vitro release test at various temperatures was also performed to study the effect of temperature on the drug release profiles. It was demonstrated that DIF release from PNIPAm-g-PPP micelles was slower at the temperature of 37˚C than that at 4˚C. Hu Yan, et al have developed rapidly thermoresponsive NIPA gel containing polymer surfactant PMDP (NIPA-PMDP gel) as a potential drug carrier using (+)-l-ascorbic acid. In the NIPA-PMDP gel system micelles of polymer surfactant PMDP (shown Fig. 3A and 3B) are trapped by the entanglement of polymer chains inside the gel networks [61]. The NIPAPMDP gels were repeatedly washed by immersion in pure water for several days. The NIPA gels were similarly synthesized but without PMDP. Therefore, in 1 213 1


2.2.2. Chemical stimuli induced pulsatile systems

principle the gel system tightly stores targeted drug in the micelles and rapidly releases controlled amount of the drug by switching on–off of external stimuli such as temperature or infrared laser beam. The conventional NIPA gel released more slowly limited amount of the drug above the phase transition temperature while similarly did to the NIPA-PMDP gel below the temperature (shown Fig. 4). Mixed micelles formed from graft and diblock copolymers for application in intracellular drug delivery [62], A novel mixed micelle that comprised of poly(N-isopropylacrylamide-co-methacrylic acid)graft- poly(D,L-lactide) (P(NIPAAm-co-MAAc)-gPLA) with methoxy poly(ethylene glycol)-β-poly(D,Llactide) (mPEG-β-PLA) was developed for application in cancer therapy. The mixed micelle had an multifunctional inner core of P(NIPAAm-co-MAAc)-g-PLA to enable intracellular drug delivery and an extended hydrophilic outer shell of mPEG to hide the inner core. A change in pH deformed the structure of the inner core from that of aggregated P (NIPAAm-co-MAAc), causing the release of a significant quantity of Dox from mixed micelles. Clear differences between free Dox and Dox-mixed micelles were observed using confocal laser scanning microscopy (CLSM).

2.2.2.1. Glucose-responsive insulin release devices There has been much interest in the development of stimuli-sensitive delivery system that releases therapeutic agents in presence of specific enzyme or protein. In these systems there is release of the drug after stimulation by any biological factor like enzyme, pH or any other chemical stimuli. Kazunori Kataoka, et al a remarkable change in the swelling induced by glucose was demonstrated for the gel composed of PNIPAAm with phenylboronic acid moieties. On-off regulation of insulin release from the gel was achieved through a drastic change in the solute transport property as a result of the formation and disruption of the surface barrier layer of the gel [63]. This novel type of glyco-sensitive gel may have potential utilities in self-regulated drugreleasing systems as well as in other applications such as actuators, regulators, and separation systems with glyco-sensitivity. The fabrication of insulin delivery systems for the treatment of diabetic patients. Delivering insulin is different from delivering other drugs, since insulin has to be delivered in an exact amount at the exact time of need. Many devices have been developed for this purpose and all of them have a glucose sensor built into the system. In a glucose-rich environment, such as the bloodstream after a meal, the oxidation of glucose to gluconic acid catalysed by glucose oxidase can lower the pH to approximately 5.8. This enzyme is probably the most widely used in glucose sensing, and makes possible to apply different types of pHsensitive hydrogels for modulated insulin delivery [64]. This pH change induces swelling of the polymer which results in insulin release. Insulin by virtue of its action reduces blood glucose level and consequently gluconic

(A)

CH

H2 C

In these systems the polymer undergoes swelling or deswelling phase in response of chemical reaction with membrane, alteration of pH and Inflammation induce, release drug from polymer by swelling the polymer. Chemical stimuli are shown Table 2.

O HN CH

CH3

H3 C

N-Isopropylacrylamide (NIPA) (B)

H

CH3

C

C

n

H

C

O H

O

C H

O 10

O

P

OH

OH

Poly(2-(Methacryloyloxyl)decylphosphate) (PMDP) Fig. 3. Chemical structure of NIPA polymer (A) and PMDP polymer (B) surfactant.

1 214 1


acid level also gets decreased and system turns to the deswelling mode thereby decreasing the insulin release. Seong L Kang, et al developed a new glucosesensitive hydrogel, based on sulfonamide chemistry with covalently conjugated glucose oxidase and catalase [65], was synthesized and tested. The pH-induced full swelling transition of the gel occurred in the range of pH 6.5/7.5. In a glucose concentration range of 0–300 mg/dl in an isotonic phosphate buffered saline solution, the pH inside the gel varied from pH 7.4 to 7.2. At the same glucose concentration range, the gel showed reversible glucose dependent swelling without hysteresis from 12 to 8, expressed in water (g) /polymer (g). Hua Li, et al developed a multi-effect-coupling glucose-stimulus (MECglu) model and solved numerically for the swelling behavior of soft hydrogels responding to changes in the environmental glucose

concentration. The effect of the glucose oxidation reaction catalyzed by enzymes including glucose oxidase and catalase. The formulation of the fixed charge groups bound onto the cross-linked polymer network is associated with the change of the ambient solution pH [66]. A parameter study is then conducted by steady-state simulations to ascertain the impact of various solvent parameters on the responsive swelling behavior of the hydrogel. One key parameter is the glucose concentration, which is varied within the range of practical physiological glucose concentrations from 0 to 16.5 mM (300 mg/ml) to support the design of an insulin delivery system based on a glucose-sensitive hydrogel with immobilized glucose oxidase and catalase. Jung Ju Kim, et al used glucose-sensitive hydrogels that undergo sol–gel phase transition to develop

Polymerization PMDP

NPA Micelles of PMDP NPA-PMDP gel Fig. 4. A schematic showing the synthesis step of NIPA-PMDP gel..

