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A REVIEW ON CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS
INTRODUCTION
St Josephs College of Pharmacy ,Cherthala .
INTRODUCTION Biological rhythms are an adaptive phenomena relating to predictable changes in environmental factors that regulate many body functions like metabolism, sleep pattern, hormone production, hormone production and physiology .Variation in body function cause changes both in diseases state and in plasma drug concentration. Many functions of the human body vary considerably in a day. These variations cause changes both in disease state and in plasma drug concentrations. Human circadian rhythm is based on sleep activity cycle, is influenced by our genetic makeup and hence, affects the bodys functions day and night (24-hour period) 1. The dependence of bodily functions in certain disease states on circadian rhythm is well known. A number of hormones are released by the brain in the morning, while others are released during sleep. Blood pressure and heart rate are highest during the hours of 6.00 a.m. to 12.00 noon 2. Diseases, such as hypertension, asthma, peptic ulcer, arthritis, etc, follow the body's circadian rhythm . 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 . CHRONOBIOLOGY 3: The term "Chrono" pertains to time and "Biology" is the science of life, thus, chronobiology concerns with the observation of every metabolic event goes through rhythmic changes in time that can be measured from seconds to seasons . Typical examples are levels of plasma testosterone and cortisol, which typically peak in the early morning, and the secretion of growth hormone, which peaks during sleep.
CHRONOPHARMACOKINETICS 3: Studies show that time of drug administration especially with reference to circadian rhythm can impact the kinetics and dynamics of various classes of medicines studies have been reported that the time of administration of many drugs is a possible factor in variation of the pharmacokinetics of a drug. . Different pharmacokinetics constraints of time like elimination
St Josephs College of Pharmacy ,Cherthala . 3
rate, peak concentration, volume of distribution, and AUC of a number of drugs are affected by circadian rhythms relates to the dosing-time, which could be expressed as rhythmdependent, under the divergences in the effects of drugs. CHRONOTHERAPEUTICS 3: It refers to the clinical practice of harmonizing delivery of the drug in accordance with body's circadian rhythm including ailment states to create maximum benefit and minimizing harm . CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEM 3: ChrDDs refers to a treatment method in which in vivo drug availability is timed to match circadian rhythms of disease in order to optimize therapeutic outcomes and minimize side effects. OBJECTIVES OF WORK: The aim of project work is to study in general about various pharmaceutical aspect of chronotherapeutic drug delivery system in solving many formulation problem and to conduct literature survey and characterisation ,to summarise the further scope as well as in application in pharmacy IDEAL CHARACTERISTICS OF CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEM 4: Ideal ChrDDS should:
be non-toxic within approved limits of use, have a real-time and specific triggering biomarker for a given disease state, have a feed- back control system (e.g. self -regulated and adaptative capability to circadian rhythm and individual patient to differentiate between awake sleep status). be biocompatible and biodegradable, especially for parenteral administration, be easy to manufacture at economic cost. be easy to administer in to patients in order to regimen. enhance compliance to dosage
ADVANTAGES OF CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEM 5 : 1. Extended day time activity or night time activity. 2. Reduced side effect. 3. Reduced dosage frequency. 4. Reduction in dose size. 5. Improved patients compliance.
6. Lower daily cost to patient due to fewer dosage unit are required by the patients
7. Drug adapt to suit circadian rhythm of body function or diseases.

8. Drug targeting to specific site. e .g colon
9. Avoids degradation of in upper gastrointestinal tract.(proteins and peptides) .

