Recent Patents on Drug Delivery & Formulation 2009, 3, 64-70
Site Specific Chronotherapeutic Drug Delivery Systems: A Patent Review Nitin Saigal, Sanjula Baboota, Alka Ahuja and Javed Ali* Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, Hamdard Nagar, New Delhi - 110 062, India Received: December 26, 2007; Accepted: November 6, 2008; Revised: November 10, 2008
Abstract: Oral dosage forms are known to provide a zero order or first order release in which the drug is released at a substantially steady rate of release per unit of time. However, there are instances where maintaining a constant blood level of a drug is not desirable. In such cases a pulsatile drug delivery may be more advantageous. Pulsatile drug delivery systems can be classified into site-specific systems in which the drug is released at the desired site within the intestinal tract (e.g., the colon), or time-controlled devices in which the drug is released after a well-defined time period. Environmental factors like pH or enzymes present in the intestinal tract control the release of a site-controlled system whereas the drug release from time-controlled systems is controlled primarily by the delivery system and not by the environment. The delayed liberation of orally administered drugs has been achieved through a range of formulation approaches, including single or multiple unit systems provided with release-controlling coatings, capsular devices and osmotic pumps. Our aim in this review is to outline the rational and prominent design strategies behind site-specific oral pulsatile delivery. The present article provides a good patent review regarding the Site Specific Chronotherapeutic Drug Delivery Systems.
Keywords: Pulsatile release, colon specific systems, lag time, burst release, enteric coating, methylmethaacrylate copolymers. INTRODUCTION The oral route of drug delivery is typically considered the favored and the most user-friendly means of drug administration having the highest degree of patient compliance, as a result of which much effort are aimed to identify orally active candidates that would provide reproducible and effective plasma concentrations in vivo . Traditionally, drug delivery systems have focused on constant/sustained drug output with the objective of minimizing peaks and valleys of drug concentrations in the body to optimize drug efficacy and to reduce adverse effects. A reduced dosing frequency and improved patient compliance can also be expected for the controlled/sustained release drug delivery systems, compared to immediate release preparations . However, in the field of modern drug therapy, growing attention has lately been focused on pulsatile delivery of drugs for which conventional controlled drug-release systems with a continuous release are not ideal. Anil K. Anal  in his review gave a description on the recently filed patents related to pre-programmed or time-controlled pulsatile drug delivery. Many systems in the human body such as cardiovascular, pulmonary, hepatic and renal systems show variation in their function throughout a typical day. They are naturally synchronized by the internal body clocks and are controlled by the sleep wake cycle. Each bodily system exhibits a peak time of functionality that is in accordance with these rhythmical cycles. Similarly, disease states affect the function of some of these systems in the body and therefore, they too exhibit a peak time of activity within a circadian rhythm . A delivery system with a release profile that is *Address correspondence to this author at the Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, Hamdard Nagar, New Delhi - 110 062, India; Tel: + 00- 91- 9811312247; Fax: + 00- 91- 11- 2605 9663; E-mail: [email protected]
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characterized by a time period of no release (lag time) followed by a rapid and complete drug release (pulse release) can be called as an ideal pulsatile drug delivery system. In other words, it is required that a drug should not be released at all during the initial phase of dosage form administration. Lag time is defined as the time between when a dosage form is placed into an aqueous environment and the time at which the active ingredient begins to get released from the dosage form. While not meant to be limiting, one way to measure lag time is to determine the amount of time before 5% of the drug dose is released from a device when the device is exposed to an appropriate aqueous environment in a United States Pharmacopoeia paddle stirring dissolution apparatus (USP 2) operated at 50 rpm. A lag time of at least 0.5h or longer is considered to be important while a lag time of less than 0.5 h is of little significance. Lag times of more than 4h are desired for delivery of drug into the lower portion of the small intestine while lag times of between 0.5 and 4h are desirable in drug delivery in the upper regions of the gastrointestinal tract . The pulsatile release of an active agent is desirable when treating diseases that require drug delivery in a manner to maintain therapeutic levels albeit circadian rhythms . A large body of literature can be found on oral pulsatile drug delivery systems, which have been accepted as potentially useful to the chronotherapy of some common diseases, such as bronchial asthma, hypertension, angina pectoris, allergic rhinitis and osteo-/ rheumatoid- arthritis with mainly night or early morning symptoms [7- 13]. The shift from conventional sustained release approach to modern pulsatile delivery of drugs can be credited to the following reason(s): 1.