Table 2 Effect of different chemical stimuli on the release of drug from smart hydrogels [48]. Stimulus

Hydrogel

Type release mechanism

pH

Acidic or basic hydrogel

Change in pH—swelling—release of drug

Ionic strength

Ionic hydrogel

Change in ionic strength—change in concentration of ions

Chemical species Hydrogel containing electron-accepting groups

Electron-donating compounds—formation of charge-transfer complexes—change in swelling—release of drug

Enzyme substrate

Hydrogel containing immobilized enzymes

Substrate present—enzymatic conversion—product changes swelling of gel—release of drug

Magnetic

Magnetic particles dispersed in microspheres

Applied magnetic field—change in pores in gel—change in swelling—release of drug

Thermal

Thermo-responsive hydrogel

Change in temperature—change in polymer–polymer and water –polymer interactions—change in swelling—release of drug

Electrical

Polyelectrolyte hydrogel

Applied electric field—membrane charging—electrophoresis of charged drug—change in swelling—release of drug

1 215 1


modulated insulin delivery systems. Glucose-sensitive hydrogels were prepared by mixing glucose-containing polymers and PEGylated concanavalin A (Con A). Glucose was incorporated into the polymer backbone by copolymerization of allyl glucose with comonomers [67], such as 3-sulfopropylacrylate, potassium salt (SPAK), N-vinyl pyrrolidone (VP), and acrylamide (AM). Con A grafted with five PEG molecules were used to improve the stability of Con A. Three different types of insulin delivery systems were examined: diffusion-controlled reservoir, diffusion-controlled matrix, and erosioncontrolled matrix systems. Insulin release through the glucose-sensitive hydrogel membrane and from the glucose-sensitive hydrogel matrix was dependent on the glucose concentration in the receptor chamber. As the glucose concentration was increased from 1 to 4 mg/ ml, the release rate increased. The insulin release rate decreased as the glucose concentration was reduced to 1 mg/ ml. Modulated insulin release was achieved using the glucose-sensitive membrane and matrix systems. On the other hand, the glucose-sensitive erodible system did not show modulated release as the glucose concentration was changed between 1 and 4 mg/ml.

Which containing polyethylene glycol and Eudragit S was added slowly to allow it to dissolve. To this mixture a disintegrant may be added. The coating suspension was applied to capsule [68]. The system is based on the non-percolating incorporation of disintegrants in a coating which consists further of a continuous matrix of pH-responsive polymer (Eudragit S). A proof-ofconcept study in human subjects was performed to investigate the performance of the new system in vivo. Coated capsules containing the stable isotope 13C6glucose as the test compound were administered and the occurrence of 13CO2 in the breath of the subjects was measured. It could be shown that the coating is able to resist the environmental conditions in the stomach and duodenum and delay release until deeper parts of the intestines are reached. Furthermore, the capsule is able to maintain a pulsatile release profile. Mastiholimath, et al attempted to make pulsatile device to achieve time and/or site specific release of theophylline, based on chronopharmaceutical consideration. The basic design consists of an insoluble hard gelatin capsule body, filled with eudragit microcapsules of theophylline and sealed with a hydrogel plug. The entire device was enteric coated, so that the variability in gastric emptying time can be overcome. The theophylline microcapsules were prepared with Eudragit L-100 and S-100 by varying drug to polymer ratio and evaluated. Different hydrogel polymers were used as plugs, to maintain a suitable lag period and it was found that the drug release was controlled by the proportion of polymers used. So, by using the mixture of the polymers, i.e. Eudragit L and Eudragit S in proper proportion, pH dependent release was obtained [69,70]. Programmable pulsatile, colonspecific release has been achieved from a capsule device over a 2–24 h period, consistent with the demands of chronotherapeutic drug delivery. H. N. Shivakumar et al developed a pH sensitive tablet in capsule system intended to approximate the chronobiology nocturnal asthma is proposed for site specific release. The system comprising of Eudragit S-100 coated minitablets was designed for chronotherapeutic delivery of theophylline in view to specifically target the nocturnal peak symptoms of asthma [71]. The drug-

2.2.2.2. pH sensitive drug delivery system pH-sensitive polymers are polyelectrolytes that bear in their structure weak acidic or basic groups that either accept or release protons in response to changes in environmental pH. In case of pH dependent system advantage has been taken of the fact that there exists different pH environment at different parts of the GIT. By selecting the pH dependent polymers drug release at specific location can be obtained. Examples of pH dependent polymers include cellulose acetate phthalate, polyacrylates, sodium carboxy methyl cellulose. These polymers are used as enteric coating materials so as to provide release of drug in the small intestine. R.C.A. Schellekens, et al developed new systems for site-specific pulsatile delivery in the ileo-colonic regions are described. The capsules were manually filled with a premix of active ingredient and excipients (Avicel PH100 and colloidal anhydrous silica). The capsules were coat with different coating suspensions. 1 216 1