10. Drug loss is prevented by extensive first pass metabolism. 11. Extended release of drug in pulsatile manner .
12. Right timing and the amount of medication optimizes the drug's desired effects and minimize the undesired ones. DISADVANTAGES OF CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEM5: 1. It develops a non 24 hours sleep wake syndrome after the treatment as the person sleeps for over 24 hours during the treatment. Its not quite common but the degree of risk is not known.
2. Person may also be sleep deprived sometimes. Person become less productive during
chronotherapy and staying awake till the other schedule will be bit uncomfortable.
3. Medical supervision is mandatory for this therapy. And regular consulting of sleep
speacitists is recommended. 4. One has to keep himself awake till the next sleep schedule .so he have to get himself busy so that he stay awake till the other schedule. 5. Person going through the therapy may feel unusually hot or cold sometimes.
6. Have to consult the doctor regularly to avoid side effect. 7. Major drawbacks of existing oral chronotropic systems are their dependence human
action to trigger the drug release.
APPROACHES FOR CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEM
APPROACHES FOR CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEM 6: Controlled release formulations can be divided into subgroups of rate-controlled release, delayed-release and pulsed-release formulations. Delayed-release formulations include time controlled release and site specific dosage forms .When constant drug plasma levels need to be avoided, as in chronotherapy, time-controlled or pulsed-release formulations are preferable, especially in the treatment of early morning symptoms. By timing drug administration, plasma peak is obtained at an optimal time and the number of doses per day can be reduced. Saturable first-pass metabolism and tolerance development can also be avoided .
1. ENTERIC COATED SYSTEM 6:
Enteric coatings have traditionally been used to prevent the release of a drug in the stomach Enteric coatings are pH sensitive and drug is released when pH is raised above 5 in the intestinal fluid. These formulations can be utilised in time-controlled drug administration when a lag time is needed. Because of the unpredictability of gastric residence, such systems cannot be the first choice when a time-controlled release is required. In the treatment of nocturnal asthma, as albutamol formulation containing a barrier coating which is dissolved in intestinal pH level above about 6, has been successfully used. The system contains a core which is film coated with two polymers, first with HPMC and then with a gastro-resistant polymer (Eudragit),cellulose acetate phthalate, hydroxyl propylmethylcellulose are used for coating which protects the dosage forms from the acidic environment of the GIT and allows delivery of the drug to the small or large intestine based on solubility, pH and coating thickness of the polymeric layer .In this system the duration of the lag phase in absorption can be controlled by the thickness of the HPMC layer. Enteric coated systems are used for site specific and time controlled drug delivery.
2 .LAYERD SYSTEM 6: These are one or two impermeable or semi permeable polymeric coatings (films or compressed) applied on both sides of the core . To allow biphasic drug release, a three-layer tablet system was developed . The two layers both contain a drug dose. The outer drug layer contains the immediately available dose of drug. An intermediate layer, made of swellable polymers ,separates the drug layers. A film of an impermeable polymer coats the layer containing the other dose of drug. The first layer may also incorporate a drug-free hydrophilic polymer barrier providing delayed (5 h) drug absorption. Multi-layer tablet system it consists of a matrix core containing the drug dose. This kind of three layer device has been used in the treatment of Parkinsonian patients using L-- dopa/ benserazide. Night time problems and early-morning symptoms of Parkinsonism can be avoided by using a dual release formulation, which allows daily doses of drug to be reduced and leads to extent of bioavailability 40 % greater than when a traditional controlled release formulation is employed 3.TIME-CONTROLLED EXPLOSION SYSTEM(TES) 7: These have been developed for both single and multiple unit dosage forms . In both cases, the core contains the drug, an inert osmotic agent and suitable disintegrates. Individual units can be coated with a protective layer and then with a semi permeable layer, which is the rate controlling membrane for the influx of water into the osmotic core. As water reaches the core ,osmotic pressure is built up. The core ultimately explodes, with immediate release of the drug. The explosion of the formulation can also be achieved through the use of swelling agents. Lag time is controllable by varying the thickness of the outer polymer coating . 4.SIGMOID RELEASE SYSTEM(SES) 7: For the pellet-type multiple unit preparations, SRS containing an osmotically active organic acid have been coated with insoluble polymer to achieve different lag-times . By applying different coating thicknesses, lag times in vivo of up to 5 hours can be achieved. Release rates from SRS, beyond the lag time, has been found to be independent of coating thickness.
6.PRESS-COATED SYSTEM 8: Delayed-release and intermittent-release formulations can be achieved by press-- coating. Press coating, also known as compression coating, is relatively simple and cheap, and may involve direct compression of both the core and the coat, obviating the need for a separate coating process and the use of coating solutions. Materials such as hydrophilic cellulose derivatives can be used and compression is easy on a laboratory scale. On the other hand, for large-scale manufacture, special equipment is needed. The major drawbacks of the technique are that relatively large amounts of coating materials are needed and it is difficult to position the cores correctly for the coating process .In recent years, various controlled release, especially time-controlled release, drug delivery systems based on compression coating technology have been studied. Most of such formulations release drug after a lag phase, followed by a rapid dissolution of the core. a press coated device in which the inner core contains the drug and the outer coat is made of different types of polymers. The outer barrier, which controls drug release, can be either swellable or erodible. Lag times can be varied by changing the barrier formulation or the coating thickness . Hydrophilic polymers such as hydroxypropyl methylcellulose and sodium alginate have been used in the coat to control drug release. 7.PULSINCAP 8:
It is a single unit system comprised of a water insoluble capsule body enclosing the drug reservoir. The capsule body is closed at one end with a swellable hydro gel plug. Various hydro gels such as hydroxypropyl methylcellulose, hydroxypropyl,polyvinyl pyrrolidone are used as plug materials. Enzymatically controlled erodible polymers such as pectin can also be used as plugging material. When the capsule comes in contact with water it absorbs water and swells. After a lag time the plug gets pushed out and the drug gets release rapidly in the form of a pulse. The total length of the plug, its position of the insertion into the capsule and the polymer used for making the plug controls the lag time of the system. Rapid release of the drug can be ensured by the inclusion of effervescent agents, super disintegratnts and osmotic agents. 8.SWELLING AND ERODIDLE SYSTEM 9: Swelling and erodible systems released after the lag time. The coating layer is made up of various hydrophilic polymers .In addition to this enteric coating can be applied outside to overcome the gastric pH effect on the drug. The lag time of the system can be controlled by thickness of the polymeric coat and the viscosity grade of the polymer used. 9.MULTIPARTICULATE SYSTEM 9:
More reliable gastric emptying pattern is observed for multiparticulate systems and is based on changes in membrane permeability and rupture of the coating. The drug is coated on non-peril sugar seeds followed by coating with swellable polymeric layer. The swelling agents include super disintegrates, effervescent agents and osmotic agents. Upon ingress of water, the swellable layer expands resulting in rupture of the film and rapid drug release. Several delivery systems based on ion exchange principle have been developed. Other used polymers such as Eudragits RS30D. It contains positively charged quaternary ammonium groups in the side chain accompanied by negative hydrocolloid counter ions. The ammonium
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groups interact with water, change the permeability and allow water to penetrate in to the core layer in a controlled manner. 10.ULTRASOUND DRUG DELIVERY SYSTEM 9: Ultrasound is an enhancer for improvement of drug penetration through biological barriers such as skin, blood vessels etc. The ultrasound effect enhances degradation of the polymer in which the drug molecules are incorporated. The drug can be released by repeated ultrasound exposure. Pulse delivery is achieved by on off application of ultrasound.
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CHRONOPHARMACEUTICAL TECHNOLOGIES
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CHRONOPHARMACEUTICAL TECHNOLOGIES 10:
Currently key technologies in chronopharmaceutics includes: CONTINR PHYSICO- CHEMICAL MODIFICATION OF A.P.I: OROSR CODASR CEFORMR, DIFFUCAPSR CHRONOTOPIC TECHNOLOGY: EGALET TECHNOLOGY: GEOCLOCK TECHNOLOGY: CHRONOMODULATING INFUSION PUMPS
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CHRONODOSE SYSTEM: CRYSTAL RESERVOIR SYSTEM: TIMERxR CONTROLLED-REALSE MICROCHIPS PORT TECHNOLOGY THREE DIMENSIONAL PRINTING(3DP) TECHNOLOGY
1.CONTINR TECHNOLOGY