First pass metabolism: Some drugs, such as beta blockers, and salicylamide, undergo extensive first pass metabolism and require fast drug input to saturate
© 2009 Bentham Science Publishers Ltd.
Site Specific Chronotherapeutic Systems
metabolizing enzymes in order to minimize pre-systemic metabolism. Thus, a constant/sustained oral method of delivery would result in reduced oral bioavailability. 2.
Biological tolerance: Continuous release drug plasma profiles are often accompanied by a decline in the pharmacotherapeutic effect of the drug, e.g., biological tolerance of transdermal nitroglycerin.
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 of the 24 hour day, e.g., asthma and angina pectoris attacks are most frequently in the morning hours.
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 minimize side effects.
Gastric irritation or drug instability in gastric fluid: For compounds with gastric irritation or chemical instability in gastric fluid, the use of a sustained release preparation may exacerbate gastric irritation and chemical instability in gastric fluid.
Drug absorption differences in various gastrointestinal segments: In general, drug absorption is moderately slow in the stomach, rapid in the small intestine, and sharply declining in the large intestine. Compensation for changing absorption characteristics in the gastrointestinal tract may be important for some drugs. For example, it is rational for a delivery system to pump out the drug much faster when the system reaches the distal segment of the intestine, to avoid the entombment of the drug in the feces .
Pulsed dose delivery systems, prepared as either single unit or multiple unit formulations, and which are capable of releasing the drug after a predetermined time, have been studied to address the aforementioned problematic areas for sustained release preparations. These same factors are also problematic in pulsed dose formulation development. For example, gastrointestinal transit times vary not only from patient to patient but also within patients as a result of food intake, stress, and illness; thus a single-unit pulsed-release system may give higher variability compared to a multiple unit system. Additionally, drug layering or core making for multiple unit systems is a time-consuming and hard-tooptimize process. Particularly challenging for formulation scientists has been overcoming two conflicting stumbling blocks for pulsatile formulation development, i.e., lag time and rapid release . “SITE-SPECIFIC” OR “POSITION CONTROLLED” PULSATILE DRUG DELIVERY Drug efficacy generally depends upon the ability of the drug to reach its target in sufficient quantity to maintain therapeutic levels for the desired time period . Oral drug delivery can be manipulated to deliver to specific sites in the GI tract. Although, the colon does not inherently possess the ideal anatomical and physiological features, it is the site of
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significant absorption. Targeted delivery of drugs to the colon can be done to achieve many objectives like reduction in dosing frequency, to deliver drug to a region that is less hostile metabolically etc. . In addition, targeted delivery to the colon represents an advantageous approach for the treatment of widespread inflammatory bowel disease (IBD) including ulcerative colitis and crohn’s disease, as well as for tumoral, infective or neurovegetative colonic pathologies. Other commercial benefits can be the ever-greening of already existing patents and the ability to promote new claims. In the past few years many colon specific dosage forms have been developed including pro-drugs, drug embedded in cross-linked hydrogel matrices, coated dosage forms, osmotic controlled drug delivery systems and timed release systems. Ideally, the approach based on combination of pH dependent and time-controlled release mechanism seems encouraging. The approaches of colon targeting mentioned above have been summarized in Table 1. The coated dosage forms are preferred because of innovations in the coating technology and wide flexibility in the design . A study on several examples for both single and multiple unit gastroretentive drug delivery systems has been done by Streubel et al. . The rationale of drug targeting to the colon which we would be focusing on in this review is to delay delivery to a time appropriate to treat acute phases of a disease i.e., to achieve a chronotherapeutic drug delivery response. Table 1.