loaded core minitablets [72] were produced by wet granulation procedure using alcoholic solution of PVP K30 as a binder. Different coat weights of Eudragit S100 were applied to the drug loaded core minitablets in a conventional coating pan to produced pH sensitive minitablets. SEM revealed distinct continuous acrylic coat free from cracks or pores. In vitro dissolution preformed pH progression method demonstrated that the drug release from the coated minitablets depended on the coat weights applied and pH of the dissolution media. Hongfei Liu, et al, prepared the salbutamol sulfate pulsatile-release capsules with the pH-sensitive ion exchange resin as the carriers [73]. Investigated the pharmacokinetics of the salbutamol sulfate pulsatilerelease capsules in beagle dogs. The pharmacokinetics parameters of pulsatile-release salbutamol sulfate and reference tablet were AUC0-24 (ng·h/ml), Cmax (ng/ml) 172.4 ± 21.4, 179.3 ± 26.1, tmax (h), tlag (h) 2.7 ± 0.5, 0.3 ± 0.2. The results showed that the test dosage forms was bioequivalent with reference dosage form, and had an obviously pulsatile-release effect. L.Y. Qiu, et al developed cylindrical dosage form comprising a laminated composite polymer core and a hydrophobic polycarbonate coating was proposed for programmable drug delivery. In the core, poly[(ethyl glycinate) (benzyl amino acethydroxamate) phosphazene] was synthesized as drug-loaded layers for its strong pHsensitive degradation [74]. Poly(sebacic anhydride)b-polyethylene glycol or poly(sebacic anhydride-cotrimellitylimidoglycine)-b-poly(ethylene glycol) was selected as isolating layers for their good processing properties at room temperature and suitable erosion duration. The cooperative effect of polyanhydrides and pH-sensitive degradable polyphosphazene was specially demonstrated, which offers a new idea to develop a programmable drug delivery system for single dose vaccine and other related applications.

are produced from these inflammation-responsive cells. When human beings receive physical or chemical stress, such as injury, broken bones, etc., inflammation reactions take place at the injured sites. At the inflammatory sites, inflammation-responsive phagocytic cells, such as macrophages and poly morphonuclear cells, play a role in the healing process of the injury. During inflammation, hydroxyl radicals (OH) are produced from these inflammation-responsive cells [75]. 2.3. Externally regulated pulsatile release In this drug delivery are not self-operated, but instead required externally generated environmental changes to initiate drug delivery. These can include magnetic fields, ultrasound, electric field, light, and mechanical force. Developed lipid-coated microgels for the triggered release of drugs. Ionic microgels are synthesized from the monomers of methylenebisacrylamide (MBAM), methylacrylic acid (MAA) and 4-nitrophenyl methacrylate (NPMA) and coated with a lipid bilayer. The release of drug is triggered from the gels using either lipid solubilizing surfactants or electroporation [76]. The described the events for the swelling and release of drugs in three stages: i) the permeability of the membrane might be sufficiently compromised, but only to an extent that allows proton efflux from the microgel and a sodium ion influx into the gel particle; ii) microgel begins to swell due to occurrence of exchange process, allowing additional ions to be transported across the membrane and so that disruption of membranes causes uncoating of microgel; and iii) drug is exchanged from the hydrogel by Na+ ions and diffuse down its concentration gradient out of the expanded polymer network into the surrounding medium over a period of time, resulting in a triggered release. 2.3.1. Magnetic induces release

2.2.2.3. Inflammation-induced pulsatile release Magnetic carriers receive their magnetic response to a magnetic field from incorporated materials such as magnetite, iron, nickel, cobalt etc. For biomedical applications, magnetic carriers must be water-based,

On receiving any physical or chemical stress, such as injury, fracture etc., inflammation take place at the injured sites. During inflammation, hydroxyl radicals 1 217 1


biocompatible, non-toxic and non-immunogenic. Christopher S. Brazel, et al has development of magnetothermally-triggered drug delivery systems, whereby magnetic nanoparticles are combined with thermally-activated materials. By combining superparamagnetic nanoparticles with lower critical solution temperature (LCST) polymers, an alternating current (AC) magnetic field can be used to trigger [77] localized heating in vivo, which in turn causes a phase change in the host polymer to allow diffusion and release of drugs. The use of magnetic nanoparticles for biomedical applications as well as the design of thermally-activated polymeric systems. Magnetic-sensitive behavior of intelligent ferrogels for controlled release of drug by Tingyu Liu, et al. An intelligent magnetic hydrogel (ferrogel) was fabricated by mixing poly(vinyl alcohol) (PVA) hydrogels and Fe3O4 magnetic particles through freezing-thawing cycles [78]. Although the external direct current magnetic field was applied to the ferrogel, the drug was accumulated around the ferrogel, but the accumulated drug was spurt to the environment instantly when the magnetic fields instantly switched “off”. Furthermore, rapid to slow drug release can be tunable while the magnetic field was switched from “off” to “on” mode. The drug release behavior from the ferrogel is strongly dominated by the particle size of Fe3O4 under a given magnetic field. The best “magnetic-sensitive effects” are observed for the ferrogels with larger Fe3O4 particles due to its stronger saturation magnetization and smaller coercive force. The pulsed reversible release of dual drugs from biodegradable polymeric multireservoir devices is successfully demonstrated by Kaiyong Cai and coworker. The controlled release is achieved by incorporating magnetic particles in the devices as switch carriers [79]. It is possible to intentionally switch on/off the drug release at any desired time for a chosen duration. When a magnetic field was added above the sealed porous membrane using a magnet, the magnetic Fe3O4 particles jumped up to fill in the pores, the release of drugs is thus switched off. When the magnetic field was imposed on the opposite (below) side of the device, the Fe3O4 particles precipitated down to the bottom of the