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In this technology, molecular coordination complexes are formed between a cellulose polymer and a non-polar solid aliphatic alcohol optionally substituted with an aliphatic group by solvating the polymer with a volatile polar solvent and reacting the solvated cellulose polymer directly with the aliphatic alcohol, preferably as a melt. This constitutes the complex having utility as a matrix in controlled release formulations since it has a uniform porosity (semi permeable matrixes) which may be varied . This technology has concretely enabled the development of tablet forms of sustained-release aminophylline, theophylline, morphine, and other drugs. Research suggested that evening administration of UniphylR (anhydrous theophylline) tablets represented a rational dosing schedule for patients with asthma who often exhibit increased broncho constriction in the morning. CONTINR technology provides for closer control over the amount of drug released to the bloodstream, and benefits patients in terms of reducing the number of doses they need to take every day, providing more effective control of their disease (particularly at night), and reducing unwanted side effects . 2.PHYSICO- CHEMICAL MODIFICATION OF A.P.I 10: Method is used to modify the physicochemical properties (e.g. .solubility, partition coefficient, membrane permeability, etc.) of the API to achieve the Chronopharmaceuticals objective. The rationale for such approach is based on the solubility and permeability are critical factors governing drug bioavailability. Typical examples of the use of this strategy in chronotherapy are those of antihyperlipidemic statins (HMG-Co A reductase inhibitors) and ant ulcerative agents(histamine H2 receptor-antagonists) . Basically, the introduction a methyl group in the chemical structure of lovastatin leads to the production of simvastatin. Such modifications change the melting point (m.p.) of these compounds from 174.5 to 135138 jC
for lovastatin and simvastatin, respectively .Molecular weight and m.p. of compounds are related to their solubility. Physicochemical modifications affect the time to reach the maximum plasma concentration (Tmax) for these compounds. The Tmax varies from 2 to 4 h for lovastatin and simvastatin, respectively. Prodrug approach may also be used to obtain a ChrDDS. For example, lovastatin and simvastatin are lactone prodrugs that are modified in the liver to active hydroxyl acid forms. Since, they are lactones, they are less water soluble than other statins .
3.OROS TECHNOLOGY 11:
OROSR technology uses an osmotic mechanism to provide pre-programmed, controlled drug delivery to the gastrointestinal tract. The dosage form comprises a wall compartment. The active drug is housed in a reservoir, surrounded by a semi-permeable membrane/wall (e.g. cellulose esters, cellulose ethers and cellulose esterethers) and formulated into a tablet. The tablet is divided into two layers, an active drug layer and a layer of osmotically active agents (e.g. polyethylene oxide)) comprising means for changing from a non-dispensable viscosity to a dispensable viscosity when contacted by fluid that enters the dosage form. while the cap is made of proprietary waterpermeable blends of polycaprolactone and flux enhancers For example, water from the gastrointestinal tract diffuses through the membrane at a controlled rate into the tablet core, causing the drug to be released in solution or suspension at a pre determined rate. This creates a pump effect that pushes the active drug through a hole in the tablet. This technology, especially the OROSR
Delayed Push Pull System, also known as controlled on extended release (COER) was used to design Covera-HSR, a novel antihypertensive product. It actually enabled delayed, overnight release of verapamil to help prevent the potentially dangerous surge in BP that can occur in the early morning . 4.CODASR TECHNOLOGY 11: The Chronotherapeutic Oral Drug Absorption System (CODASR) is a multiparticular system which is designed for bedtime drug dosing, incorporating a 45 h delay in drug delivery. This delay is introduced by the level of non-enteric release-controlling polymer applied to drug loaded beads. The release controlling polymer is a combination of water soluble and water insoluble polymers. As water from the gastrointestinal tract comes into contact with the polymer coated beads, the water soluble polymer slowly dissolves and the drug diffuses through the resulting pores in the coating. The water insoluble polymer continues to act as a barrier, maintaining the controlled release of verapamil . The rate of release is essentially independent of pH, posture and food. The night time dosing regimen of (CODASR-Verapamil)was not associated with excessive BP reductions during the sleeping hours. The CODASR verapamil extended release capsules (VerelanR PM) as ChrDDS actually provided enhanced BP reduction during the morning period when compared with other time intervals of the 24-h dosing period . 5.CEFORMR TECHNOLOGY 11: The CEFORMR technology allows the production of uniformly sized and shaped microspheres of pharmaceutical compounds. This ChrDDS approach is based on meltspinning,which means subjecting solid feedstock i.e. biodegradable polymer/bioactive agents combinations to the combination of temperature, thermal gradients, mechanical forces, flow, and flow rates during processing. The microspheres obtained are almost perfectly spherical, having a diameter that is typically 150180 Am, and allow for high drug content. The microspheres can be used in a wide variety of dosage forms, including tablets, capsules, suspensions, effervescent tablets, and sachets. The microspheres may be coated for controlled release either with an enteric coating or combined into a fast/ slow release combination. This technology has been actually used to develop CardizemR LA, 1-day diltiazem formulation as ChrDDS .
6.DIFFUCAPSR TECHNOLOGY 12: In the DIFFUCAPSR technology, a unit dosage form, such as a capsule for delivering drugs into the body in a circadian release fashion, comprises of one or more populations of drug containing particles (beads, pellets, granules, etc.). Each bead population exhibits a pre-designed rapid or sustained release profile with or without a predetermined lag time of 35 h. The active core of the dosage form may comprise an inert particle or an acidic or alkaline buffer crystal (e.g. cellulose ethers), which is coated with an API-containing filmforming formulation and preferably a water-soluble film forming composition (e.g. hydroxyl propylmethylcellulose,polyvinyl pyrrolidone) to form a water-soluble/dispersible particle. The active core may be prepared by granulating and milling and/or by extrusion and spheronization of a polymer composition containing the API. Such a ChrDDS is designed to provide a plasma concentrationtime profile, which varies according to physiological need during the day, i.e. mimicking the circadian rhythm and severity/manifestation of a cardiovascular disease, predicted based on pharmacokinetic and pharmacodynamic considerations and in vitro/in vivo correlations. This technology has been used to formulate the first and recently FDA approved propranolol containing ChrDDS (InnopranR XL) for the management of hypertension. Diffucaps beads are <1.5 mm in diameter and can be filled into capsules or compressed into orally disintegrating tablets. Advantages of Diffucaps Ideal for drugs exhibiting poor solubility in lower intestinal pH, in environments with pH above 8.0, or in physiological fluids Can combine multiple drugs and/or multiple release profiles in the same dosage form Simple formulation of doseproportional strengths. Can minimize food effect
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Cross section of Diffucaps
7.CHRONOTOPIC TECHNOLOGY 13: It consists of a core containing drug reservoir coated by a hydrophilic polymer hydroxylpropyl methylcellulose (HPMC). An additional entericcoated film is given outside this layer to over come intrasubject variability in gastric emptying rates. The lag time and the onset of action are controlled by the thickness and the viscosity grade of HPMC.
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8.EGALET TECHNOLOGY 13: It offers a delayed release. System consists of an impermeable shell with two lag plugs, active drug after the inert plugs have eroded, the drug is released, thus a lag time occurs. Time of release can be modulated by the length and composition of the plugs. The shells are made of slowly biodegradable polymers (such as ethyl cellulose) and include plasticizers (such as cetostearyl alcohol), while the matrix of the plugs is made up of a mixture of pharmaceutical excipients including polymers like polyethylene oxide (PEO). g is sandwiched between the plugs.
Egalet: (a) Intact Unit (b) Erosion of the time delay insert plugs, and (c) Drug release
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9.GEOCLOCK TECHNOLOGY 14: Geoclock tablets have an active drug inside an outer tablet layer consisting of a mixture of hydrophobic wax and brittle material in order to obtain a pHindependent lag time prior to core drug delivery at a predetermined release rate. developed to achieve an onoff switching drug delivery for transdermal application via the externally repeated cycle of temperature change.
X ray of Geoclock tablets 10.CHRONOMODULATING INFUSION PUMPS 14: The portable pumps are usually characterized by a light weigh (300500 g) for easy portability and precision in drug delivery. For example portable programmable multi-channel pumps allowed demonstration of the clinical relevance of the chronotherapy principle in a sufficiently large patient population. Specifically, a clinical phase III trial involving several patients with metastatic gastrointestinal malignancies compared a flat versus the chronomodulated three-drug regimen, and demonstrated large, simultaneous improvements in both tolerability and response rates in patients with metastatic colorectal cancer receiving chronotherapy.