Approaches to Attain Lag and Target Colon 
Colon targeting approach
pH sensitive polymers coating
Formulation coated with enteric polymers (methylmethaacrylate copolymers) release the drug when formulation reaches down towards the alkaline pH range in the intestine
Biodegradable polymers coating
Degradation of the polymer due to the action of the colonic bacteria releases the drug
Biodegradable matrices and hydrogels
Drug is released by the swelling and/or erosion of the polymer and by the biodegradable action of the polysaccharide
pH sensitive matrices
Drug released by the degradation of the pH sensitive polymer in the GIT
Formulation coated with bioadhesive polymers that selectively provides adhesion to the colonic mucosa release the drug in the colon
Osmotic controlled drug delivery
Drug releases through semi-permeable membrane after a lag time due to osmotic pressure build up
Timed released systems
Formulation is designed such that the drug releases after a lag time of 3-5 h that is equivalent to small intestinal transit time
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SINGLE PULSE AND MULTIPLE PULSE SYSTEMS A chronotherapeutic drug delivery system may be classified as per the function of the dosage form into single pulse system and multiple pulse system. The former as the name suggests releases whole drug from the formulation at one go in a conventional immediate release manner after a well defined lag time which is optimized depending on the peak symptom manifestation of the disease condition such as hypertension, asthma, osteo-and rheumatoid arthritis etc. A single pulse system after a lag time releases majority of the drug in a specific part of the GIT, which may be distal part of the small intestine or the colon depending on the prearranged lag time. A multiple pulse system delivers the drug in divided doses in concomitant pulses to provide advantages such as reduced dose, reduced drug related side effects, improved patient compliance and most importantly as in case of antibiotics better or improved accomplishment of the objective of effectively killing bacteria by not allowing them to develop biological tolerance by switching over to a dormant and more resistant state. A multiple pulse system may be programmed to release fractions of drug in different parts of the GIT viz. stomach, distal jejunum and transverse colon as in case of a three pulse system. FORMULATION OPTIMIZATION OF CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS Be it single pulse or multiple pulse system a rate delaying polymer always is an imperative part of the formulation which is essential for providing the necessary lag time with a subsequent pulse release which may be time controlled or site specific. A basic chronotherapeutic system consists of a drug containing core and the approach is to prevent the drug release from the core from occurring in the initial hours by providing a barrier in the form of a polymer. The barrier may prevent the drug release from occurring either by its slow erosion or slow dissolution or swelling or rupture due to osmosis or may be the mechanism can be based on pH dependent solubility of the polymer as in methylmethaacrylates (MMA) to provide the necessary lag time required. The polymers (non-exhaustive) which may be employed for the purpose may be MMAs (Eudragit L-30 D 55, Eudragit R, S, RS, FS 30 D etc.), Polyvinyl acetate phthalate, hydroxypropyl methyl cellulose (Methocel E5, E15, E3, E50, K4M, K15M, K100LV, K100M), hydroxypropyl cellulose (HPC-L, HPC-M, HPC-H), ethyl cellulose with a pore former, polyvinyl alcohol (PVA), carnauba wax or bees wax with surfactant like polyoxyethylene monooleate (Tween 80), polyethylene oxide (PEOs), polyethylene glycol, carbopols etc. Once this barrier perishes or ruptures, the drug gets released in a pulse as in case of a single pulse system. A multiple pulse delivery unit may consist of a system which consists of the dose of the drug divided into 3-4 fractions in the form of pellets or minitabs one of which may be the immediate release fraction (uncoated IR fraction) for release in the stomach and the others may be delayed release fractions (coated with polymers meant for extending or delaying the release with different weight build up levels) customized to release the drug in different other parts of the GIT. The pellets may be compressed in the form of a tablet with some disintegrant incorporated or may be filled inside a