reservoirs, and the drug release is thus switched on. Tingyu Liu, et al developed the magnetic hydrogels were successfully fabricated by chemically crosslinking of gelatin hydrogels and Fe3O4 nanoparticles (ca. 40–60 nm) through genipin (GP) as cross-linking agent [80]. Moreover, in vitro release reveal that drug release profile of the resulting hydrogels is controllable by switching on or off mode of a given magnetic field. Based on this on-and-off mechanism, the smart magnetic hydrogels based on the gelatin-ferrite hybrid composites can be potentially developed for application in novel drug delivery systems. Saslawski, et al. has developed different formulations for in vitro magnetically triggered delivery of insulin based on alginate spheres [81]. In an experiment, ferrite microparticles (1 mm) and insulin powder were dispersed in sodium alginate aqueous solution. The ferrite-insulin-alginate suspension was later dropped in aqueous calcium chloride solution which causes the formation of cross linked alginate spheres, which were further cross linked with aqueous solution of poly(llysine) or poly-(ethylene imine). Applications as high frequency gave a significant release enhancement for the second magnetic field application, after which the enhancement level decreased due to the faster depletion at these frequencies. 2.3.2. Ultrasound induces release Ghaleb A. Husseini, et al the high toxicity of potent chemotherapeutic drugs like doxorubicin (Dox) limits the therapeutic window in which they can be applied. This window can be expanded by controlling the drug delivery in both space and time such that nontargeted tissues are not adversely affected. Recent research has shown that ultrasound (US) can be used to control the release of Dox and other hydrophobic drugs from polymeric micelles in both time and space. Dox activity can be enhanced by ultrasound in one region, while in an adjacent region there is little or no effect of the drug. We review the in vivo and in vitro research being conducted in the area of micellar drug delivery and ultrasound to cancerous tissues. Attempt to represent the release and reencapsulation phenomena 1 218 1


of Dox from Pluronic ® P105 micelles upon the application of ultrasound [82]. The potential benefits of such controlled chemotherapy compels a thorough investigation of role of ultrasound (US) and the mechanisms by which US accomplishes drug release and/or enhances drug potency. The interactions of ultrasound with biological tissues are divided into two broad categories: thermal and nonthermal effects. Thermal effects are associated with the absorption of acoustic energy by the fluids or tissues [83]. Non-thermal bio-effects are generally associated with oscillating or cavitating bubbles, but also include non-cavitation (shown Fig. 5) effects such as radiation pressure, radiation torque, and acoustic streaming. With respect to drug delivery, these latter effects are probably not involved except to the degree that fluid or particle motion (via acoustic streaming or radiation pressure) increases convection and transport of drug. Bio-effects related to cavitation can produce strong stresses on cells, which may increase drug interactions with the cell, including increased transport toward and into the cell.

polyelectrolytes (polymers which contain relatively high concentration of ionisable groups along the backbone chain) and are thus, pH-responsive as well as electro-responsive. Under the influence of electric field, electro-responsive hydrogels generally deswell or bend, depending on the shape of the gel lies parallel to the electrodes whereas deswelling occurs when the hydrogel lies perpendicular to the electrodes. An electroresponsive drug delivery system was developed by R. V. Kulkarni, et al., using poly(acrylamide-grafted-xanthan gum) (PAAm-gXG) hydrogel for transdermal delivery of ketoprofen. The electrically sensitive PAAm-g-XG copolymer was synthesized by free radical polymerization under nitrogen atmosphere followed by alkaline hydrolysis. The electroresponsive drug delivery system (EDDS) was prepared by entrapping the hydrogel within a shallow compartment molded from a backing layer and rate controlling membranes (RCM). When a swollen PAAm-g-XG hydrogel was placed in between a pair of electrodes, deswelling of the hydrogel was observed in the vicinity of electrodes carrying the electric stimulus [84]. The membrane-controlled drug delivery systems were prepared using drug-loaded PAAm-g-XG hydrogel as the reservoir and crosslinked with poly(vinyl alcohol) to form films as rate controlling membranes (RCM). A pulsated pattern of drug release was observed as the electric stimulus was switched ‘on’ and ‘off.’ These PAAm-g-XG hydrogel could be useful as transdermal drug delivery systems actuated by an electric signal to provide on-demand release of drugs. Implantable electronic devices such as pacemakers and neural implants are often used for electrical stimulation by A. C. Richards Grayson, et al. The usage of microfabrication techniques to produce microelectro mechanical systems (MEMS) has allowed engineers to address a wider range of clinical indications. A new direction in the area of MEMS technology is the goal of achieving pulsatile drug delivery. The digital capabilities of MEMS may allow greater temporal control over drug release compared to traditional polymer-based systems [85]. A repertoire of structures, including microreservoirs, micropumps, valves, and sensors, is being developed that will provide a strong

Fig. 5. A schematic showing the proposal mechanism of ultrasonic release of Dox from Pluronic micelles [82].

2.3.3. Electric field induces release As an external stimulus have advantages such as the availability of equipment, which allows precise control with regards to the magnitude of current, duration of electric pulses, interval between pulses etc. Electrically responsive delivery systems are prepared from 1 219 1


foundation for the design of integrated, responsive MEMS for drug delivery. Precise control over the release of drug from devices implanted in the body, such as quantity, timing, is highly desirable in order to optimize drug therapy. Sudaxshina Murdan et al was develop electrically controllable drug release from polyelectrolyte hydrogels has been demonstrated in vitro and in vivo. Pulsatile drug release profiles, in response to alternating application and removal of the electric field have been achieved. Responsive drug release from hydrogels results from the electro-induced changes in the gels, which may deswell, swell or erode in response to an electric field [86]. The mechanisms of drug release include ejection of the drug from the gel as the fluid phase synereses out, drug diffusion along a concentration gradient, electrophoresis of charged drugs towards an oppositely charged electrode and liberation of the entrapped drug as the gel complex erodes. Ji Sun Park, et al. developed the potential of gold nanoparticles (20 nm) to deliver electrical stimulation to nerve cell cultures in vitro to induce nerve regeneration was evaluated. In order to use these biomaterials to deliver an electrical stimulus, we devised a novel method for the fabrication of a nanostructured 2D substrate comprising gold nanoparticles attached to the surface of a cover glass via an adsorption system. In this strategy, gold nanoparticles are created and then coated onto a positively charged cover glass [87] that has been pretreated with polyethyleneimine (PEI). In addition, the neurite outgrowth of PC12 cells in response to pulsed and constant electrical stimulation was evaluated by live/dead cell determination. However, the neurite outgrowth length without electrical stimulation was approximately 10–20 μm. Moreover, the alternating current stimulation also showed good viability, while a high amount of cell death (more than 30%) was observed with constant current stimulation. Thus, the gold nanoparticles with pulsed current stimulation may provide suitable tools for the nerve regeneration using neuronal cells. Soon Hong Yuk, et al. developed monolithic devices composed of sodium alginate and polyacrylic acid was