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11.CHRONODOSE SYSTEM 14 : The ChronoDose system is a revolutionary drug delivery device, worn like a wristwatch, which can be pre-programmed to administer drug doses into the body automatically, at different times of the day and with varying dose sizes. 12..CRYSTAL RESERVOIR SYSTEM 14: A transdermal system for chronotherapy of asthma. A thermo responsive membrane was developed to achieve an onoff switching drug delivery for transdermal application via the externally repeated cycle of temperature change.
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13.TIMERxR TRCHNOLOGY 15:
The TIMERxR technology (hydrophilic system) combines primarily xanthan and locust bean gums mixed with dextrose. The physical interaction between these components works to form a strong, binding gel in the presence of water. Drug release is controlled by the rate of water penetration from the gastrointestinal tract into the TIMERxR gum matrix, which expands to form a gel and subsequently releases the active drug substance. This system can precisely control the release of the active drug substance in a tablet by varying the proportion of the gums, together with the third component, the tablet coating and the tablet manufacturing process. Potential application of this technology is the development of an oral, CR opioid analgesic oxymorphone . 14.CONTROLLED-REALSE MICROCHIPS 15: An alternative method to achieve pulsatile or Chronopharmaceuticals drug release involves using micro fabrication technology. A solid-state silicon microchip that can provide controlled release of single or multiple chemical substances on demand. The release
mechanism was based on the electrochemical dissolution of thin anode membranes covering micro reservoirs filled with chemicals in solid, liquid or gel form. Initially conducted proof-of-principle release studies with a prototype microchip using gold and saline solution as a model electrode material and release medium, and demonstrated controlled, pulsatile release of ch poly(L-lactic acid) and had poly(D,L-lacticco- glycolic acid) membranes were fabricated that released four pulses of radio labelled dextran, human growth hormone or heparin. This technology has the potential to be used in the design of ChrDDS with a better control over drug release kinetic in order to match biological requirement over a versatile period of time. 15.PORT TECHNOLOGY 16: The Programmable Oral Release Technologies (PORT) system is a uniquely coated, encapsulated system that can provide multiple programmed release of the drug. It contains a polymeric core coated with a semipermeable, rate-controlling polymer. Poorly soluble drugs can be coated with solubilising agents, to ensure a uniform controlled release from the dosage form. In the capsule form, the gelatine capsule is coated with a semi permeable, ratecontrolling polymer. Active medicament mixed with an osmotic agent is kept inside the capsule shell. A water-insoluble plug is used to seal the capsule shell. Immediate release compartment can be added according. The Port System - consists of a gelatine capsule coated with a semi permeable membrane (e.g.: cellulose acetate) housing an insoluble plug ( e.g.: lipidic) and an osmotically active agent along with the drug formulation . When it comes in contact with the aqueous medium, water diffuses across the semi permeable membrane, resulting in increased inner pressure that ejects the plug after a time lag. The time lag is controlled by the thickness of semi permeable membrane. In order to deliver drug in liquid form, an osmotically driven capsular system was developed. In this system, liquid drug is absorbed into highly porous particles, which release the drug through an orifice of a semi permeable capsule supported by an expanding osmotic layer after the barrier layer is dissolved. The capsular system delivers drug by the capsule's osmotic infusion of moisture from the body. The capsule wall is made up of an elastic material and possesses an orifice. As the osmosis proceeds, the pressure within the capsule rises, causing the wall to stretch. The orifice is small enough so that when the elastic wall relaxes, the flow of the drug through the orifice essentially stops, but when the elastic wall is distended beyond threshold value, the orifice
expands sufficiently to allow drug release at a required rate. Elastomers, such as styrenebutadiene copolymer have been suggested .
16.THREE
DIMENTIONAL
PRINTING
(3DP)
TECHNOLOGY
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Three-dimensional printing (3DP) is a novel technique used in the fabrication of complex oral dosage delivery pharmaceuticals, based on solid freeform fabrication methods. It is possible to engineer devices with complicated internal geometries, varying densities, diffusivities, and chemicals. Different types of complex oral drug delivery devices have been fabricated using the 3DP process: immediate-extended release tablets, pulse release, breakaway tablets, and dual pulsatory tablets. The enteric dual pulsatory tablets were constructed of one continuous enteric excipient phase into which diclofenac sodium was printed into two separated areas. These samples showed two pulses of release during in vitro with a lag time between the pulses of about four hours. This technology is the basis of the Therefore technology.
MARKETED PRODUCTS 17: A.P.I VerapamilHCL VerapamilHCL Famotidine Product Covera HS VerelanPM Pepcid Manufacturer Pfizer Schwarz Merk Chr.technology OROS CODAS PMAPI Indication Hypertension Hypertension Ulcer
Theophyllin
Uniphyl ER
Purduepharma.
CONTIN
Asthma
Simvastatin
Zocor
Merck
PMAPI
Hyperlipedimia
DiltiazemHCL
Cardiazem LA
Biovail
CFFORMR
Hypertension
Propranolol
InnopranXL
Glaxo
DIFFUCAPSR
Hypertension
Simvastatin
Lopovas
Merk
PMAPI
Hyperlipedimia
Famotidine
Gaster
Astellas
PMAPI
Ulcer
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EVALUATION TECHNIQUES
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EVALUATION TECHNIQUES 18: 1)STABILITY STUDY 18: A short term stability test was conducted by storing tablets in glass bottles at 25C and 40C for three months. Then product evaluated for, buoyancy, drug content and invitro dissolution test and appropriate results obtained. 2)DRUG CONTENT 19: To evaluate a tablet potential for efficacy, the amount of drug per tablet needs to be monitored from tablet to tablet, and batch to batch. To perform the test, 10 tablets were crushed using mortar pestle. Quantity equivalent to 100 mg of drug was dissolved in 100 ml phosphate buffer curve. 3)PARTICLE SIZE ANALYSIS 19: The core pellets were subjected to sieve analysis using a set of standard sieves (1700, 1400, 1000, 710, and 600 mm) in a vibratory sieve shaker for a period of 10 min. The weight distribution data were fitted into log-normal distribution and the geometric mean diameter was computed from the log probability plots 4)BUNOYANCY DETERMINATION 19: The buoyancy test of triple layer tablet and floating pulsatile release 25 tablets was studied by placing them in 500 ml beaker containing 0.1 N HCl, then tablet from same batches were placed in dissolution test apparatus containing 0.1N HCl, maintained at 37+-0.1C and agitated at 100 rpm. The floating onset time (time period between placing tablet in the
pH 6.8,
filtered
and diluted
up
to
50g/ml,
and
analyzed
spectrophotometrically. The concentration of drug was determined using standard calibration
medium and buoyancy beginning) and floating duration of tablet was determined by visual observation. 5) INVITRO DISSOLUTION STUDY 20: Invitro dissolution test was performed using USP type II dissolution test apparatus. The drug release study was carried out in 0.1 N HCl for 2 h, mixed phosphate buffer of pH 5.5 for 1 hour, phosphate buffer of pH 6.8 for 2 hour followed by mixed phosphate buffer of pH 7.5 till the end of the test. The temperature of the dissolution fluid was maintained at 370.5 with a stirring speed of 100 rpm. The samples withdrawn every hour were filtered (0.22 m, Millipore) and assayed spectrophotometrically dissolution data was analyzed to calculate the amount of drug released and percentage cumulative drug released at different time intervals. 6)STUDY OF IN- PROCESS QUALITY CONTROL(IPQC) PARAMETERS 20: The Weight Variation of the tablets was evaluated on 20 tablets using a Digital Balance Sartorius CP124S. Friability test was performed at the speed of 25rpm with tablets dropping from height of six inches with each revolution for 4minutes on automated Friabilator EF-2 USP .Hardness was evaluated curves (n = 6). All dissolution studies were performed in triplicate. 9)SWELLING CHARACTERISTICS 21: To evaluate the water penetration characteristics, the tablets were exposed to 500 ml distilled water in three different beakers for 6 h, and then evolution of tablet surface area was carried out by recording the change in diameter and thickness of the tablets. Change in surface area of the tablets was calculated by using following formula. SA =2 Where, SA = Surface area and r = Radius of tablet 10)SCANNING ELECTRON MICROSCOPY (SEM) 21: Morphology and surface topography of the core and the coated pellets were studied by scanning electron microscopy. The samples were mounted on the SEM sample stab, using a double-sided sticking tape and coated with gold (200A) under reduced pressure (0.001 torr)
for 5 min using an Ion sputtering device The gold-coated samples were observed under the SEM and photomicrographs of suitable magnifications obtained.
APPLICATIONS OF CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEM
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APPLICATIONS OF CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEM 22: The potential benefit of chronotherapeutic pharmaceuticals has been demonstrated by a number of DDS developed for timed release of drugs having a chronobiological behaviour or when symptoms of the diseases are circadian dependent. 1) CARDIOVASCULAR DISEASES 22: Increase in risk of myocardial infarction between 6 am and noon was found. Blood pressure was soaring in the morning, with a rise at about 6 am and increasing further from 7 am. Blood pressure reaching its lowest point around 3 am by gradual declination throughout the day and especially during sleep .The time of awakening, an increase in physical activity, serum cortisol level and catecholamine levels which all increases blood pressure, heart rate and myocardial contractility .cholesterol intake and hepatic cholesterogenesis takes place during the evening hours irrespective of fed/fasting state. An evening administration of an HMGCoA reductase inhibitor lowered serum cholesterol levels than morning dosing .HMG-CoA reductase inhibitors could be taken between the evening meal and bed time . Chronopharmaceuticals for cardiovascular diseases have been studied extensively. Presently, four drugs have been successfully incorporated into Chronopharmaceuticals for clinical use. The first established chronotherapeutic DDS for timed-release of antihypertensive /antianginal agent is OROS technology developed and marketed by Alza for controlled onset and extended release (COER) formulation of verapamil hydrochloride tablet (Covera HS, Pharmacia, USA) to reduce the peak morning of cardiovascular events.. A second chronotherapeutic drug delivery approach for hypertension was developed by Elan using chronotherapeutic oral drug absorption system (CODAS) technology for formulation of verapamil hydrochloride-ride capsule (Verelan PM, Schwarz Pharma, USA). Cardizem LA (Diltiazem hydrochloride), which is used for hypertension and angina was approved by the
FDA is marketed by Biovail. Innopran XL (Propranolol hydrochloride) extended release capsule is used for hypertension and was approved by the FDA and marketed by Reliant Pharmaceuticals, which utilizes the Eurand's Diffucaps technology. 2) INFLAMMATORY DISEASES 22: Inflammatory diseases, such as rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and gout, exhibit profound circadian rhythms (variations) in the manifestation and intensity of symptoms. Chronotherapeutic-type medications increase the effectiveness and safety of treating arthritis disorders. Such drug delivery systems enhance the desired effects of drugs and minimize side effects. The chronopharmacological studies of arthritic diseases means determining the best time to administer drugs. Long-acting NSAIDs, like flubiprofen, ketoprofen, tenoxicam and indomethacin taken at bedtime, ensure the adequate control of prominent morning symptoms of rheumatoid arthritis, while the chronotherapy of osteoarthritis involves the administration of drugs in relation to the time of day when pain is worse. If pain is worse at night or early in afternoon, an evening once-a day NSAID schedule is recommended. If pain is worse in the afternoon or night, a once-a-day morning or noontime treatment schedule is best. Rheumatoid arthritis is characterized by morning stiffness, where as the symptoms often are bad in the afternoon and evening with osteoarthritis. Cyclooxygenase-2 inhibitors, when taken in the morning lessen osteoarthritis symptoms. In the case of rheumatoid arthritis, more improved results are obtained when part of the dose is taken in the evening 3) ASTHMA 23: Circadian changes in normal lung function from alterations in pathophysiology and inflammation needs to be applied clinically. Generally the worsening of asthma occurs at night, and is often referred to as nocturnal asthma. A chronotherapeutic approach applied to nocturnal asthma is particularly important to understanding the circadian changes when choosing the dosage timing of medications. Several chronotherapeutic medications have been proposed for treatment of nocturnal asthma. Oral steroids such as corticosteroids, glucocorticoids and methylprednisolone administered at 8 a.m. rather than 8 p.m., for example, have shown higher effectiveness in treating asthma. Other studies have shown that
oral administration of prednisolone at 3 p.m. rather than 8 a.m. improved lung function and reduced airway inflammation more effectively in the treatment of nocturnal asthma. The leukotriene active agents, including zileuton, zafirlukast and montelukast, have been proven to alleviate the symptoms and the decrement in lung function in nocturnal asthma when used chronotherapeutically.Once daily dosing in the evening of theophylline tablets showed chronotherapeutic potential in the treatment of nocturnal asthma. Various tablet formulations of long acting -agonists (albuterol, bambuterol, salmeterol and formoterol) have been used in a chronotherapeutic approach for the treatment of asthma. Treatment of nocturnal asthma. Oral steroids such as corticosteroids, glucocorticoids and methylprednisolone administered at 8 a.m. rather than 8 p.m., 4)ONCOLOGY 23: Optimal drug timing (chronotherapy) in oncology resulted in allowing high-doses to be administered safely and most effectively with less toxicity, improved tumour control and patient survival. Chronotherapeutic drugs under clinical trials have shown circadian-stage dependent anti-cancer activity, confirming and emphasizing the importance of circadian drug timing. For that, modern oncology will demand circadian timing-stipulated, multi-drug regimens, biological therapies and hybrid chemo biotherapies. The first chronopharmacological studies of doxorubicin in for the treatment of a transplanted plasmacytoma in rats revealed that the rate of tumour shrinkage is dependent upon the time of day that the drug is given. To date, the toxicities and anti-tumour activities of at least 20 of the most commonly used chemotherapeutic agents-cisplatin, oxaliplatine, carboplatin, epirubicin, 6-mercaptopurine, methotrexate, 5-fluorouracil, vinblastine and cyclophosphamide-are documented as circadian stage-dependent both in animals and for many in humans. Circadian-dependent activity of some biological agents, most notably Interferon, and erythropoietin, have also been well documented.
5)CEREBROVASCULAR ACCIDENTS24: Cerebrovascular accidents are more common in the morning hours between 10A.M to 12 noon and it will decrease from noon to midnight. The main aim of chronotherapy in these
conditions is to deliver the drug in the higher doses in morning and little lower dose at noon and in midnight times. Various ACE inhibitors like Atenolol, Nifedipine and amolodipine are more effective when administered during night. 5) GASTROINTESTINAL DISEASES 24: Peptic Ulcer Disease: A histamine antagonist when given at night shows the better result unlike when given at regular intervals around the clock. This is because the more acid secretion, more pain and perforation of gastric and duodenal ulcers are more subjective at night rather than in day time. 6)ALLERGIC RHINITIS 24: Early-morning hour episode of sneezing, nasal congestion and runny nose are common to allergic rhinitis. Study also explained that a morning dose of antihistamine was not as successful as the same dose given in the evening 7)RENAL DISEASES 24: A repeated dosing study of high-dose active vitamin D3 in haemodialysis patients with secondary hyperparathyroidism was conducted. A higher dose (3 mg) was given orally to 13 haemodialysis patients at 08.00 h or 20.00 h for 12 months by a randomized, cross-over design with an 8-week washout period. Serum concentrations of calcium and inorganic phosphate were determined by orthocresolphtalein complex method, and ammonium molybdate method with an autoanalyser, respectively. The results indicate that a higher dose of oral D3 is more effective and safe after dosing at evening in patients with renal osteodystrophy . 8)DIABETICS 25: The most widespread application of chronotherapy is insulin pump, which is used to administer insulin for the treatment of diabetes mellitus. With the insulin pump, patients can customize insulin delivery to meet their particular requirements. Several systems were developed to respond the change in glucose concentration like pH sensitive hydrogel containing glucose-oxidase enzyme immobilized in hydrogel. As the blood concentration of glucose rises, glucose oxidase converts glucose into gluconic acid, which changes the pH of
system. Due to change in pH, swelling of polymer takes place and this result into insulin release. Insulin decreases the blood glucose level and consequently the gluconic acid level also declines and system turns to de-swelling and hence decreasing the insulin release .
LITERATURE REVIEW
34
LITERATURE REVIEW
1. Halas M et al (1998) Formulated and evaluated of press coatedCapsule Device for
Chronotherapeutic Delivery attempt was made to deliver theophylline into colon by taking the advantage of the fact that colon has a lower pH value (6.8) than that of the small intestine (7.07.8). So, by using the mixture of the polymers, i.e. Eudragit L and Eudragit S in proper proportion, pH dependent release in the colon was obtained 2.
2. Evans RMet al(1996 ) Formulated and evaluated Chronotherapeutic drug delivery for
in vitro
multiparticulate system of insulin based on alginate spheres. In an
experiment, ferrite microparticles (1m) 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(L-lysine) or poly(ethylene imine) 6.
3. Kato H et al (2002) Formulated and evaluated Chronotherapeutic drug delivery for
ultrasound-enhanced polymer degradation system. During polymer degradation incorporated drug as drug molecule within negatively charged P(AMPS-co-BMA) hydrogels. By applying an electric field ion exchange between transdermalTulobuterol ions and protons commenced at cathode, resulting in rapid drug release from hydrogels. This rapid drug release was attributed to the electrostatic force, squeezing effect, and electro-osmosis of the gel. Complete on-off drug release was achieved, as no drug release was apparent without the application of electric current 15.
4. Gupta et al (2003) Formulated and evaluated Chronopharmaceutical drug delivery
system of Theophylline and
its pharmacokinetics in vivo and compaired hardness
,friability, weight variation,drug content in-vivostudies in rabbit 20.