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capsule shell to form a single unit system. Similarly the minitabs can be filled inside a capsule shell. SITE SPECIFIC CHRONOTHERAPEUTIC SYSTEMS PROTOTYPES The PULSINCAP dosage form releases its drug content at either a predetermined time or at a specific site (e.g., colon) in the gastrointestinal tract [18, 19]. The drug formulation is contained within a water-insoluble capsule body and is sealed with a hydrogel plug. Upon oral administration, the capsule cap dissolves in the gastric juice and the hydrogel plug swells. At a controlled and predetermined time point, the swollen plug is ejected from the dosage form and the encapsulated drug is released. A pulsatile capsule system containing captopril with release after a nominal 5h period was found to perform reproducibly in dissolution and gamma scintigraphy studies. However, in the majority of subjects, no measurable amounts of the drug were observed in the blood, possibly due to instability of the drug in the distal intestine . Stevens et al. used a 5h delay Pulsincap to deliver dofetilide to different sites in the GI tract, employing scintigraphy and pharmacokinetic analysis to evaluate its performance in providing regional drug delivery . US7048945 explained a system flexible enough to be customized into timed controlled or position controlled drug delivery system. The inventors prepared the active drug particle by coating drug on to sugar spheres or by granulation or extrusion-marumerization techniques and coated the drug particle with a plastisized enteric coating with polymers like cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinyl acetate phthalate (PVAP), pH-sensitive methacrylic acid-methamethacrylate copolymers, shellac etc., forming a plasticized enteric coated drug particle; and coating said plasticized enteric coated drug particle with a mixture of a water insoluble polymer such as ethyl cellulose (EC), polyvinyl acetate (PVA) and neutral copolymers based on ethyl acrylate and methylmethacrylate and an enteric polymer. The second and third operations can be interchanged and this feature affords flexibility in modulating the release profile from said drug particle. The inventors also added an option of applying an organic acid (such as fumaric or succinic acid) containing membrane between the second and third coating operations to further modulate the lag time and release profile from the drug particle. While the membranes can be applied in any order, the enteric polymer membrane is usually applied as the innermost membrane [22, 23]. The formulation may employ a single form of the particulate to provide a time-controlled pulsatile release of the drug or to target to specific absorption sites, such as at or near the duodenum/jejunum or colon [24, 25]. US5914134 described pulsatile technology for diltiazem hydrochloride. This technology is based on drug layering of diltiazem hydrochloride in a suspension form on Nu Pareils (sugar spheres, 30/35 mesh). Thereafter, the drug-layered pellets were precisely divided into three fractions for subsequent application of multiple membrane coats of quaternary polymethacrylate. Depending on the number of membrane coats applied, the delivery system was designed to deliver about 40% of the total dose in a pulsatile, site-
Site Specific Chronotherapeutic Systems
specific manner, in the proximal segment of the small intestine and about 60% of the total dose in a sigmoidal, sitespecific manner in the distal segment of the small intestine and the large intestine. The drug delivery pellet unit hydrates by controlled diffusion of water into the membrane coated, drug layered pellet. The water-soluble, porosity controlling plasticizer in the membrane coat dissolves and creates waterfilled aqueous channels through which the drug permeates towards a specific segment of the digestive tract. The plasticizer triethylcitrate (TEC) in the polymeric membrane was responsible for driving the drug in the form of a pulse in solution form whereas the number and thickness of the membrane coatings dictate the precise time of drug delivery. The drug delivery system released the drug from each of the three fractions in less than 3h from the beginning of drug release. The films of quaternary polymethacrylate are not sufficiently flexible. Even with 10% plasticizer they showed some brittleness. Furthermore, a 20% plasticizer resulted in considerable increase in the elongation of break, whereas tensile strength at break was lowered. Therefore, the optimum film properties were found in between the two concentrations (10% and 20%) of the plasticizer . Midha et al. in US6217904 also described in a similar way a pharmaceutical dosage form for pulsatile delivery of d-threo-methylphenidate and a CNS stimulant. The formulation included three fractions of beads; first fraction of beads being prepared by coating an inert support material such as lactose with the drug which provides the first (immediate release) pulse. A second fraction of beads was prepared by coating immediate release beads with an amount of enteric coating material sufficient to provide a drug release-free period of 3-5 h. A third fraction was prepared by coating immediate release beads having half the methylphenidate dose of the first fraction of beads with a greater amount of enteric coating material, sufficient to provide a drug release-free period / lag phase of 7-9 h and thereafter releasing the drug in the colon. The three groups of beads were encapsulated or compressed, in the presence of a cushioning agent, into a single pulsatile release tablet . US5439689 discloses a once-a-day oral formulation of diltiazem hydrochloride having a stair stepped release profile generated by two populations of diltiazem beads which released the drug at two different intervals of time, 3-9 h following lag times of 3 h and 15-21 