prepared. A pulsatile drug release pattern was observed upon application of electrical current using the prepared monolithic devices [88]. Two release patterns of hydrocortisone were achieved by proper design of the drug delivery devices, demonstrated the feasibility of achieving a pulsatile drug delivery system depending on the environmental conditions. 2.3.4. Light induces release Light-sensitive hydrogels have potential applications in developing optical switches, display units, and opthalmic drug delivery devices. Since the light stimulus can be imposed instantly and delivered in specific amounts with high accuracy, light-sensitive hydrogels may possess special advantages over others [89]. For example, the sensitivity of temperature sensitive hydrogels is rate limited by thermal diffusion, while pH-sensitive hydrogels can be limited by hydrogen ion diffusion. The capacity for instantaneous delivery of the sol–gel stimulus makes the development of lightsensitive hydrogels important for various applications in both engineering and biochemical fields. Lightsensitive hydrogels can be separated into UV-sensitive and visible light-sensitive hydrogels. Unlike UV light, visible light is readily available, inexpensive, safe, clean and easily manipulated. The interaction between light and material can be used to modulate drug delivery. This can be accomplished by combining a material that absorbs light at a desired wavelength and a material that uses energy from the absorbed light to modulate drug delivery [90]. Gold nanoshells are a new class of optically active nanoparticles that consist of a thin layer of gold surrounding a core. The optical properties of the nanoshells can be tuned over the visible and near IR spectrum. Embedding the nanoshells in NIPAAm-coAAM hydrogel formed the required composite material. When exposed to near-infrared light, nanoshells absorb the light and convert it to heat, raising the temperature of composite hydrogel above its LCST. The hydrogel collapses and this result in an increased rate of release of soluble drug held with in the matrix.

1 220 1


2.4. Multiparticulate pulsatile drug delivery system

ingress, drug is released from the core after rupturing of the surrounding polymer layer, due to pressure buildup within the system. The pressure necessary to rupture the coating can be achieved with swelling agents, gasproducing effervescent excipients or increased osmotic pressure. Water permeation and mechanical resistance of the outer membrane are major factors affecting the lag time. Andrei Dashevsky, et al. developed a pulsatile multiparticulate drug delivery system (DDS), coated with aqueous dispersion Aquacoat® ECD. A rupturable pulsatile drug delivery system consists of (i) a drug core; (ii) a swelling layer, comprising a superdisintegrant and a binder; and (iii) an insoluble, water-permeable polymeric coating [92]. Upon water ingress, the swellable layer expands, resulting in the rupturing of outer membrane with subsequent rapid drug release. Regarding the cores, the lag time was shorter; theophylline was layered on sugar cores compared with cores consisting of theophylline. Regarding swelling layer, the release after lag time was fast and complete. Drug release was achieved after the lag time, when low-substituted hydroxypropyl cellulose (L-HPC) and sodium starch glycolate (Explotab®) were used as swelling agents. Outer membrane, formed using aqueous dispersion Aquacoat® ECD was brittle and ruptured sufficiently to ensure fast drug release, compared to ethylcellulose membrane formed using organic solution. The addition of talc led to increase brittleness of membrane and was very advantageous. Drug release starts only after rupturing of outer membrane. A. Mohamad et al to investigate the in vitro drug release performance of a rupturable multiparticulate pulsatile system, coated with aqueous polymer dispersion Aquacoat® ECD [93]. Drug release was typical pulsatile, characterized by lag time, followed by fast drug release. Macroscopically observation of the pellets during release experiment confirms that the rupturing of outer membrane was the main trigger for the onset of release. At the end of release outer membrane of all pellets was destructed and the content completely released.

Recent trends indicate that multiparticulate 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 different release patterns as well as reproducible and short gastric residence time. The release of drug from microparticles depends on a variety of factors including the carrier used to form the multiparticles [91] and the amount of drug contained in them. Consequently, multiparticulate drug delivery systems provide tremendous opportunities for designing new controlled and delayed release oral formulations, thus extending the frontier of future pharmaceutical development. The purpose of designing multiparticulate dosage form is to develop a reliable formulation that has all the advantages of a single unit formulation and yet devoid of the danger of alteration in drug release profile and formulation behavior due to unit to unit variation [12]. The expected drug-release mechanism and corresponding target bimodal plasma concentration profile of the above designed multiparticulate pulsatile system is depicted in Fig. 6. In the following sections; recent innovations in multiparticulate systems for pulsatile delivery have been reviewed.

Swelling layer Core pellet Enteric coating

Fig. 6. Hypothetical design of a multiparticulate pulsatile system.