5. Michael et al (2009) Formulated and evaluated Chronotherapeutic drug delivery
system for Timed release filmcoated Felodipine tablets for chronotherapeutic application in heart disease using guar gum and in combination with other
35
polymers.Tablets were subjected for the evaluation of particle size, encapsulation efficiency ,swellable and in-vitro release27.
FUTURE PROSPECTS
36
FUTURE PROSPECTS26,27:
The medical and pharmaceutical scientists should now focus profoundly over the importance of triggered/pulsed release of drugs. chronotherapeutic drug delivery system for the treatment of primary open-angle glaucoma. Dual-action, chronotherapeutic drug delivery system Controls intraocular pressure over 24 hours, reducing nocturnal pressure spikes Increases patient compliance by easy, once-a-day insertion.PH-enzyme dependent chronotherapeutic drug delivery system of theophylline for nocturnal asthma. . Biological and chronobiological activities of synthetic or natural compounds. Chronotherapy in Indian, Chinese, and other such traditional herbal medicine systems. Design and development of drug delivery systems for treatment of diseases on chronopharmacologicalbasis . Development of Drug targeting systems, protein and peptide delivery systems, sustained and controlled release systems. Ability of the brain to repair DNA damage was at a minimum in the early morning and reached a maximum in the evening due to the effects of an enzyme called XPA, which is linked to skin cancer, it could suggest specific times of the day to avoid cancercausing sunrays.
Laminate ophthalmic insert that is administered once-a-day, at night, improving patient compliance. The insert is produced from materials suitable for ophthalmic use, and is capable of releasing two drugs at different rates. The first drug is released at a slow, continuous rate. The second has a delayed onset and rapid release, to prevent possible IOP spikes during the early morning. This innovative treatment represents the first chronotherapeutic
37
SUMMARY AND CONCLUSION
38
SUMMARY AND CONCLUSION The effectiveness and toxicity of certain drugs depends on dosing time associated with 24hr rhythms under control of circadian clock. The application of biological rhythm to pharmacotherapy can be correlated by approximate timing of dosing of drugs to synchronise drug concentration to rhythms in diseases state. Advance in chronobiology and chronopharmacology has demonstrated the importance of biological rhythms in the treatment of diseases and this has led to a new approach to the development novel drug delivery system-chronotherapeutic drug delivery systems. Chronotherapeutic drug delivery systems is useful in the treatment of diseases in which drug availability is the timed to match rhythms of diseases, in order to optimise therapeutic effect and minimize side effect.Variouus technologies such as time controlled,pulsed,triggered,programmed drug delivery devices have been developed and extensively studied in recent years for chronotherapeutical drug delivery. Some of the disease conditions where in chronotherapeutics are promising include duodenal ulcer, cardiovascular diseases asthma, diabetics, neurological disorder, cancer, hypertension, hyper cholestremia. The use of chr.DDS offer a solution for delivery of drugs exhibiting a chronobiological behaviour and such as DDS seems to constitute more dependable means of matching drug level to biologic need and tolerance chronotherapeutics approach surely provides the enormous scope for research and has promise for a bright future to control diseases according to the bodys physiological needs.
39
REFERENCE
40
REFERENCE
1. BiBotti C. Youan Chronopharmaceutics: gimmick or clinically
relevant
approach
to
drug
delivery?.
Journal
of
Controlled
Release2004. Volume 98, Issue 3, pg.337353,