h following a lag time of 15 h. Although such a formulation releases diltiazem hydrochloride over 24 h, it relied heavily on the drug release based on organic acids, which are irritant to the mucosa . US5834023 (Andrx Pharmaceuticals Inc., Cooper City, US) described a once-a-day controlled release diltiazem formulation which includes 20 to 50% by weight of enteric polymeric membrane coated pellets comprising a polymer membrane coated core which comprises of a biologically inert core which is coated with a first layer which consists essentially of diltiazem and a polymeric binder; and a second layer which comprises a membrane comprising a pH dependent polymeric material; and if the polymer is 50% to 80% by weight of delayed pulse polymeric membrane coated pellets comprising a polymeric membrane coated core which comprises a biologically inert core which is coated with a first layer which consists essentially of diltiazem and a
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polymeric binder and a second layer which comprises a polymeric membrane which will substantially maintain its integrity in the varying pH conditions of the gastrointestinal tract but is permeable to diltiazem; and a unit dose containment system . CA2215378 assigned to Andrx Pharmaceuticals Inc., US describes unit dosage forms of diltiazem hydrochloride which comprise a two fraction system, enteric polymeric membrane coated pellets and delayed pulse polymeric membrane coated pellets. This invention relies on the biological system for subject-to-subject and within subject reliability of gastrointestinal movement of enteric-coated pellets and dissolution of the complete enteric coat for bioresponse in the initial phase . US6635277 issued to Sharma et al., gives the composition for pulsatile delivery of diltiazem which is bioequivalent in plasma profile of the innovator Cardizem CD. The composition is a three pellet quaternary polymethacrylate based system including a fast release fraction (FRF), medium release fraction (MRF) and a slow release fraction (SRF). The preferred proportion of these fractions is 35-40FRF/24-28MRF/35-40SRF (e.g., 37/26/37). The preferred weight gain of these fractions is 12-15%, 36-39% and 48-50 with respect to the coatings. The fast release membrane composition includes an anionic surface-active agent such as sodium lauryl sulfate. A hydrophilization of the fast release fraction (FRF) creates a microporous structure, assuring total drug release delivered as a pulse. In the absence of such a release profile for the FRF, the product is not believed to provide a bioequivalent plasma release profile. The medium release fraction (MRF) and the slow release fraction (SRF) are plasticized with suitable concentrations of plasticizer such as TEC for optimum film coating performance. With a TEC concentration of 20%, a talc concentration of 20% and a syloid concentration of 2% (based on dry quaternary polymethacrylate weight), the fluidization patterns can not be optimized with changing fluidization plates, partition heights, and optimized spray patterns by changing nozzle positions and apertures. A decrease of TEC concentration to 16% and a simultaneous increase of syloid to 5% (based on dry quaternary polymethacrylate weight) results in a highly efficient, reproducible, and scalable film coating operation . US6605300 and US6322819 issued to Burnside et al., gives a method of preparing an oral pulse dose drug delivery system. The present invention comprised of a core or starting seed, either prepared or commercially available product. The methods of preparing the core given in the patent were extrusion-spheronization, high shear granulation or solution/suspension layering. The diameter of the core pellets was kept in the range of 100-800 m. A protective coating layer (HEC, HPC, HPMC, PVP, PVA, EC and the like) was applied (2-4% coating level) immediately outside the core (drug-containing or drug-layered) by conventional coating techniques such as pan coating or fluid bed coating using solutions of polymers in water. The enteric coating layer of CAP, cellulose acetate trimellitate (CAT), HPMCP, PVAP, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters etc. was applied onto the cores with or without seal coating by
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conventional coating techniques, such as pan coating or fluid bed coating using solutions of polymers in water or by using aqueous polymer dispersions. The enteric polymers used in this invention were modified by mixing with other known coating products that are not pH sensitive which included a water penetration barrier layer of a semipermeable polymer e.g. cellulose acetate butyrate, cellulose acetate propionate, EC, fatty acids and their esters, waxes, zein, and aqueous polymer dispersions such as Eudragit RS and RL 30D, Eudragit NE 30D, Aquacoat , Surelease , cellulose acetate latex etc. which were successively coated after the enteric coating to reduce the water penetration rate through the enteric coating layer and thus increasing the lag time of the drug release. An overcoating layer (2-3% w/w coating level) was further applied to the