2.4.1. Reservoir systems with rupturable polymeric coatings Most multiparticulate systems are reservoir devices coated with a rupturable polymeric layer. Upon water

1 221 1


This phenomenon was described previously and explained by decreased liquid flow in the lower part of intestine. This disadvantage can be considered as a limitation for drugs (like acetaminophen) with high dose and moderate solubility; however, it should not diminish performance of the investigated system in principle.

acid and styrene cross-linking with divinylbenzene were synthesized by free radical polymerization. The copolymer microspheres showed pulsatile swelling behavior when the pH of the media changed. The pHsensitive microspheres were loaded with diltiazem hydrochloride (DH) [95]. The release characteristics of the free drug and the drug-loaded microspheres were studied under both simulated gastric conditions and intestinal pH conditions. The in vivo evaluation of the pulsatile preparation was subsequently carried out using beagle dogs. In vivo evaluation of a pulsatile dosage form is determined by gamma scintigraphy (Table 3) Fatemeh Atyabi, et al was to prepare a double coated multiparticulate system for 5- aminosalicylic acid delivery using gelatin and ethylcellulose as the primary and secondary polymer respectively [96,97]. Gelatin microspheres containing 5-aminosalicylic acid was produced using the solvent evaporation method. Prepared gelatin microspheres were spherical, free flowing, non-aggregated and showed no degradation in the acidic medium. That drug release was fast and complete and is affected by the amount of core material entrapped. Gelatin microspheres were then coated by ethylcellulose using a coacervation phase separation technique. The idea for this approach was to prepare a delayed drug delivery system, in which, ethylcellulose protects particles for the first 6 h transit through the GIT. However, it was shown that this system could provide a suitable drug release pattern for colonic delivery of active agents, as 30% of the drug was released from the ethylcellulose-coated microcapsules within 6 h, while this amount was 90% of the loaded drug for gelatin microspheres under the same condition. Yao Liu, et al. studied three-layered, pH-independent pulsatile release pellets system containing isosorbide5-mononitrate. The process of the heart disease such as angina has a close relationship to the chronobiology, which gives rise to the need of a pulsatile drug deliver system for the anti-anginal drug. Pellets containing isosorbide-5-mononitrate were firstly prepared as the core [98], and then layered with a swelling layer followed by an water insoluble control layer. The core pellets were formulated with microcrystalline cellulose

2.4.2. Reservoir systems with soluble or eroding polymer coatings Another class of reservoir-type multiparticulate pulsatile systems is based on soluble/erodible layers in place of rupturable coatings. The barrier dissolves or erodes after a specific lag time followed by burst release of drug from the reservoir core. In general, for this kind of systems, the lag time prior to drug release can be controlled by the thickness of the coating layer. However, since from these systems release mechanism is dissolution, a higher ratio of drug solubility relative to the dosing amount is essential for rapid release of drug after the lag period. Gopal Venktesh Shavi et al to develop an entericcoated multiunit dosage form containing aceclofenac, a nonsteroidal anti-inflammatory drug. The pellets were prepared by using extrusion/spheronization method, and the core pellets were coated with a pH-sensitive poly (meth) acrylate copolymer (Eudragit L100-55) to achieve site-specific drug release. Lactose, Avicel PH 101, Aceclofenac, and PVP K30 were thoroughly mixed and the granulating fluid (water) was added in small increments until a homogenous damp mass was achieved [94]. The PEG 6000 solution was mixed with Eudragit L100-55 dispersion using magnetic stirrer. The pellets were coated in a modified traditional coating pan. The release of the aceclofenac from formulated pellets was established to be minimum in the pH 1.2 for a period of 2 h, and at pH 6.8, it shows the maximum release (within 1 h) which indicates gastric resistance of the formulated pellets. The formulated multiparticulate dosage forms can be used as an ideal drug delivery system for the Aceclofenac. C. Sun, et al. developed novel pH-sensitive copolymer microspheres containing methylacrylic 1 222 1


Table 3 In-vivo method for evaluation of pulsatile drug delivery. Drug (polymer)

Theophylline core tablet, L-HPC, Glyceryl behenate,

Method

Ref.

Four male beagle dogs weighing 14–17.5 kg. The dogs were fasted for at least 14 h, were administration tablets containing 99 mTc-DTPA labelled lactose giving 1 MBq of activity. External positional reference markers of 0.1 MBq 99mtechnetium were placed at the base of the tail and between the shoulders. A gamma scintigraphic camera equipped with a low energy collimator was used to acquire images at predetermined time intervals until tablet disintegration was observed.

27

Verapamil hydrochloride, hydroxypropyl methylcellulose (HPMC, Methocel® E5, E15, E50), ethylcellulose (EC, Ethocel® 45P)

Gamma scintigraphy: six healthy males administrated two capsules each volunteer, 4 h after dinner and then remained supine 8 h following the dose, with 200 ml of water containing 99mTc-DTPA. The images taken at 30-min intervals by a gamma camera the gastrointestinal transit of the dosage forms

30

Dofetilide (PulsincapTM), ethylcellulose, polyethylene glycol

An open, four-way crossover study in which male fasted subjects. In addition to the three doses of dofetilide administered to eleven subjects gamma camera fitted with a medium energy collimator, scintigraphic images of 30 s duration. Each imaging interval a blood sample (5 ml) was taken from a forearm vein.

45

Metoprolol tartrate, impermeable capsule

Two male and two female mongrel dogs administered hard gelatin capsules packed with two doses (50 mg + 120 mg) were studies carried out on over night fasting condition. Plasma samples were taken by repeated.

47

Six male beagle dogs were fasted overnight for at least 12 h Salbutamol sulfate, pH-sensitive ion exchange resin

The two preparations were (1) the drug-loaded microspheres with salbutamol sulfate pulsatile released in vitro, (2) the conventional SS tablet (CT)

72

The experimental design: crossover design, 1-week washout time, plasma samples were taken by repeated venipuncture at upper part of the leg. Acetaminophen, Methocel® E5, Aquacoat®, ECD

Five healthy volunteers administered pellets with with 250 ml water after a 10 h overnight fasting. Saliva collected at predetermined time intervals were kept frozen at 60˚C until analytical assessment.