2. Halsas M, Hietala J, Veski P, Jrjenson H, Marvola M. Morningvs.
evening dosing of ibuprofen using conventional and timecontrolled release formulations. Int J Pharm 1999; 189: 179 185
3. Halsas M, Ervasti P, Veski P, Jrjenson H, Marvola M. Biopharmaceutical evaluation
of timecontrolled presscoated tablets containing polymers to adjust drug release. Eur J Drug Metabol Pharmacokinet 1998; 23: 190196
4. Rita Lala, Nikita A. Nandgaonkar Chronotherapeutical Drug Delivery Systems.
Pharma Times. 42,2010 Issue 12, pg.2022.

5. Shigehiro, Ohdo Chronotherapeutic strategy: Rhythm monitoring, manipulation and
disruption. Advanced Drug Delivery Reviews. 62,2010, Issues 910, pg.859875,

6. Evans RM, Marain C. Taking Your Medication: A Question of Timing. American
Medical Association: 1996:38 Evans RM, Marain C, et al, editors.eds. Taking Your Medication: A Question of Timing. Chicago, IL: American Medical Association; 1996. Pp 38.
7. Asim Sattwa Mandal, Nikhil Biswas, Kazi Masud Karim, Arijit Guha, Sugata
Chatterjee, Mamata Behera, Ketousetuo Kuotsu : Drug delivery system based on chronobiologyA Review. Journal of Controlled Release. 147,2010 pg.314325.
8. Lamberg L. Chronotherapeutics: implications for drug therapy. American Pharmacy
1991; NS31(11): 2023.