composition. Opadry and corresponding colorless grades which can be used to protect the pellets from being tacky and provide colors to the product were used for the purpose. The composition, preferably in beadlet form was incorporated into hard gelatin capsules, either with additional excipients, or alone [2, 32]. US6555136 explains the use of hydrocolloid gums to be effective to provide for colonic delivery, e.g., guar gum, locust gum, bena gum, gum tragacanth, and karaya gum. Other materials suitable for effecting colonic drug delivery include polysaccharides, mucopolysaccharides, and related compounds, e.g., pectin, arabinogalactose, chitosan, chondroitin sulfate, dextran, galactomannan, and xylan. The invention is based on pharmaceutical dosage form for pulsatile delivery of methylphenidate and explains the use of three kinds of minitablets or bead or particle fractions in a capsule which have different drug and polymer coating levels out of which the third tablet or bead or particle fraction provides for release of the active agent in the colon, in which polymeric or other materials were used that enables drug release within the colon [27, 33]. Enteric coating of the hard gelatin capsules provides with drawbacks like shell becoming brittle during coating or on long-term storage. Furthermore, the smooth surface of the gelatin shell results in poor adhesion of the coating, there is a risk of the coat cracking on handling the capsule, and there is an interaction of the coating with the gelatin shell resulting in changed dissolution performance on long term storage. For these reasons an enteric capsule has not been an obvious choice if an enteric drug delivery device has to be selected. US6228396 based invention provides a drug delivery composition for delivering a drug to the colonic region comprising an injection molded starch capsule containing the drug and wherein the starch capsule is provided with a coating such that the drug is predominantly released from the capsule in the colon and/or terminal ileum. Unlike gelatin capsules, there is no overlap between the body and the cap of the starch capsule and this allows for easy application of the coating. The method of making the starch capsules is well known in the art. Preferred coating materials are those which dissolve at a pH of 5 or above. The coating therefore only begins to dissolve when they leave the stomach and enter the small intestine. A thick layer of coating is provided which dissolved after a lag of 3-4 h thereby allowing the capsule underneath to breakup only when it has reached the terminal ileum or the colon. Such coating was made from a variety of
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polymers such as CAT, HPMCP, PVAP, CAP and shellac etc. . US6200602 provided a drug delivery composition for colonic delivery comprising a polar drug, an absorption promoter comprising a mixture of a fatty acids and a dispersing agent. A particularly preferred mixture of fatty acids used was AKOLINE (available from Karlshamns, Sweden). Akoline is a mixture of mono-diglycerides of medium chain fatty acids. Dispersing agent functioned to position itself at the interphase between the formulation phase and the aqueous phase in the colon and thereby reducing the interfacial tension between the two phases and promote the dispersion of the formulation in the lumen of the colon. Dispersing agents included polyglycolyzed glycerides (e.g., LABRASOL), polyoxyethylene sorbitan fatty acid esters, e.g., polyoxyethylene 20 sorbitan monolaurate (Tween 20), polyoxyethylene etc. The ratio of the fatty acid to the dispersing agent was kept in the range of 1:3 to 3:1. The composition was formulated as a capsule formulation using hard or soft gelatin capsules or starch capsules, the polar drug being suspended in the dispersing agent-fatty acid mixture or the dispersing agent-di-triglyceride mixture or the dispersing agent-mono/diglyceride mixture. The composition can also be formulated to contain known pharmaceutical excipients to obtain optimal pharmaceutical properties such as Avicel, HPMC and the like or can also be formulated as a tablet or pellets (microcapsules) using known tablet constituents and methods. A coating of methylmethacrylates or copolymers of methacrylic acid and methylmethacrylate e.g. Eudragit based polymers was provided on the capsule, tablet or pellet to prevent release until the tablet, capsule or pellet reaches the proximal colon. The thickness of the coating was kept in between 150 and 200 . Gazziranga et al. (1995) developed a site specific (colon targeted) pulsatile drug delivery system consisting of a drug containing core coated with different amounts of low viscosity grade HPMC, which maintained the lag time which was proportionally prolonged with increase in the HPMC amount. However higher amounts of HPMC coating resulted in slower release after the lag phase . Fan et al. (2001) designed a time dependent release tablet system, which avoided the release in stomach and released the drug in intestines after a predetermined lag time of 3 h. The system was made up of a core containing the drug and cross linked PVP as swelling