93

Diltiazem HCl, polymer use HCO, PEG and PVC

Three healthy male beagle dogs volunteers administered a dry coated tablet with 30 ml of water 30 min after the the dogs were fed 150 g of solid food. Blood specimens (4 ml) were collected at each predetermined time.

103

Acetaminophen, Polyox WSR 303, Macrogol 6000, dextran blue 2000

Four male beagle dogs weighing 11.4–13.6 kg were fasted for 20 h before administration. Timed-release compression-coated tablets, containing 50 mg of acetaminophen were separately administered orally with 30 ml of water. Blood samples were collected at predetermined time intervals.

104

Antipyrine, Methocel E50, PEG400, Eudragit L 30 D

Four healthy male volunteers (age 36–45 years, weight 70–80 kg) oral administration of tablet with 200ml water. Saliva samples were collected at predetermined time intervals. γ -Scintigraphic study: Six healthy male volunteers administered to each volunteer, fasted overnight, with 200 ml of water containing 99mTc-DTPA, to outline the gastrointestinal tract. Through the images taken at 30-min intervals by a γ-camera the gastrointestinal transit of the dosage forms

The eight volunteers, aged 19–23 years, weighing After fasting for at least 12 h, Diltiazem and verapamil, sodium the volunteers were administered with 200 ml water. The two treatments were (i) carboxymethyl starch, ethyl cellulose, one 60 mg pulsatile release tablet (PT) and (ii) two 30 mg conventional tablets Eudragit L (CT). Blood samples were taken immediately before administering the drug

1 223 1

105

106


(MCC) and lactose, and were prepared by extrusionspheronization. The core pellets were coated by a fluidized bed coater, and pellets with various coating types and coating levels were studied by in vitro dissolution tests. The effects of both swelling layer and control layer on the lag time and the drug release time were studied, in order to predetermine the lag time and release time.

diclofenac sodium intended for chronopharmacotherapy. Floating pulsatile concept was applied to increase the gastric residence of the dosage form having lag phase followed by a burst release [100,101]. To overcome limitations of various approaches for imparting buoyancy, hollow/porous beads 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 h. 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. A blend of floating and pulsatile principles of drug delivery system, and a multiparticulate floatingpulsatile drug delivery system were developed by Sameer Sharma, et al. using porous calcium silicate (Florite RE®) and sodium alginate, for time and site specific drug release of meloxicam [102]. Meloxicam was adsorbed on the Florite RE® (FLR) by fast evaporation of solvent from drug solution containing dispersed FLR. Formulations show a lag period ranging from 1.9 to 7.8 h in acidic medium followed by rapid release of meloxicam in simulated intestinal fluid USP, without enzymes (SIF). Complete drug release in SIF occurred in less than 1 h from the formulations. Floating time was controlled by density of beads and hydrophobic character of drug. A pulsatile release of meloxicam was demonstrated by a simple drug delivery system which could be useful in chronopharmacotherapy of rheumatoid arthritis. Also single unit capsules or tablets are limitation to pulsatile drug delivery, associated with an “all or none concept,” but this can be overcome by formulating multiple unit systems. Table 4 enlists examples of various drugs formulated as different forms of pulsatile drug delivery system.

2.4.3. Floating multiparticulate pulsatile systems Multiparticulate pulsatile release dosage forms mentioned above are having longer residence time in the GIT and due to highly variable nature of gastric emptying process, may resulted in in vitro-in vivo relationship was poor and bioavailability problems. In contrary, floating multiparticulate pulsatile dosage forms reside in stomach only and not affected by variability of pH, local environment or gastric emptying rate. These dosage forms are also specifically advantageous for drugs either absorbed from the stomach or requiring local delivery in stomach. Overall, these considerations led to the development of multiparticulate pulsatile release dosage forms possessing gastric retention capabilities. Shaji Jessy et al to develop a multiple-unit, floatingpulsatile drug delivery system for obtaining no drug release during floating and in the proximal small intestine followed by pulsed, rapid drug release in distal small intestine to achieve chronotherapeutic release of indomethacin [99]. The system consists of drug containing core pellets prepared by extrusionspheronization process, which were coated with an inner pH-dependent layer of Eudragit S100 and outer effervescent layer of sodium bicarbonate and HPMC K100M. Pellets showed instantaneous floating with no drug release in acidic medium followed by pulsed drug release in basic medium. The system showed excellent lag phase followed by burst release in the distal small intestine which gives site and time specific delivery of indomethacin acting as per chronotherapy of rheumatoid arthritis. Shraddha S. Badve, et al. developed hollow calcium pectinate beads for floating-pulsatile release of

2.4.4. Marketed technologies The marketed technologies of pulsatile delivery systems are listed in Table 5. PULSYSTM system (MiddleBrook™ Pharmaceuticals, Inc) was delivery of antibiotic amoxicillin in regular concomitant pulses, 1 224 1


Table 4 List of drugs formulated as single and multiple unit dosage forms of pulsatile drug delivery system. Dosage forms

Table 4 (Continued) List of drugs formulated as single and multiple unit dosage forms of pulsatile drug delivery system.