9. BiBotti C. Youan (ed). ,Chronopharmaceutics Science and Technology for
Biological RhythmGuided Therapy and Prevention of Diseases. USA: John Wiley & Sons, (2010).
10. Naoto Burioka, Yasushi Fukuoka, Satoru Koyanagi, Masanori Miyata, Miyako
Takata, Hiroki Chikumi, Hiroshi Takane, Masanari Watanabe, Masahiro Endo,

Takanori Sako, Hisashi Suyama, Shigehiro Ohdo, Eiji Shimizu , Asthma: Chronopharmacotherapy and the molecular clock. Advanced Drug Delivery Reviews,. 62,2010 Issues 910, pg.946955.
11. Norihiko Takeda, Koji Maemura ; Cardiovascular disease, chronopharmacotherapy,
and the molecular clock. Advanced Drug Delivery Reviews,. 62, Issues 910, pg. 956966
12. Sajan, J.; Cinu, T.A.; Chacko, A.J.; Litty, J. & Jaseeda, T. ; Chronotherapeutics and
Chronotherapeutic Drug Delivery Systems. Tropical Journal of Pharmaceutical Research, Vol. 8, No. 5, 2009, pg. 467475.
13. Rajan K. Verma and Sanjay Garg ; Current Status of Drug Delivery Technologies and
Future Directions,. PharmaceuticalTechnology OnLine. 25 (2),2001 pg.114.

14. Sachin Survase and Neeraj Kumar ; Pulsatile drug delivery:Current scenario. CRIPS.
8 No. 2,2007 pg.2733.

15. Kato, H., Nagata, O., Yamazaki, M., Suzuki, T. and Nakano, Y. Development of
Transdermal Formulation of Tulobuterol forthe Treatment of Bronchial Asthma. ChemInform. 33, Issue 22, 2002pg 3139.
16. Strausak s, Leuenberger H. Inventors; Asulab, SA, USA, assignee. US Patent,
5,370,635, 1994.
17. Giannos SA, Dinh SM, Berner B. Temporally controlled drug delivery systems. U.S.
Patent 6,068,853, 2000.

18. Bruguerolle B, Labrecque G, Rhythmic pattern in pain and their chronotherapy;
Advance Drug
19. Delivery Reviews, 2007, 59: 883895 20. Gupta, Vishweshwar Regulatory Scenario. Pharma Technology2003 pg.1922. 21. Smolesnky M, Peppas N, Chronobiology, drug delivery, and chronotherapeutics
Advances Drug Delivery Reviews, 2007, 59:(9); 828851.

22. Nagar Mayank , Singhai Sanjay , Chopra V. S. , Gautam Namrata , Trivedi Piyush .
Chronotropic Systems; an Emerging Trend in Drug Delivery for Pulsed Release in Chronopharmacotherapy. International Journal of Pharmaceutical and Clinical Research 2010; 23. Belgumwar Veena S,Gaikwad Madhuri V,Patil B Ganesh, Sharma Surana.Pulsatile Drug Delivery System.Asian Journal Of Pharmaceutics 2008;7,8:141-145.
42
24. Saigal Nitin , Baboota Sanjula , Ahuja Alka and Ali Javed . Site Specific Chronotherapeutic Drug Delivery Systems: A Patent Review. Recent Patents on Drug Delivery & Formulation 2009, 3, 64-70. 25. Ohdo Shigehiro. Chrono-drug delivery focused on biological clock :intra- and inter individual variability of molecular clock. Advanced Drug Delivery Reviews.2010. 62(2010)857858 5. 26. Chronopharmaceutical drug delivery systems: Hurdles, hype or hope? Advanced Drug Delivery Reviews.2010. 62 (2010) 898-903
27.
Michael PL. Chronobiology and Chronotherapeutics - Possible Strategy for Hypertension and Ischemic Heart Disease [Cited 2009 May 28]. Available from: http://www.touchcardiology.
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A REVIEW ON CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS

St Josephs College of Pharmacy ,Cherthala .

A REVIEW ON CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS

St Josephs College of Pharmacy ,Cherthala .

A REVIEW ON CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS

A REVIEW ON CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS

St Josephs College of Pharmacy ,Cherthala .

A REVIEW ON CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS

7. Drug adapt to suit circadian rhythm of body function or diseases.

9. Avoids degradation of in upper gastrointestinal tract.(proteins and peptides) .

action to trigger the drug release.

St Josephs College of Pharmacy ,Cherthala .

A REVIEW ON CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEMS

APPROACHES FOR CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEM

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1. ENTERIC COATED SYSTEM 6:

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CHRONOPHARMACEUTICAL TECHNOLOGIES 10:

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3.OROS TECHNOLOGY 11:

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Cross section of Diffucaps

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13.TIMERxR TRCHNOLOGY 15:

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spectrophotometrically. The concentration of drug was determined using standard calibration

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APPLICATIONS OF CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEM

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