layer and a coating of a mixture of ethylcellulose and Eudragit L. Eudragit L was used as an enteric coating as well as pore forming polymer which dissolved above pH 6. Ingress of water from the surrounding medium in to the system caused expansion of swelling agent which eventually led to burst and complete release of drug in one pulse . CA2305762 described a targeted drug delivery system accompanied with burst release of drug after a well defined lag time to one or more specific location in the alimentary canal. The delivery system contained a core and a coating. The core contained a drug in combination with a carrier material (e.g., calcium pectinate, calcium alginate and pectin) which had the property of swelling upon in contact with an aqueous medium. Other important components of the core included a disintegrant (e.g., crosspovidone) and a
Site Specific Chronotherapeutic Systems
hardness enhancer (e.g., microcrystalline cellulose). Due to the presence of disintegrant, the core had a characteristic of disintegrating rapidly after the coating is broken. Thus, the coating used for the invention prevented drug release until the predetermined time when particulates in the coating have swollen enough to form channels from the outer part to the inner core and allowed entry of aqueous medim into the core which lead to breakage of the outer coating. The disintegration of the unveiled core released the drug load in an immediate pulse . Sangalli et al. (2001) performed an in vitro and in vivo evaluatation of Chronotropic™ System for time and sitespecific (colon targeted) drug delivery after a predetermined lag phase, the duration of which depended on the thickness of the polymer layers applied on the cores. Both the pharmacokinetic and scintigraphic data pointed the capability of the system of releasing drugs in the GIT after a programmed lag and a colon-specific drug delivery to be attained in the case of gastroresistant systems . Vandelli et al. (1996) proposed a delivery system for colonic delivery of a drug after a controllable lag time. The delivery system was designed fitting a core of drug (8 or 6 mm in diameter) within a hollow cylindrical matrix (13 ± 0.1 mm diameter, 3.0 ± 0.2 mm thickness) of hydroxy propyl cellulose-SL alone and coating with ethylene: vinyl acetate copolymer by hand the flat surface of the two bases to have only the exterior surface of the delivery system as the exposed surface. Owing to the water impermeable coating, water penetrated and the polymer eroded in the radial direction from the exterior surface towards the drug core. Thus, the medium could reach the drug only after a lag time which was related to the wall thickness of the cylindrical matrix (3.5 or 2.5 mm for the system enclosing 6 or 8 mm core, respectively). A lag time of more than 6 h was achieved, however the system is quite difficult to prepare owing to the use of hollow matrices and the application of a coating . Marvola et al. (1999) investigated the posibility to delay the drug release in a new way, by preparing film coated matrix pellets using enteric polymers as both matrix binders and coating materials . Sinha and Kumria (2002) did an in vitro evaluation of xanthan gum, guar gum, chitosan and eudragit E as binders for colon drug delivery out of which xanthan gum as a binder was regarded as best suited for time-controlled release systems for colon targeting which initially retards the drug release due to the lag time required for swelling and after swelling, a rapid drug release was obtained. Systems formulated using chitosan (3%) as binder seems to be highly sitespecific due to the release of majority of drug only upon the breakdown by the bacterial microflora of the colon .
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figured out for the same. Also amongst the numerous researches done on these systems, only a few have been able to find themselves placed on the pharmacist shelf due to the issues like difficulty in scale up operations, practical inapplicability, cost ineffectiveness and the potential limitation of the size or materials used for dosage forms. An extensive research investigation on these devices is needed before these promising technologies become clinically accessible. Development of some more sophisticated engineering technologies for the large scale execution of these systems needs to be initiated. ACKNOWLEDGEMENTS The authors are grateful to University Grants Commission, New Delhi, India for providing financial assistance to this project as Major Research Project No. F. 32-125/2006 (SR). CONFLICT OF INTERESTS: There is no conflict of interest in the present manuscript. REFERENCES 
     
      
CURRENT & FUTURE DEVELOPMENTS Chronotherapeutic drug delivery systems are gaining a lot of interest in this epoch of novel drug delivery systems. However some researchers do not find any differences amongst site specific pulsatile systems and the basic and more conventional colon targeted systems due to the mechanism of both being almost similar even though the intention of the formulator being different. A difference needs to be
  
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