Drugs

Dosage forms

Propranolol hydrochloride [5]

Diltiazem hydrochloride [70]

Salbutamol sulphate [15]

Propranolol hydrochloride [92]

Ranitidine HCl [16]

Aceclofenac [94]

Verapamil HCl [20]

Tablets

Drugs

Pellets

Isosorbide-5-mononitrate [98]

Ketoprofen [22,115]

Indomathacin [99]

Acetaminophen [24,104]

5-aminosalicylic acid [114]

Felodipine[25]

Diclofenac sodium [114]

Theophylline, [27,31,107]

Diltiazem hydrochloride [53, 95]


Theophylline [69]

Buflomedil hydrochloride [32]

Microspheres

Isoniazid [108]

Salbutamol sulfate (pH-sensitive ion exchange resins) [72]

Nifedipine [109] Chlorpheniramine maleate [110]

5-aminosalicylic acid, [96] ira. J. pharm. Res.

Antipyrine [112]


Pseudoephedrine hydrochloride [112] Acetaminophen [34,35]

Theophylline [116], other-1

Propranolol hydrochloride [40,42]

Diltiazem hydrochloride [52] Indomethacin [58]

Thermo-responsive hydrogel

Diltiazem hydrochloride [43]

Sulfonamide, [65] Gentamicin [54]

Dofetilide [45] Ibuprofen [46]

Diflunisal [60]

Micelles

Metoprolol tartrate [47] Mesalazine [68]

Doxorubicin [62] Insulin [117]

Films

Nifedipine [113] Spheres

Meloxicam [102]

Valsartan [38] Diclofenac sodium [41] Capsules

Aceclofenac [101]

Beads


Electrical device

Acetaminophen [93]

Ketoprofen [84]

Table 5 Marketed technologies of pulsatile drug delivery system. Technology

Proprietory name and dosage forms

Active ingredient

Mechanism

Disease

Ref.

PULSYSTM

MoxatagTM tablets

Amoxicillin

Multiparticulate system

Infection

119

TIMERx®

OPANA® ER tablets

Oxymorphone

Erodible/soluble barrier coating

Pain management

120

CODAS®

Verelan® PM XL release capsules

Verapamil HCl

pH dependent system

Hypertension

121

DIFFUCAPS®

Innopran® XL tablets

Verapamil HCl Propranolol HCl

Multiparticulate system

Hypertension

122

PulsincapTM

PulsincapTM

Dofetilide

Rupturable system

Hypertension

123

1 225 1


drugs based on the bacteria exposed to antibiotics in front-loaded, sequential bursts, or pulses, are killed more efficiently and effectively [119]. TIMERx®, Geminex® and SyncroDoseTM (Penwest Pharmaceuticals and Co., USA) was develop The TIMERx® oral drug delivery system achieves a variety of release profiles (first order, zero order, burst release, etc.) for a wide range of drugs, accommodating even the most difficult actives [120]. CODAS® (Elan Drug Technologies) as multiparticulate pH dependent system, for delivery of verapamil HCl (Verelan® PM) in form of extended release capsule. This delay in release is introduced by the level of release-a controlling polymer applied to the drug-loaded beads [121]. Diffucaps ® (Eurand Pharmaceutical, Vandalia, Ohio.) technology is a multiparticulate system that the water-insoluble and enteric polymers are molecularly dispersed in the lag-time coating membrane, for chronotherapeutic delivery of a combination of two drugs [122]. Pulsincap® (R. P. Scherer International Corporation, Michigan, US) is one such system that comprises of a water-insoluble capsule enclosing the drug reservoir. A swellable hydrogel plug was used to seal the drug contents into the capsule body [123].

pharmaceutical industry could turn out detrimental even when affording noteworthy technical advantages. This is especially true for synthetic polymers, biodegradability being a key requisite for acceptable utilisation in drug formulations. Hence, it is conceivable that more indepth in vivo investigations will be undertaken, with the aim of evaluating the impact of physiological and pathological gastrointestinal conditions on the release behaviour and relevant reproducibility. Inter- and intrasubject variability of data, in fact, represents one of the most challenging aspects which are to be faced in the course of any pharmaceutical development. Therefore, despite the broad scientific involvement in this specific area, many different biological, technical and regulatory issues will have to be thoroughly addressed before patients may finally benefit from the emerging pulsatile delivery technologies.

4. Conclusion There is a constant need for new delivery systems that can provide increased therapeutic benefits to the patients. Universally sustained and controlled release products provide a desired therapeutic effect, but fall for diseases following biological rhythms. Circadian disorders were requiring chronopharmaceutics. Developing pulsatile drug delivery like time controlled PDDS which includes delivery systems with rupturable or erodible coating layers or with release controlling plug, stimuli induced and chemical stimuli induced systems and externally regulated system. The time controlling system character of these systems is useful for treatment of patients, due to their resulting efficiency and lack of undesirable adverse effects to the whole body. Delivering drug at the right time, right place, and in right amounts, holds good promises of benefit to the patients. Today’s drug delivery technologies enable the incorporation of drug molecules into a new delivery system, thus providing numerous therapeutic and commercial advantages. We are sure that with increase in technological advancement and better design parameters these hurdles can be overcome in the near future and more number of patients will be greatly benefited by these systems.

3. Challenges and perspectives of the delivery system Remarkable emphasis has been recently laid on the potential of oral pulsatile delivery. The rapidly growing interest in this particular research area is high-compliance drug treatments which may fulfill chronotherapeutical requirements for a number of widespread pathologies. In addition, colon delivery, which is attainable relying on time-controlled release performances, is presently holding appeal for pharmaceutical scientists, after it has been ascertained that the large bowel not only is endowed with nonnegligible absorption properties, but may also represent a favourable release site for numerous drugs with stability and/or permeability limitations. All the selection of excipients which have not extensively been studied from the tolerability standpoint and/or may not rely on a long-lasting employment within the food or

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